Overcoming Psychomotor Slowing in Psychosis (OCoPS-P): a 3-week, Randomized, Double-blind, Placebo-controlled Trial of add-on Repetitive Transcranial Magnetic Stimulation for Psychomotor Slowing in Psychosis
Phase: NA
Conditions: Schizophrenia and Related Disorders, Schizophrenia, Schizoaffective Disorder, Brief Psychotic Disorder
Sponsor: University of Bern

Overcoming psychomotor slowing in psychosis 
(OCoPS-P) - A 3-week, randomized, double-blind, 
placebo-controlled trial of add-on repetitive 
transcranial magnetic stimulation for psychomotor 
slowing in psychosis 
Clinical Study Protocol 
Short Title: 
Translation 
OCoPS-P 
Überwinden von psychomotorischer Verlangsamung bei Psychosen - 
eine randomisierte, doppelblinde, plazebo-kontrollierte Studie zur 
Wirkung 
von 
transkranieller 
Magnetstimulation 
auf 
die 
psychomotorischer Verlangsamung bei Psychosen 
Study Type: 
Study Categorisation: 
Study Registration: 
Study Identifier: 
Sponsor, Sponsor-Investigator or 
Principal Investigator: 
lnvestigational Product: 
Protocol Version and Date: 
Clinical trial testing the effects of 15 sessions of repetitive 
transcranial magnetic stimulation on psychomotor slowing in 
psychosis 
Risk category A 
Intended registry: clinicaltrials.gov 
Registration number (from FOPH portal) eventually other 
registries and numbers if applicable 
OCoPS-P, BASEC-Nr: 2018-02164 
Prof. Dr. med. Sebastian Walther, University Hospital of 
Psychiatry, University of Bern, Murtenstrasse 21, 3008 
Switzerland 
Phone: 031 632 8979, fax: 031 632 8950, Email: 
sebastian.walther@upd.unibe.ch 
Transcranial Magnetic Stimulation 
Version 2.0 December 13th 2018 
CONFIDENTIAL 
The information contained in this document is confidential and the property of Prof. Dr. med. Sebastian Walther 
(the sponsor). The information may not - in full or in part - be transmitted, reproduced, published, or disclosed to 
others than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies) without prior written 
authorisation from the sponsor except to the extent necessary to obtain informed consent from those who will 
participate in the study. 

Signature Page(s) 
Study number 
Study Title 
BASEC 2018-02164 
Overcoming psychomotor slowing in psychosis (OCoPS-P) - A 
3-week, randomized, double-blind, placebo-controlled trial of 
add-on repetitive transcranial magnetic stimulation for 
psychomotor slowing in psychosis 
The Sponsor-Investigator and trial statistician have approved the protocol version 2.0 (13.12.2018), 
and confirm hereby to conduct the study according to the protocol, current version of the World 
Medical Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable and 
the local legally applicable requirements. 
Sponsor-Investigator: 
Prof. Dr. med. Sebastian Walther 
c:;LCrL I lo IZ Zo/9 
Place/Date 
Signature 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 2 of 56 

Local Principal Investigator at study site*: 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
Site 
University Hospital of Psychiatry, Bern 
Principal investigator 
Prof. Dr. med. Sebastian Walther 
1uL, Zo.l'l lolì 
¿o_ru 
Place/Date 
Signature 
*Note: ln multicentre studies, this page must be individually signed by all participating Local Principal 
Investigators. 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 3 of 56 

Table of Contents 
STUDY SYNOPSIS 
8 
ABBREVIATIONS 
12 
STUDY SCHEDULE 
13 
1. 
STUDY ADMINISTRATIVE STRUCTURE 
15 
1.1 
Sponsor, Sponsor-Investigator 
15 
1.2 
Principal lnvestigator(s) 
15 
1.3 
Statistician ("Biostatistician") 
15 
1.4 
Laboratory 
15 
1.5 
Monitoring institution 
15 
1.6 
Data Safety Monitoring Committee 
15 
1. 7 
Any other relevant Committee, Person, Organisation, Institution 
15 
2. 
ETHICAL AND REGULATORY ASPECTS 
16 
2.1 
Study registration 
16 
2.2 
Categorisation of study 
16 
2.3 
Competent Ethics Committee (CEC) 
16 
2.4 
Competent Authorities (CA) 
16 
2.5 
Ethical Conduct of the Study 
16 
2.6 
Declaration of interest. 
16 
2. 7 
Patient Information and Informed Consent. 
16 
2.8 
Participant privacy and confidentiality 
17 
2.9 
Early termination of the study 
17 
2.1 O 
Protocol amendments 
17 
3. 
BACKGROUND AND RATIONALE 
18 
3.1 
Background and Rationale 
18 
3.1.1 Schizophrenia 
18 
3.1.2 Motor system pathology in schizophrenia 
18 
3.1. 3 Psycho motor slowing 
19 
3.1.4 Current treatment options of psycho motor slowing 
19 
3.1.5 Psycho motor slowing and motor network dysfunction 
19 
3.1.6 lntracortical excitability 
20 
3.1. 7 Brain stimulation for psychomotor slowing 
21 
3.1.8 State of research summary 
21 
3.2 
lnvestigational Product (treatment, device) and Indication 
22 
3.3 
Preclinical Evidence 
22 
3.4 
Clinical Evidence to Date 
22 
3.5 
Dose Rationale/ Medical Device: Rationale for the intended purpose in study (pre-market MD)22 
3.6 
Explanation for choice of comparator (or placebo) 
22 
3. 7 
Risks / Benefits 
22 
3.8 
Justification of choice of study population 
23 
4. 
STUDY OBJECTIVES 
24 
4.1 
Overall Objective 
24 
4.2 
Primary Objective 
24 
4.3 
Secondary Objectives 
24 
4.4 
Safety Objectives 
24 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 4 of 56 

5. 
STUDY OUTCOMES 
24 
5.1 
Primary Outcome 
24 
5.2 
Secondary Outcomes 
24 
5.2.1 Clinical outcomes 
24 
5.2.2 Behavioral outcomes 
25 
5.2.3 Physiological outcomes 
25 
5.2.4 Neuroimaging outcomes 
25 
5.3 
Other Outcomes of Interest 
25 
5.4 
Safety Outcomes 
25 
6. 
STUDY DESIGN 
25 
6.1 
General study design and justification of design 
25 
6.2 
Methods of minimising bias 
26 
6.2.1 
Randomisation 
26 
6.2.2 Blinding procedures 
26 
6.2.3 Other methods of minimising bias 
26 
6.3 
Unblinding Procedures (Code break) 
26 
7. 
STUDY POPULATION 
26 
7.1 
Eligibility criteria 
26 
7.2 
Recruitment and screening 
27 
7.3 
Assignment to study groups 
27 
7.4 
Criteria for withdrawal/ discontinuation of participants 
27 
8. 
STUDY INTERVENTION 
28 
8.1 
Identity of lnvestigational Products (treatment/ medical device) 
28 
8.1.1 
Experimental Intervention (treatment/ medical device) 
28 
8.1.2 Control Intervention (standard/routine/comparator treatment I medical device) 
28 
8.1.3 Packaging, Labelling and Supply (re-supply) 
28 
8.1.4 Storage Conditions 
28 
8.2 
Administration of experimental and control interventions 
28 
8.2.1 
Experimental Intervention 
28 
8.2.2 Control Intervention 
29 
8.3 
Dose I Device modifications 
29 
8.4 
Compliance with study intervention 
29 
8.5 
Data Collection and Follow-up for withdrawn participants 
29 
8.6 
Trial specific preventive measures 
29 
8.7 
Concomitant Interventions (treatments) 
29 
8.8 
Study Drug/ Medical Device Accountability 
29 
8.9 
Return or Destruction of Study Drug I Medical Device 
29 
9. 
STUDY ASSESSMENTS 
30 
9.1 
Study flow chart(s) / table of study procedures and assessments 
30 
9.1.1 
Patients of treatment groups 1-3 
30 
9.1.2 Patients of treatment group 4 (waiting group) 
33 
9.1.3 Control subjects 
36 
9.2 
Assessments of outcomes 
37 
9.2.1 Assessment of primary outcome 
38 
9.2.2 Assessment of secondary outcomes 
38 
9.2.3 Assessment of other outcomes of interest 
39 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 5 of 56 

9.2.4 Assessment of safety outcomes 
39 
9.2.5 Assessments in participants who prematurely stop the study 
40 
9.3 
Procedures at each visit 
40 
9.3.1 
Screening visit 
40 
9.3.2 Visit 2 (baseline, week O) 
40 
9.3.3 Visit 3 and 4 (week 1 and 2) 
40 
9.3.4 Visit 5 (end of intervention, week 3) 
40 
9.3.5 Visit 6 and 7 (follow-up, week 6 and 24) 
41 
10. SAFETY 
41 
10.1 
Medical Device Category A studies 
41 
10.1.1 Definition and Assessment of safety related events 
41 
10.1.2 Reporting of (Serious) Adverse Events and other safety related events 
42 
10.1.3 Follow up of (Serious) Adverse Events 
43 
11. STATISTICAL METHODS 
43 
11.1 
Hypotheses 
43 
11.2 Determination of Sample Size 
44 
11.3 Statistical criteria of termination of trial. 
44 
11.4 Planned Analyses 
44 
11.4.1 Datasets to be analysed, analysis populations 
44 
11.4.2 Primary Analysis 
44 
11.4.3 Secondary Analyses 
45 
11.4.4 Interim analyses 
45 
11.4.5 Safety analysis 
45 
11.4.6 Deviation(s) from the original statistical plan 
45 
11.5 Handling of missing data and drop-outs 
45 
12. QUALITY ASSURANCE AND CONTROL 
46 
12.1 
Data handling and record keeping/ archiving 
46 
12.1.1 Case Report Forms 
46 
12.1.2 Specification of source documents 
46 
12.1. 3 Record keeping / archiving 
46 
12.2 Data management 
46 
12.2.1 Data Management System 
47 
12.2.2 Data security, access and back-up 
47 
12.2.3 Analysis and archiving 
47 
12.2.4 Electronic and central data validation 
47 
12.3 Monitoring 
47 
12.4 Audits and Inspections 
48 
12.5 Confidentiality, Data Protection 
48 
12.6 Storage of biological material and related health data 
48 
13. PUBLICATION AND DISSEMINATION POLICY 
48 
14. FUNDING AND SUPPORT 
48 
14.1 
Funding 
48 
14.2 Other Support 
48 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 6 of 56 

15. INSURANCE 
49 
16. REFERENCES 
50 
17. APPENDICES 
56 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 7 of 56 

STUDY SYNOPSIS 
Sponsor/ Sponsor- 
Prof. Dr. med. Sebastian Walther, 
Investigator 
University Hospital of Psychiatry, University of Bern, Murtenstrasse 21, 3008 
Switzerland 
Phone: 031 632 8979, fax: 031 632 8950, Email: 
sebastian.walther@upd.unibe.ch 
Study Title: 
Overcoming psychomotor slowing in psychosis (OCoPS-P) - A 3-week, 
randomized, double-blind, placebo-controlled trial of add-on repetitive 
transcranial magnetic stimulation for psychomotor slowing in psychosis 
Short Title/ Study ID: 
OCoPS-P, KEK 2018-02164 
Protocol Version and 
Protocol version 2.0 (13th December 2018) 
Date: 
Trial registration: 
Intended at clinicaltrials.gov 
Study category and 
Category A: TMS device with CE certificate and use according to 
Rationale 
guidelines and manual. ln addition short cerebral MRI and TMS 
experiments at baseline and endpoint. Minimal risk involved. 
Clinical Phase: 
Not applicable. 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 8 of 56 

Background and 
Rationale: 
Schizophrenia is a chronic disorder causing tremendous burden to the 
patients, families and society. Besides prominent symptoms such as 
hallucinations, delusions, and thought disorder, the majority of patients also 
experiences motor abnormalities. Converging evidence links aberrant 
structure and function of the cerebral motor network to schizophrenia 
pathology, particularly to motor abnormalities. One of the most frequent 
motor abnormalities is psychomotor slowing (PS), which may impact both 
gross and fine motor behavior. While PS causes significant distress and 
predicts poor outcome, researchers are just starting to understand its 
pathobiology. First evidence points to aberrant functional and structural 
connectivity within the cerebral motor network in schizophrenia patients 
with PS, particularly in connections between premotor/motor cortex and 
thalamus, as well as between motor cortex and cerebellum. ln addition, 
severe motor inhibition was linked to increased neural activity in the 
premotor cortex. Repetitive transcranial magnetic stimulation (rTMS) may 
□□□□□□mJt□~□□□Fd~~m ~ffif!l~~~~H~r~1i~1 
,w,~f 'L»ftmi □uu 
ê'lì□ilñ~JJHC~<MHlíJl:l □~ 'l.,~~ª □uit~L®~ □uit~L®~ □~,\~~ª □~ ~< 
®~ □ilii~ 'L□~ □uit~L□iìr.£ □Hllífh□~ -Jo~ □ilii~iCi!I H ¥&J -J□ifr.£ 
DUIN H ¥&i 1.,-□ifr.£ Di!wrill1WJrfD 1., □~ Diìr.:#X -thobiology 
of PS, 
however, 
is still unknown. This study will combine a motor battery, 
íffi~clál~ 
di1Wri'sl-'We and rTMS to probe the cerebral motor network 
contributions to PS. 
(1) to investigate clinical and neural changes following 3 weeks of rTMS 
treatment (inhibitory, facilitatory or placebo), (2) to characterize neural 
correlates of psychomotor slowing (PS) on the network level, (3) to explore 
short term changes of PS by testing a waiting list cohort, and (4) to test the 
clinical outcome of rTMS for PS at 6-month follow-up. 
To reach these aims, we plan to investigate four groups of schizophrenia 
patients (total 88) in a randomized, double blind, 4-arm sham-controlled 
trial of 15 rTMS sessions in 3 weeks with pre and post intervention MRI 
scans and a clinical follow-up at 6 months. One group will first be kept on a 
3 week waiting list and then enter the study. Longitudinal MRI scans and 
motor tests separated by 3 weeks will also be applied to a control group of 
40 healthy subjects for comparisons with the patient groups. We 
hypothesize that (1) PS would be linked to increased functional connectivity 
in motor cortical-basal ganglia loops as well as motor cortical-cerebellar 
loops, (2) inhibitory rTMS to the premotor cortex will reduce motor network 
functional connectivity and thus alleviate PS, (3) patients on the waiting list 
may experience stable PS severity, and finally, (4) patients responding to 
rTMS treatment of PS will have superior clinical and functional outcomes at 
6-month follow-up. Thus, the study will substantially contribute to the 
understanding of PS by describing and probing the neural alterations in the 
motor network in schizophrenia associated with behavioral PS. Therefore, 
the study will impact future treatment strategies for PS and inform on the 
causal network oatholoav in schizophrenia 
Objective(s): 
1. 
investigate clinical and neural changes following 3 weeks of rTMS 
treatment (inhibitory, facilitatory or placebo) 
2. 
characterize neural correlates of psychomotor slowing (PS) on the 
network level 
3. 
explore short term changes of PS by testing a waiting list cohort 
4. 
test the clinical outcome of rTMS for PS at 6-month follow-up. 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 9 of 56 

Outcome(s): 
1. Change from baseline to week 3 in SRRS scores. Furthermore, 
proportion of responders per study arm after 15 sessions rTMS 
(response= 30% reduction in SRRS scores from baseline) 
2. 
Associations between multiple measures of motor function and 
neuroimaging markers, e.g. resting state perfusion or functional 
connectivity within the motor system 
3. 
Change in SRRS from baseline to week 3 within the waiting list 
group, also comparison of SRRS change from baseline between 
waiting list group and placebo group. 
4. 
Change in symptoms (PANSS, BNSS, SRRS) and functioning 
(SOFAS) from baseline to 6-month follow-up 
Study design: 
randomised, double-blind, four-arm, placebo-controlled trial of 3 weeks 
add-on rTMS for psvchomotor slowinq in schizophrenia spectrum disorders 
Inclusion / Exclusion 
Inclusion: 
criteria: 
• 
Right-handed subjects, ages 18-60 years . 
• 
Patients: schizophrenia spectrum disorders according to DSM-5 
with psychomotor slowing (SRRS score ~ 15). Patients are 
necessary, because only patients have the target symptoms, i.e. 
psychomotor slowing 
• 
Controls: only for pre-/post comparisons of neuroimaging and 
physiology, no intervention in controls 
Exclusion: 
• 
General: Substance abuse or dependence other than nicotine . 
Past or current medical or neurological condition associated with 
impaired or aberrant movement, such as brain tumors, stroke, M. 
Parkinson, M. Huntington, dystonia, or severe head trauma with 
subsequent loss of conciousness. Epilepsy or other convulsions. 
History of any hearing problems or ringing in the ears. Standard 
exclusion criteria for MRI scanning and TMS; e.g. metal implants, 
claustrophobia. Women who are pregnant or breast feeding 
• 
Patients only: any TMS treatment in the past 3 months 
• 
Controls: history of any psychiatric disorder. First-degree relatives 
with schizophrenia spectrum disorders. 
Measurements and 
Participants will be screened and randomized to one of four arms before 
procedures: 
baseline assessments. Intervention period will be three weeks. Each week 
the primary outcome variable and safety will be assessed. At baseline and 
end of intervention (week 3), patients will be assessed with clinical and 
motor rating scales, tasks assessing fine and gross motor behaviour, TMS 
measures of cortical excitability, posturography, MRI neuroimaging, and 
tests of social and community functioning. Follow-ups will be conducted at 
week 6 and 24 including clinical and motor measures, cortical excitability, 
and social and community functioning. For cross-sectional comparisons of 
cortical excitability and neuroimaging, a group of 40 healthy control 
subjects matched for age, gender, and education, will be tested 
longitudinally with neuroimaging, motor tests, cortical excitability and 
posturography at baseline and week 3. Controls will not receive any 
intervention. 
Study Product/ 
low-frequency rTMS has inhibitory effects on brain function. We will apply 
Intervention: 
1 '000 pulses at 1 Hz over the left SMA at an intensity of 110% of the 
resting motor threshold (approximate duration 17 minutes) in a total of 15 
daily sessions (5 per week) 
KEK 2018-02164, OCoPS-P, Version 02 of 13112/2018 
Page 10 of 56 

Control Intervention 
Active control: 
Intermittent theta burst (iTBS) enhances local brain 
(if applicable): 
activity. We will apply 600 pulses at 50 Hz (stimulation in 2 sec trains every 
1 O sec for 190 sec in total) over the left SMA at an intensity of 80% of the 
resting motor threshold. iTBS will be repeated after15 min totaling to 1200 
pulses per session in a total of 15 daily sessions (5 per week). 
Placebo control: We will use a placebo-coil that looks identical to the real 
one and makes identical noises. Stimulation parameters are the same as in 
the active intervention, except that no magnetic pulse is emitted. Thus, 
placebo coil will be placed over the left SMA with 1000 clicks at 1 Hz 
(approximate duration 17 minutes) in a total of 15 daily sessions (5 per 
week). 
Waiting list: This group will have baseline measures at baseline and week 
3 and receive the active protocol from week 3 to week 6. 
Number of 
Number of participants in the intervention: 88 patients (22 per protocol 
Participants with 
arm). ln addition, to complement neuroimaging and neurophysiological 
Rationale: 
analyses (no intervention) we will include 40 healthy control subjects 
matched for aqe, qender, and education. 
Study Duration: 
Total study duration will be 4 years. Total duration of participant recruitment 
will be 3 years. 
Study Schedule: 
Planned 03/2019 of First-Participant-ln 
Planned 06/2022 of Last-Participant-Out 
lnvestigator(s): 
- see Sponsor-Investigator 
Study Centre(s): 
Single-centre trial at the University Hospital of Psychiatry, Bern 
Statistical 
The main effects of the 3-week interventions on PS (SRRS scores) will be 
Considerations: 
calculated in a repeated measures design including 2 measures (Baseline, 
week 3) and four groups (lf-rTMS, iTBS, sham, waiting group-lf-rTMS). 
Assuming a moderate effect size (f = 0.23) as indicated by our pilot data in 
a repeated measures ANOVA with moderate correlation between time 
points (0.5), a power of 0.95 and an alpha = 0.05, we would need 88 
patients (22 per crouo). 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as 
far as applicable) as well as all national legal and regulatory requirements. 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 11 of 56 

ABBREVIATIONS 
AE 
BASEC 
BNSS 
CA 
CEC 
CRF 
ClinO 
eCRF 
CTCAE 
DSUR 
GCP 
IB 
Ho 
H1 
HRA 
IMP 
IIT 
ISO 
iTBS 
ITT 
MD 
MedDO 
PANSS 
Pl 
PS 
rTMS 
SAE 
SDV 
SMA 
SOP 
SPC 
SRRS 
SOFAS 
SUSAR 
TMF 
UPSA Brief 
Adverse Event 
Business Administration System for Ethical Committees, 
(https://submissions.swissethics.ch/en/) 
Brief Negative Symptom Scale 
Competent Authority (e.g. Swissmedic) 
Competent Ethics Committee 
Case Report Form 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: OC/in, 
in Italian: OSRUm) 
Electronic Case Report Form 
Common terminology criteria for adverse events 
Development safety update report 
Good Clinical Practice 
Investigator's Brochure 
Null hypothesis 
Alternative hypothesis 
Federal Act on Research involving Human Beings (in German: HFG, in French: LRH, 
in Italian: LRUm) 
lnvestigational Medicinal Product 
Investigator-initiated Trial 
International Organisation for Standardisation 
Intermittent Theta Burst Stimulation 
Intention to treat 
Medical Device 
Medical Device Ordinance (in German: MepV, in French: ODim) 
Positive And Negative Syndrome Scale 
Principal Investigator 
Psychomotor Slowing 
Repetitive Transcranial Magnetic Stimulation 
Serious Adverse Event 
Source Data Verification 
Supplementary Motor Area 
Standard Operating Procedure 
Summary of product characteristics 
Salpêtrière Retardation Rating Scale 
Social and Occupational Functioning Scale 
Suspected Unexpected Serious Adverse Reaction 
Trial Master File 
UCSD Performance-based Skills Assessment Brief version 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 12 of 56 

STUDY SCHEDULE 
Study Periods 
Scree 
Treatment, Intervention 
Follow-up 
ning 
Period 
Visit 
1 
2* 
3 
4 
5 
6 
7 
Time (week) 
-1 
o 
1 
2 
3 
6 
24 
Patient Information and Informed Consent 
X 
Dernocraohìcs 
X 
CASH and SCIO (historv) 
X 
ln- /Exclusion Criteria 
X 
Phvsical Examination 
X 
Preqnancv Test 
X 
Psvchopatholoqy (TALO, NES) 
X 
Randomisation 
X 
Administer rTMS (5 sessions oer week) 
X 
X 
X 
Primary Variable SRRS 
X 
X 
X 
X 
X 
X 
Motor scales U PORS, BFCRS, AIMS, IPAQ 
X 
X 
X 
X 
Psychopatholoqv (PANSS, BNSS, SNS) 
X 
X 
X 
X 
Actiqraphv and coin rotation 
X 
X 
X 
X 
Posturoaraphy 
X 
X 
TMS cortical excitability 
X 
X 
X 
X 
Cerebral MRI 
X 
X 
Functional outcome (SOFAS, GAF, UPSA-brief) 
X 
X 
X 
Concomitant Therapy 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
* please note that in the waiting group assessments of visit 2 will be repeated after 3 weeks and 
thereafter the protocol will be identical (see below). 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 13 of 56 

Study protocol for patients in the waiting group 
Study Periods 
Scree 
Treatment, Intervention Period 
Follow-up 
ning 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Time (week) 
-1 
o 
3 
4 
5 
6 
9 
24 
Patient Information and Informed Consent 
X 
Dernooraohics 
X 
CASH and SCIO (history) 
X 
ln- /Exclusion Criteria 
X 
Physical Examination 
X 
Pregnancy Test 
X 
Psychopathology (TALO, NES) 
X 
Randomisation 
X 
Administer rTMS (5 sessions per week) 
X 
X 
X 
Primary Variable SRRS 
X 
X 
X 
X 
X 
X 
X 
Motor scales UPDRS, BFCRS, AIMS, IPAQ 
X 
X 
X 
X 
X 
Psvchooatholouv (PANSS, BNSS, SNS) 
X 
X 
X 
X 
X 
Actiqraphv and coin rotation 
X 
X 
X 
X 
X 
Posturography 
X 
X 
X 
TMS cortical excitability 
X 
X 
X 
X 
X 
Cerebral MRI 
X 
X 
X 
Functional outcome (SOFAS, GAF, UPSA-brief) 
X 
X 
X 
X 
Concomitant Therapy 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
Study protocol for control subjects 
Study Periods 
Screening 
Observation period 
Visit 
1 
2 
3 
Time (week) 
-1 
o 
3 
Proband Information and Informed Consent 
X 
Dernooraohics 
X 
SCIO 
X 
ln- /Exclusion Criteria 
X 
Physical Examination 
X 
Preanancv Test 
X 
Primary Variable SRRS 
X 
X 
Motor scales UPDRS, BFCRS, AIMS, IPAQ 
X 
X 
Actioraohv and coin rotation 
X 
X 
Posturoqraphv 
X 
X 
TMS cortical excitability 
X 
X 
Cerebral MRI 
X 
X 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
Page 14 of 56 

1. STUDY ADMINISTRATIVE STRUCTURE 
1.1 
Sponsor, Sponsor-Investigator 
Prof. Dr. med. Sebastian Walther, 
University Hospital of Psychiatry, University of Bern, Murtenstrasse 21, 3008 Bern, Switzerland, 
phone: 031 632 4635, fax: 031 632 8950, Email: sebastian.walther@upd.unibe.ch 
Prof. Walther will be Sponsor-Investigator; no further international sites are planned 
Roles: protocol, study design, supervision of data collection and management, data analysis, data 
interpretation and writing of the report. 
1.2 
Principal lnvestigator(s) 
Identical to sponsor, see 1.1. 
1.3 
Statistician ("Biostatistician") 
Dr. Petra Viher, PhD, University Hospital of Psychiatry, University of Bern, Bolligenstrasse 111, 3000 
Bern, Switzerland. Phone: 031 930 9757, Email: petra.viher@upd.unibe.ch 
1.4 
Laboratory 
All of the procedures except neuroimaging will be performed at the University Hospital of Psychiatry, 
Bern. The devices and infrastructure are provided by the Translational research center at the 
University Hospital of Psychiatry, Bern, Bolligenstrasse 111, 3000 Bern 60, Switzerland. 
Neuroimaging acquisition (magnetic resonance imaging - MRI) will be performed at the University 
Hospital Inselspital Bern, Institute of Diagnostic and lnterventional Neuroradiology. Collaborator Prof. 
Dr. med. Roland Wiest. 
1.5 
Monitoring institution 
Dr. phil. Jessica Peter, University Hospital of Old Age Psychiatry and Psychotherapy, University of 
Bern, 
Bolligenstrasse 
111, 
3000 
Bern, 
Switzerland. 
Phone: 
031 
932 
8903 
Email: 
Jessica. peter@upd.unibe.ch 
1.6 
Data Safety Monitoring Committee 
DSMC is not needed. The study aim is not to test the efficacy of a specific product. The objective is to 
test whether repetitive transcranial magnetic stimulation may improve psychomotor slowing and how it 
interferes with neurophysiology. 
1.7 
Any other relevant Committee, Person, Organisation, Institution 
Study collaborators 
Prof. Dr. Roland Wiest, University Institute of Diagnostic and lnterventional Neuroradiology, Inselspital 
Bern, Switzerland. MRI acquisition 
Prof. Dr. Andrea Federspiel, Neuroimaging Unit, Translational Research Center, University Hospital of 
Psychiatry, Bern, Switzerland, MRI analyses 
Prof. Dr. Jessica Bernard, Department of Psychological and Brain Sciences, Texas A & M University, 
College Station, TX, USA, MRI analyses support 
Prof. Dr. Roger Kalla, Department of Neurology, University Hospital Inselspital, Bern, Switzerland, 
posturography 
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2. 
ETHICAL AND REGULATORY ASPECTS 
The decision of the CEC concerning the conduct of the study will be made in writing to the Sponsor- 
Investigator before commencement of this study. The clinical study can only begin once approval from 
all required authorities has been received. Any additional requirements imposed by the authorities 
shall be implemented. 
2.1 
Study registration 
Registration is planned in ClinicalTrials.gov and the Swiss KOFAM site 
2.2 
Categorisation of study 
The trial is in Risk Category A There is only minimal risk associated with the trial. The TMS device 
has CE certification and approved for clinical use. lt will be applied according to the manual and 
guidelines 
1
· 
2
. TMS has been widely used in neuroscience, and in clinical trials on depression, 
schizophrenia and chronic pain. Participants will receive 15 daily stimulations. Effects are expected to 
last for 2-4 weeks after the last stimulation. TMS is also safe in repeated administration 1· 2. 
Assessments include standard clinical rating scales, short specific tests of motor behaviour, and a 
standard cerebral magnetic resonance imaging at baseline and after 3 weeks of stimulation. All 
assessments have been applied to schizophrenia patients before and are generally well tolerated. 
2.3 
Competent Ethics Committee (CEC) 
The local Bern Ethics Committee is the Competent Ethics Committee (CEC). No sites outside the 
canton of Bern are planned. 
The Bern Ethics Committee will receive reports of all changes in the research activity and all 
unanticipated problems involving risks to humans; including in case of planned or premature study end 
and the final report. No changes are made to the protocol without prior Sponsor and CEC approval, 
except where necessary to eliminate apparent immediate hazards to study participants. Premature 
study end or interruption of the study is reported within 15 days. The regular end of the study is 
reported to the CEC within 90 days, the final study report shall be submitted within one year after 
study end. Amendments are reported according to chapter 2.1 O. 
2.4 
Competent Authorities (CA) 
Not applicable - Category A 
2.5 
Ethical Conduct of the Study 
The study will be carried out in accordance to the protocol and with principles enunciated in the 
current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by 
ICH, in case of medical device: the European Regulation on medical devices 2017/745 and the ISO 
Norm 14155 and ISO 14971, the Swiss Law and Swiss regulatory authority's requirements. The CEC 
and regulatory authorities will receive annual safety and interim reports and be informed about study 
stop/end in agreement with local requirements. 
2.6 
Declaration of interest 
There is no conflict of interest. Funding is provided by independent grants and the Swiss National 
Science Foundation (see funding 14.1) 
2. 7 
Patient Information and Informed Consent 
Participants will be informed by members of the study team about the aims of the study, planned 
procedures and risks involved. They will receive written information on the study. This information will 
be provided prior to study inclusion during screening. The participants will also be informed about the 
compensation of 200 CHF after they completed the study procedures. The participant will be informed 
by the investigators that his/her medical records may be examined by authorised individuals other 
than their treating physician. 
All participants for the study will be provided a participant information sheet and a consent form 
describing the study and providing sufficient information for participant to make an informed decision 
about their participation in the study. A minimum of 24 h time will be given to participants to decide on 
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whether to participate or not. Whenever necessary, the potential participant can take up to 2 weeks to 
decide on participation. 
The patient information sheet and the consent form will be submitted to the CEC and to the competent 
authority (as applicable) to be reviewed and approved. The formal consent of a participant, using the 
approved consent form, must be obtained before the participant is submitted to any study procedure. 
The participant should read and consider the statement before signing and dating the informed 
consent form, and should be given a copy of the signed document. The consent form must also be 
signed and dated by the investigator (or his designee) and it will be retained as part of the study 
records. 
2.8 
Participant privacy and confidentiality 
The investigator affirms and upholds the principle of the participant's right to privacy and that they 
shall comply with applicable privacy laws. Especially, anonymity of the participants shall be 
guaranteed when presenting the data at scientific meetings or publishing them in scientific journals. 
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising 
subject identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorised representatives of the Sponsor (-Investigator) or an ethics 
committee may require direct access to parts of the medical records relevant to the study, including 
participants' medical history. 
2.9 
Early termination of the study 
The Sponsor-Investigator may terminate the study prematurely according to certain circumstances, for 
example: 
• 
ethical concerns, 
• 
insufficient participant recruitment, 
• 
when the safety of the participants is doubtful or at risk, respectively, 
• 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise, 
• 
early evidence of benefit or harm of the experimental intervention 
2.1 O 
Protocol amendments 
Substantial amendments are only implemented after approval of the CEC and CA respectively. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well- 
being of human subjects may proceed without prior approval of the sponsor and the CEC/CA. Such 
deviations shall be documented and reported to the sponsor and the CEC/CA as soon as possible. 
All non-substantial amendments are communicated to the CA as soon as possible if applicable and to 
the CEC within the Annual Safety Report (ASR). 
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3. 
BACKGROUND AND RATIONALE 
3.1 
Background and Rationale 
3.1.1 
Schizophrenia 
Schizophrenia is a severe disorder with a life-long course affecting approximately 2-3% of the 
population. Even though the outcome is heterogeneous, schizophrenia usually causes tremendous 
individual burden, intense costs for society, reduced quality of life, impaired occupational performance 
and reduction of life expectancy by 10-20 years 3. Schizophrenia is an adolescent-onset disorder with 
neurodevelopmental origins
3
. Current models suggest that genetic risk, early hazards to brain 
maturation, social adversities during childhood and the evolution of cognitive biases predispose 
subjects to psychosis in times of stress". The schizophrenia syndrome is characterized by symptom 
clusters including positive symptoms (e.g. delusions and hallucinations), negative symptoms (e.g. 
avolition and affective flattening), disorganized thought, motor abnormalities, mood disturbances, 
impaired cognition, anxiety and lack of insight5
. Brain structure and function in schizophrenia is 
abnormal at multiple levels. For example, schizophrenia patients share altered organization of 
functional brain networks
6 and underlying white matter fiber connections7
· 8. Therefore, schizophrenia 
has been conceptualized as a disconnection syndrome, which may explain some of the typical 
symptoms". Indeed, first evidence indicates an association between abnormal motor behavior and 
structural as well as functional alterations in the motor network in schizophrenia 10
· 11. Researchers are 
just starting to understand the network alterations linked to clinical symptoms in schizophrenia 12. The 
ultimate goal would be to normalize altered brain function at the network level in order to 
improve the clinical significant behavioral abnormalities. 
3.1.2 
Motor system pathology in schizophrenia 
A set of motor abnormalities including signs such as bizarre posture, peculiar gait, facial and limb 
dyskinesia, immobility, rigor, or excessive movement have been reported in schizophrenia. 
Motor abnormalities have long been exclusively linked to medication side effects; however, converging 
evidence demonstrates that motor abnormalities frequently occur before medication is commenced 
and even long before the onset of psychosis 
10
· 
13-15. Up to 67% of first episode, treatment naïve 
patients experience at least one motor sign 
16. The contribution of medication is heterogeneous and 
probably overestimated. 
Motor abnormalities are key cues for stigmatization and pose significant distress on patients 17
· 18_ 
Furthermore, recent evidence supports the predictive value of motor abnormalities in psychosis for 
poor functional outcome 
15
· 19
. For example, motor abnormalities impact nonverbal behaviors such as 
gestures
20
, which are critical for social functioning21. This way, motor abnormalities contribute to poor 
functional outcome in schizophrenia. 
A large network of the brain is devoted to motor behavior, including cortical frontal motor and premotor 
areas, the basal ganglia, thalamus, brainstem and cerebellum (see figure 1 ). Evidence across multiple 
neuroimaging approaches supports that schizophrenia pathobiology is tied to alterations within the 
cerebral motor system22. 
Figure 1. Key components of the motor network 
preSMA 
....,;¡~¡.... caudate 
cerebellum Thalamus STN 
M1 
primary motor cortex 
SMA 
supplementary motor area 
pre-SMA pre-supplementary motor area 
dACC dorsal anterior cingulate cortex 
STN 
subthalamic nucleus 
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3.1.3 
Psychomotor slowing 
One important domain of motor abnormalities in schizophrenia is psychomotor slowing (PS), which 
can be observed in fine motor behavior such as writing, gross motor behavior such as gait, and it may 
refer to single movements or continuous movement. PS includes movement planning, initiation, 
execution, timing and motor control 
15
· 23-25. Typical examples of PS in schizophrenia are reduced 
levels of spontaneous gross motor activity as measured by actiqraphy": 26-28, slowed gait29, slowed 
aiming arm rnovernents'", slowing in fine motor tasks26
· 31' 32 or in bradykinesia of parkinson ism 31. 
Multiple reports suggest that 30-50% of schizophrenia patients present with PS33
· 34. Furthermore, PS 
is seen in all stages of the disorder. Even though, PS severity seems to increase with illness 
chronicity35
, it does also occur in early psychosis or in subjects at risk for psychosis34
· 36-40. ln 
psychosis, PS is critically linked to several disadvantages23. For example, PS is associated with poor 
cognition, sedentary behavior and cardiometabolic risks": 42. Moreover, PS correlates with distress 
and poor quality of life 17
· 43' 44
. Finally, several reports indicate that PS predicts poor outcome in terms 
of cognition, quality of life and real world functioning in early psychosis, although at baseline patients 
with PS were not specifically impaired in function36
· 45-47
_ ln sum, PS is a frequently observed 
phenomenon across schizophrenia stages, associated with poor quality of life, sedentary behavior 
and predictive of poor cognition and outcome. ln order to design new treatment options to overcome 
this problematic symptom domain, it is essential to know the pathobiology of PS. 
PS is particularly suitable for objective instrumental assessment. There are valid measures of fine 
motor and gross motor slowing that can be acquired by instrumentation 15. These measures allow 
dimensional assessment of PS and are therefore ideal candidates when exploring associations 
between brain and behavior. Instrumentation is also not prone to conceptual overlap. We have applied 
wrist actigraphy in a series of studies and repeatedly demonstrated reduced gross motor activity in 
schizophrenia, which was linked to negative syndrome severity and psychomotor slowing as 
measured by the Salpêtrière Retardation Rating Scale (SRRS)26
· 48-50. Likewise, finger tapping test as 
a measure of PS in fine motor behavior is also consistently poorer in schizophrenia patients and linked 
to negative symptoms". ln addition, the video rated coin rotation test is a simple and reliable measure 
of manual dexterity51
· 52
. Another interesting marker of motor behavior is increased postural sway, 
which results from poor cerebellar function and is increased in psychosis53
· 54. Postural sway was 
correlated with negative syndrome severity in patients'" 54. Therefore, we expect increased postural 
sway to be associated with PS in schizophrenia. ln sum, PS can be reliably measured by observer 
ratings such as the SRRS or by instrumental measures of gross motor behavior (activity level from 
actigraphy) or fine motor behavior (finger tapping and coin rotation). 
3.1.4 
Current treatment options of psychomotor slowing 
As mentioned above, motor symptoms including PS are neither simply explained by antipsychotic drug 
effects
23 nor does PS disappear after antipsychotic drug withdrawal. An excellent study in treatment 
naïve first episode subjects demonstrated the heterogeneity of drug effects on motor abnormalities, 
with 30% of patients in whom parkinsonism or catatonia was ameliorated by antipsychotic drugs55. 
Likewise, in many studies of our own group and others we failed to detect a correlation between 
antipsychotic dosage and measures of PS11' 26' 31' 49' 50. However, symptoms tend to improve with 
treatment but from the naturalistic studies conducted it is currently unclear, whether the improvement 
is due to a direct effect on motor behavior or whether the benefit results from amelioration of other 
psychosis symptoms, such as disorganization or avolition56
· 57. Our own study on the longitudinal 
course of PS in acute schizophrenia found an amelioration of PS with treatment, which was tightly 
linked to a decline of negative symptom scorss'". Finally, there are no trials demonstrating a beneficial 
effect of antipsychotic medication or trainings to improve psychomotor slowing in schizophrenia. Thus, 
alternative treatment options for PS are clearly needed. 
3.1.5 
Psychomotor slowing and motor network dysfunction 
Conceptually, various aspects of motor behavior are modulated by three key circuits: inhibition and 
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excitation of movements is related to a circuit including pre-/motor cortex and basal ganglia, timing of 
movements is linked to another circuit including motor cortex, thalamus and cerebellum, while 
psychomotor speed and planning involves a cortical network including medial prefrontal cortex, 
cingulate motor areas, SMA, M1, and posterior parietal cortex 12. However, PS is not exclusively 
related to one of the abovementioned behaviors and probably involves all of the three circuits, even 
though the basal ganglia circuit is the most probable 22. 
The current understanding of the pathology in PS is limited due to methodological issues, such as 
focus on single brain regions, single neuroimaging modalities, and heterogeneous patient samples 10
· 22. 
Two types of approaches have mainly been adopted: first, actigraphically assessed motor activity 
levels were correlated with structural and functional magnetic resonance imaging (MRI) markers in the 
brain. Results suggested that unlike in controls, motor activity levels are not associated with 
structural connectivity within the basal ganglia loop in schizophrenia. Instead, motor activity was 
linked to cortical motor loops, which was interpreted as compensatory mechanism because patients 
with PS (i.e. lower activity) had particularly lower CBF and reduced white matter integrity within these 
cortical motor loops": 58-60
. Likewise, white matter ultrastructure of the corpus callosum and cingulum 
mediated psychomotor speed in schizophrenia61. A second line of evidence stems from functional and 
structural MRI studies testing associations with finger movements such as finger tapping, sequential 
finger-thumb opposition, etc. These studies reported poorer tapping performance and reduced 
functional activation in SMA, M1, and cerebellum in schizophrenia62. Further evidence comes from the 
few studies on schizophrenia patients with catatonia, who usually present with behavioral motor 
inhibition. ln a resting state perfusion MRI study, my group identified that catatonic schizophrenia is 
associated with specifically increased cerebral blood flow (CBF) in the supplementary motor area 
(SMA) and primary motor cortex (M1) in comparison to schizophrenia patients who had never 
experienced catatonia before. State CBF values were highest among those patients with severe motor 
inhibition. However, SMA perfusion was not different between state catatonia and controls63. The 
findings suggest a critical role of the SMA in movement initiation deficits in schizophrenia with state 
catatonia. However, from these data it was not possible to determine whether SMA hyperperfusion 
was the result of a motor network pathology that leads to inhibited motor output or whether SMA 
pathology drives this behavioral inhibition. Furthermore, finger tapping studies in catatonia patients 
indicated that M1 and SMA were less active during the task'": 65. Given the limitations of most previous 
studies focusing on one task or brain region, the next step must include a network perspective to 
understand the pathobiology of motor inhibition as seen in PS. A first cross-sectional study of my 
group applied resting state fMRI in order to test functional connectivity within the motor networks in 
schizophrenia. We found that schizophrenia was characterized by increased connectivity between key 
regions of the motor network, particularly between thalamus and motor/premotor cortex, M1 and 
cerebellum, cingulate seeds and STN11. Furthermore, the functional abnormalities between M1 and 
thalamus or cerebellum at rest were linked to observer ratings and instrumental measures of PS in 
schizophrenia. Even though there is evidence suggesting that aberrant thalamocortical as well 
as cerebellar-cortical functional and structural connectivity may contribute to psychomotor 
slowing, the mechanism is still not entirely clear. This issue needs to be addressed at a 
network perspective and requires an exploration of the neural effects of interventions targeting 
psychomotor slowing. 
3.1.6 
lntracortical excitability 
Transcranial magnetic stimulation (TMS) allows for testing cortical neurophysiology in vivo. 
Converging evidence supports defective intracortical inhibition in M1 indexed by paired-pulse TMS in 
all stages of psychosis'": 
67
. Indeed, short-interval intracortical inhibition (SICI) is linked to GABAergic 
interneuron function. Reduced SICI values indicate cortical disinhibition in patients, which correlate 
with lower fractional anisotropy in motor tracts as well as lower processing speed". Thus 
psychomotor slowing could be associated with aberrant motor cortex excitability, i.e. reduced 
SICI. 
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3.1.7 
Brain stimulation for psychomotor slowing 
Repetitive transcranial magnetic stimulation (rTMS) temporarily alters brain function in the targeted 
cortical areas. ln addition, distant effects occur due to changes in network properties69. Depending on 
the frequency and type of stimulation, distinct effects on brain function are expected. Low-frequency 
rTMS (lf-rTMS) and continuous theta burst stimulation (cTBS) have inhibitory effects, while high- 
frequency rTMS (hf-rTMS) and intermittend theta burst (iTBS) have facilitatory effects. The 
preliminary knowledge of the pathobiology of PS suggests that rTMS could improve PS by changing 
aberrant motor network connectivity. Still, there are no published reports on the effects of non-invasive 
brain stimulation on PS. However, my group is conducting a randomized, double-blind, sham- 
controlled trial of rTMS for psychomotor slowing in major depressive disorder and schizophrenia 
(NCT03275766, clinicaltrials.gov). Treatment is based on rTMS in 4 arms: 1) facilitatory hf-rTMS over 
the left dorsolateral prefrontal cortex (DLPFC), 2) inhibitory lf-rTMS over the supplementary motor 
area (SMA), 3) facilitatory iTBS over the SMA, and 4) sham stimulation with a placebo coil. The 
primary outcome parameter is the percentage of responders (> 30% reduction in the Salpêtrière 
Retardation Rating Scale (SRRS) from baseline). Across the whole group of 34 randomized subjects 
(22 with schizophrenia and 12 with depression), there is a group difference in the number of 
responders after 15 rTMS sessions applying the last-observation-carried-forwaro method (Chi2=11.3, 
df=3, p=.007) with 78% responders under lf-rTMS over SMA and no responder under iTBS over 
SMA. When we exclusively focus on schizophrenia, this effect is also detected (Chi2=6.6, df=3). Thus, 
lf-rTMS over SMA ameliorates PS. 
The neurophysiologie effects of rTMS treatment can be probed by perfusion MRI for local effects on 
metabolism, by fMRI on the network level and by TMS paradigms testing changes of cortical 
excitability of M1. Studies on inhibitory rTMS over the left SMA indicated short-term alterations of 
functional connectivity from SMA to M1 in healthy subjects along with changes of local metabolic 
activity in focal dystonia patients and controls70-72. While we don't know whether similar effects would 
occur in patients with altered baseline functional connectivity in the motor network, we may expect to 
see neural changes (functional connectivity and regional perfusion) following rTMS treatment. 
Furthermore, single inhibitory rTMS for 15 mins over the premotor cortex led to increased motor 
cortical excitability in schizophrenia evidenced by reduced resting motor thresholds and increased 
motor evoked potentials, supporting our clinical findings of an amelioration of PS73. 
3.1.8 
State of research summary 
Motor abnormalities are a core feature of psychotic disorders, particularly in the schizophrenia 
spectrum, indicating poorer outcome 
10
· 
15
· 74
. Motor abnormalities are linked to alterations within the 
cerebral motor networks
22
. One important domain is psychomotor slowing (PS) that impacts gross and 
fine motor behavior. PS causes distress and functional disability. Moreover, PS can be reliably 
assessed by instrumentation 
15
. But the underlying neurobiology of PS is not well understood. Prior 
work from correlational studies reported PS to be linked to aberrant functional and structural 
connectivity between M1 and thalamus or cerebellum 
11
· 60
. Particularly, patients with severe PS display 
hyperconnectivity and hyperperfusion in the premotor and motor cortices. Currently, no treatments 
specifically target PS in schizophrenia. But preliminary data from an rTMS study of my group indicate 
that inhibitory rTMS over the SMA alleviates PS. ln addition, one session of inhibitory rTMS over SMA 
altered motor cortex excitability in psychosis73
. Given, that the motor circuitry is associated with 
PS and that inhibitory rTMS over SMA may improve PS in schizophrenia, we expect that 
inhibitory rTMS alters the relevant network for PS in patients. The combination of resting state 
fMRI, perfusion MRI, diffusion MRI and rTMS is particularly suited to explore the neural changes in the 
motor networks
72
. Therefore, we will conduct a prospective RCT of rTMS for PS with neuroimaging 
assessments at baseline and week 3, focusing on the motor network. Furthermore, we will explore the 
effects of rTMS on cortical excitability, clinical and functional outcome. This is the first project to 
enable causal inferences on the pathobiology of PS and further supporting the use of effective rTMS 
treatment in schizophrenia by proof of principle. 
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3.2 
lnvestigational Product (treatment, device) and Indication 
TMS device: MagPro 30 with theta burst option 
Manufacturer: MagVenture, Inc. Atlanta GA, USA 
Device is intended for a broad range of neuroscientific research in humans. 
There is CE conformity according to the ISO Norm 13485:2003. 
3.3 
Preclinical Evidence 
Low-frequency rTMS (1 Hz) has been tested in many studies of human neurophysiology, typically as 
single session rTMS with transient behavioral effects. Lf-rTMS over the SMA alters functional 
connectivity in the motor system in healthy subjects". Likewise, lf-rTMS over M1 demonstrated 
increased local neural activity with increasing stimulus intensity in healthy controls, in addition to 
distant changes in neural activity within M1 connections75. Finally, the cortical excitability is altered in 
healthy subjects following lf-rTMS of M 176. 
3.4 
Clinical Evidence to Date 
rTMS treatment for psychomotor slowing has only been tested in Parkinson's disease": 78 and in a 
combined group of patients with major depression and schizophrenia (Walther et al. unpublished data). 
ln our own randomized double-blind placebo-controlled trial, 15 sessions of 1 Hz rTMS were effective 
in ameliorating psychomotor slowing (see also Background). The active comparator iTBS was not 
effective, but also well-tolerated. There were no exceptional side-effects beyond those regularly 
reported in studies of rTMS. 
The intended protocols (1 Hz rTMS and iTBS as active control) have been widely used in 
neuropsychiatric cohorts to treat various symptoms". Low-frequency rTMS (1 Hz) is effective in 
reducing the severity of auditory verbal hallucinations in schizophrenia spectrum disorders79-86. There 
have been numerous reports demonstrating safety and efficacy of this protocol. The active comparator 
iTBS has been tested in studies in major depressive disorder and is effective in reducing depression 
severity with minimal side effects87
· 88; most commonly transient headaches" rTMS treatment has 
been applied between 1 O and 30 sessions, usually 5 per week. There are international guidelines on 
the use of rTMS for clinical purposes, including safety measures and side effect assessments 
1 
· 2. 
3.5 
Dose Rationale / Medical Device: Rationale for the intended purpose in 
study (pre-market MD) 
As outlined in sections 3.1.7., 3.1.8., 3.3., and 3.4. rTMS has been used to modify psychomotor 
slowing in Parkinson's disease, depression, and schizophrenia. ln addition, rTMS over the premotor 
and motor cortex alters brain function. Our previous study demonstrated clinical effectiveness of 1 Hz 
stimulation over left SMA on psychomotor slowing in 15 sessions. There are no other treatment 
studies on motor function in schizophrenia. However, studies applying less than 1 O stimulation 
sessions to treat hallucinations were less effective in schizophrenia spectrum disorders82
· 89. ln major 
depression, rTMS studies with similar protocols usually treat patients for 4-6 weeks (20-30 sessions)". 
3.6 
Explanation for choice of comparator (or placebo) 
This study will have two comparators: one placebo stimulation and an active stimulation that produces 
the opposite effect of the investigated protocol, i.e. iTBS over SMA which will facilitate neural activity. 
Both comparators are necessary to demonstrate clinical utility (placebo) and the neurophysiological 
changes associated with the three treatments (placebo and iTBS). Only this approach will finally allow 
testing whether inhibitory lf-rTMS is changing the motor system in a specific direction that is causal for 
clinically relevant changes of motor behavior. The waiting list will disentangle specific stimulation 
effects from effects of time or expectation. Placebo will disentangle specific rTMS treatment effects. 
Finally, iTBS will disentangle the direction of neurophysiological changes of the motor system. All 
stimulations will target the left SMA. Mode of application, localization, frequency of sessions and 
apparatus will be identical for all protocol arms. Arms will differ in the coil used (real or sham) and in 
the frequency of the applied stimulation (1 Hz vs. iTBS). The number of pulses is similar in all 
protocols (1 '000-1 '200). 
3.7 
Risks/ Benefits 
The study intervention is adminstered as an add-on to existing treatment in inpatient (or less often 
dayclinic) settings. The study procedures pose some extra-effort and burden to the patients, 
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particularly during baseline and week 3 assessments. However, the time and inconvenience is 
acceptable and comparable to those of other studies in the field. From our extensive experience with 
studies in these patient groups we know that assessments are acceptable and may be split to different 
days if needed. The neuroimaging with MRI twice has a total duration of less than 60 mins per session 
including the preparation. Most of the scanning time, participants will be in a resting state, i.e. have no 
task - just to relax lying in the scanner. This can be accomplished by many, even very ill subjects. 
Only a short proportion of the scanning time is devoted to a simple motor task in the scanner, when 
participants are asked to move their fingers. Taken together, 
both clinical and neuroimaging 
assessments are acceptable. 
The study intervention (rTMS) has a minimal risk of increasing the severity of the disorder, i.e. 
deterioration. ln our prior clinical rTMS trial with the same stimulation protocol and 15 rTMS sessions, 
there was no case of deterioration. Only one SAE occurred which was unrelated to the intervention. ln 
addition, patients are under close observation by the study team and the hospital teams who see 
patients in the inpatient or dayclinic setting. Thus, changes are rapidly recognized and appropriate 
measures will be taken, as the study is only an add-on to standard treatment. 
This study will follow the general recommendations for safety in rTMS protocols 1· 2 and the device 
manual. ln addition, a screening standard questionnaire for rTMS candiates will be applied to ensure 
that all strict exclusion criteria for safety in the protocol will be respected. The expected main adverse 
effects could be transient headache, transient local pain, transient neck pain, transient toothache and 
transient paraesthesia. Transient hearing changes have not been reported applying theta burst TMS 
but are likely possible. Therefore hearing protection will be used (earplugs). Furthermore we will make 
prompt referral for auditory assessment in case of any individual who complains of hearing loss, 
tinnitus or aural fullness following the rTMS. Seizure induction is rare but possible in epilepsy patients, 
which are therefore excluded. Furthermore, in some patients transient impairment of working memory 
was reported. Taken together, if the safety regulations are followed, the risk for participants is minimal. 
All adverse events are only temporarily occurring and no severe adverse events have been reported in 
rTMS trials up to now. 
Magnetic fields attenuate rapidly with distance, so it seems unlikely that the fetus of a pregnant 
woman might be directly affected by rTMS. Currently, no side effects to the child were reported in 
reports of repeated rTMS in pregnant women'" 91. Still, pregnant women will be excluded from this 
study. Prior to study entry, a pregnancy test will be performed by all women in childbearing age, who 
are also asked to use a simple, effective contraceptive method during the 3 week trial. 
Participation in the study does not pose a particular risk for patients, as the rTMS will be added on to 
the existing standard medical and non-medical interventions. lt is likely that patients in the 
experimental group will experience better outcomes. However, most patients (in control arms) and 
healthy controls will not have any personal benefit from participation in the study. Still, the study will be 
an important step towards the design of specific trials to improve psychomotor slowing in 
schizophrenia. Given, that the experimental arm was superior in ameliorating psychomotor slowing, 
treatment will result in better outcomes and quality of lives. ln addition, results of this study will be 
used to plan further interventional trials in patients with schizophrenia, which may then introduce rTMS 
as a standard add-on treatment of psychomotor slowing in schizophrenia spectrum disorders. 
3.8 
Justification of choice of study population 
This study will include a group of patients with schizophrenia spectrum disorders, who will receive the 
assessments and interventions. ln addition, a group of healthy control subjects is included only for the 
assessments, but not to receive an intervention. Patients will be included if they can provide consent 
on their own (no minors and no patients incapable of understanding the study information will be 
recruited). Participation in the study does not interfere with regular treatment. Patients' interests will be 
safeguarded by the treating physicians who are not part of the study team. 
Study of patients is necessary in order to test the rTMS effect in a group with clear psychomotor 
slowing. These symptoms are only found in patients with severe psychiatric disorders. 
Study of controls is needed in order to compare motor behaviour abnormalities and alterations in brain 
network structure and function between health and disease. Controls will not receive any intervention. 
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4. 
STUDY OBJECTIVES 
4.1 
Overall Objective 
This study investigates the neural correlates of psychomotor slowing in schizophrenia spectrum 
disorders and the neurophysiologie changes associated with successful application of rTMS to 
ameliorate slowing. To reach this aim, the study combines a randomized, double-blind, placebo- 
controlled trial of rTMS in patients over 3 weeks and a cross-sectional and longitudinal study focussing 
on motor behaviour and brain imaging. Therefore, this study has four main aims. First, we aim to 
investigate the clinical and functional neural changes following 3 weeks of daily rTMS 
treatment (inhibitory, facilitatory, or placebo). An exploratory aim is to describe imaging markers of 
treatment response. Second, we aim to characterize the pathophysiology of psychomotor 
slowing (PS) in depth combining multimodal neuroimaging and electrophysiology with instrumental 
and observer-based measures of PS. Third, we aim to characterize short-term changes of PS by 
observing a waiting list cohort that is later allocated to treatment. And fourth, we aim to describe the 
clinical outcome of the rTMS intervention at 6-month follow-up. 
4.2 
Primary Objective 
The study seeks to determine the clinical and neural effects of 15 sessions of inhibitory lf-rTMS over 
SMA on psychomotor slowing in schizophrenia spectrum disorders compared to facilitatory iTBS, 
placebo or patients on a waiting list. 
4.3 
Secondary Objectives 
The study further seeks to determine, whether lf-rTMS (inhibitory) will be superior over placebo or 
iTBS (facilitatory) in all clinical and motor behavioral measures, e.g. greater reduction in BFCRS 
scores from baseline, greater increase in activity levels, or finger taps. ln addition, the study will test 
the effects of rTMS on the cerebral motor network connectivity and activity, as well as on cerebellar 
function and motor cortex excitability. Furthermore, the study will explore the neuroimaging markers of 
response to treatment. Moreover, the study will test the association between measures of PS and 
neuroimaging markers of the motor system, e.g. network connectivity, activity, and structure. Next, the 
study will investigate the temporal dynamics of PS by comparing a waiting list group to the placebo 
group. Finally, the study will test whether lf-rTMS treatment for 3 weeks will have lasting effects on PS 
at week 6 or 6-months follow-up. 
4.4 
Safety Objectives 
The study will also assess the tolerability of 15 of sessions rTMS in terms of stimulation side effects 
and duration of stimulation effects. 
5. STUDY OUTCOMES 
5.1 
Primary Outcome 
The primary outcome variable is the SRRS score as a surrogate marker of psychomotor slowing. The 
primary endpoint will be the change SRRS ratings from baseline to week 3 measured with the SRRS92 
The SRRS is administered at baseline, week 1, week 2, week 3, week 6, and week 24. lt is an 
observer rated scale quantifying the severity of psychomotor slowing with 15 items, each ranging 0-4. 
The SRRS has been developed to target this behavior and has been used in previous trials. 
Assessments will be performed by blinded raters, who have been trained to use the scale reliably. 
5.2 
Secondary Outcomes 
5.2.1 
Clinical outcomes 
Proportion of responders (>= 30% reduction from baseline SRRS) between groups at week 1, 2, 3, 6, 
and 24. This will provide an additional categorical measure of who benefits from the intervention in 
terms of the main target (psychomotor slowing). 
Change in other commonly observed motor symptoms from baseline, including rating scales on 
KEK 2018-02164, OCoPS-P, Version 02 of 13/12/2018 
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abnormal involuntary movements, Parkinsonism, and catatonia at week 3, 6, and 24. See section 9 for 
details on instruments. 
Change in general psychopathology using the positive and negative syndrome scale PANSS93 and the 
brief negative symptom scale BNSS94 between baseline and week 3, week 6, and week 24. 
Change in self-reported physical activity and experienced negative symptoms using the International 
Physical Activity Questionnaire (IPAQ)
9 and the self-evaluation of negative symptoms (SNS)96. 
5.2.2 
Behavioral outcomes 
Change in objective gross motor activity as measured with 24 hours of wrist actigraphy at baseline, 
week 3, 6, and 24. 
Change in fine motor function as measured with the coin rotation task at baseline, week 3, 6, and 24. 
5.2.3 
Physiological outcomes 
Changes in motor cortex excitability from baseline to week 3, 6, and 24 using a TMS paradigm of short 
interval intracortical inhibition (SICI), intracortical facilitation (ICF) and 1 mv motor evoked potentials 
(MEP). 
Changes in postural sway from baseline at week 3, using the Kistler platform and assessments with 
eyes open as well as eyes closed. 
5.2.4 
Neuroimaging outcomes 
Change in resting state perfusion within the motor network from baseline to week 3. 
Change in motor network resting state connectivity from baseline to week 3. 
Change in neural activation patterns during a finger tapping task using functional MRI at baseline and 
week 3. 
5.3 
Other Outcomes of Interest 
Change in social and community functioning using the global assessment of functioning GAF97, the 
Social and Occupational Functioning SOFAS98, and the UPSA-brief99 short assessment of functional 
capacity at baseline, week 6, and week 24. Social and community functioning is a relevant distal 
outcome for any psychiatric intervention. 
5.4 
Safety Outcomes 
After each rTMS session, participants are inquired about stimulation side effects. After sessions 5, 10 
and 15, we will apply a short rating scale to assess side effects according to the guidelines 1· 2. 
6. STUDY DESIGN 
6.1 
General study design and justification of design 
The design of this single-site study is a 4 parallel-arm, double-blind, randomized, placebo-controlled 
trial. Patients will be randomized to one of four treatment arms. Patients will all receive TMS over the 
left SMA in 15 daily sessions over 3 weeks as add-on treament. ln three groups, assessments will be 
conducted immediately before and after the three weeks treatment (1 Hz, iTBS, and Placebo), while 
the fourth group will receive active treatment (1 Hz) only after a 3 week waiting period with no 
additional intervention. After 6 months we will perform a clinical follow-up assessment. The 
interventions will be conducted by a small team (2 persons) who will know the stimulation parameters. 
All assessments will be conducted by a different team, who is completely blind to treatment and 
specifically trained to use the instruments and rating scales. Patients are also blind to treatment, 
because stimulation site is the same for all groups and there will be no change of protocols during the 
study. The placebo group will be stimulated with a placebo coil that looks identical and emits identical 
noises compared to the real TMS coil, but without any magnetic impulse emission. Assessments with 
clinical rating scales will be complemented by objective and instrumental motor tests that are not 
prone to rater bias. Therefore, both the patients and the assessors are blind to treatment protocol. 
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The study will include patients with schizophrenia spectrum disorders who currently have psychomotor 
slowing according to the SRRS. The protocol arms are chosen to test the clinical efficacy and 
neurophysiological changes of 15 sessions 1 Hz rTMS for psychomotor slowing in schizophrenia 
spectrum disorders. The placebo-arm is required to demonstrate an effect of rTMS as add-on 
treatment. The active control is required to demonstrate an opposite effect at the neural level 
compared to active treatment. Finally, the waiting list is important to characterize potential self- 
limitation of the condition under study. Because these subjects are referred to a waiting list, they will 
receive active treatment thereafter. This group will not be completely blinded, as they will know to be 
in the active treatment group from week 3 through week 6. 
We intend to enrol 88 patients with schizophrenia spectrum disorders. For the neuroimaging and 
motor behavioural assessments, we also plan to include 40 matched healthy control subjects. 
For each patient in group 1-3 the study is 3 weeks and a follow-up interview after 6 months. Patients in 
group 4 (waiting list) will have three assessments (baseline, week 3 and week 6) and a follow-up 
interview at 6 months. The total duration of the study is 4 years. 
6.2 
Methods of minimising bias 
6.2.1 
Randomisation 
Using the free software research randomizer, we will generate for the patients a list with four numbers 
indicating the group allocation, i.e. stimulation types. Allocation will be 1: 1: 1: 1 across the whole 
intended sample. Subsequent numbers of study inclusion will therefore determine to which study arm 
the patient will be randomized. The lists will only be available for the principal investigator and locked 
in his office. He will perform randomization and give the written group allocation to the investigators. 
6.2.2 
Blinding procedures 
As described in 6.1, patients will receive 15 sessions of rTMS over the left SMA in a blinded fashion. 
They will not be able to see which protocol is used (coil placement on top of their head, machine 
display behind the patients). Because of the parallel arm design, they will not know how the other 
protocols feel. Patients will be eye-blinded and ear-plugged during rTMS. 
The teams performing assessments and rTMS stimulations will be strictly distinct. Therefore, patients 
and outcome assessors will be blinded to treatment arm. 
6.2.3 
Other methods of minimising bias 
Outcomes are assessed with instrumental means or validated questionnaires. All assessments will 
follow a standard routine. Assessors will be trained to use instruments by the Pl. 
6.3 
Unblinding Procedures (Code break) 
ln case of severe adverse events, an un blinding can take place at the responsibility of the principal 
investigator. ln this case, the participant will not be able to further participate in the study. The 
allocated intervention order will be kept in a sealed envelope. The sealed envelopes will be stored at a 
central place, i.e. the office of the lab, so they can be accessed in case of any emergency. 
7. STUDY POPULATION 
The aim is to test 88 subjects with schizophrenia spectrum disorders and 40 healthy control subjects. 
Both genders will be included, age range 18 - 65 years. 
7.1 
Eligibility criteria 
Participants fulfilling all of the following inclusion criteria are eligible for the study: 
ages 18-60 years 
Right-handed subjects 
Ability and willingness to participate in the study 
Ability to provide written informed consent 
Informed Consent as documented by signature (Appendix Informed Consent Form) 
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Patients only: schizophrenia spectrum disorders according to DSM-5 with psychomotor 
slowing (SRRS score ~ 15) 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant: 
• 
Substance abuse or dependence other than nicotine 
• 
Past or current medical or neurological condition associated with impaired or aberrant 
movement, such as brain tumors, stroke, M. Parkinson, M. Huntington, dystonia, or severe 
head trauma with subsequent loss of conciousness. 
• 
Epilepsy or other convulsions 
• 
History of any hearing problems or ringing in the ears 
• 
Standard exclusion criteria for MRI scanning and TMS; e.g. metal implants, claustrophobia 
• 
Patients only: any TMS treatment in the past 3 months 
• 
Women who are pregnant or breast feeding, 
• 
Intention to become pregnant during the course of the study, 
• 
Female participants who are surgically sterilised / hysterectomised or post-menopausal for 
longer than 2 years are not considered as being of child bearing potential. 
• 
Previous enrolment into the current study, 
• 
Enrolment of the investigator, his/her family members, employees and other dependent 
persons 
• 
Controls only: history of any psychiatric disorder or first-degree relatives with schizophrenia 
spectrum disorders. 
7.2 
Recruitment and screening 
Healthy participants will be recruited by word-of-mouth, an internet link at the homepage of the 
department and flyers at supermarkets or at the University of Bern. Staff of the University Hospital of 
Psychiatry Bern will not be recruited. Furthermore, patients will be asked for participation at the 
inpatient and outpatient departments of the University Hospital of Psychiatry, Bern. All participants will 
spend approximately a total of 18 hours in the study on 7 different assessment days (screening, 
baseline, 3x during interventions and 2 follow-ups). Thus, they will be compensated by a single 
payment of CHF 200,-. Screening is described in section 9.1 and performed by master-level 
psychologists or psychiatrists. 
7.3 
Assignment to study groups 
Randomization procedure is described in section 6.2.1. When the investigators have recruited a 
patient-participant, the principal investigator will allocate the person to a study group based on the 
randomization list and the sequence of enrolment in the study. From the list of numbers, patients are 
sequentially allocated by the principal investigator to one of the four treatment arms. The principal 
investigator will provide written information to the investigators concerning the treatment arm. The lists 
with the group allocations are only accessible for the principal investigator. 
7.4 
Criteria for withdrawal/ discontinuation of participants 
Participants may discontinue the trial at any time or withdraw consent. Furthermore, the treating 
physicians may request study discontinuation in case of significant deterioration of the condition at any 
time during the intervention period. All data from subjects in the intent-to-treat population, who 
received at least one dose of rTMS will be further used in the analyses. We will apply the last- 
observation-carried-forward (LOCF) method in the final analyses. ln case a patient withdraws consent 
before the first rTMS stimulation, we will recruit an additional patient. The number of all patients 
recruited and randomized will be reported in the publications. All data from neuroimaging acquisition 
and motor behaviour will be used whenever possible, e.g. for analyses of baseline associations 
between brain imaging and behavior. ln case of withdrawal due to adverse events or serious adverse 
events there will be follow-up examinations after 14 days and repeatedly until the problem is resolved, 
see 9.2.5. 
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8. 
STUDY INTERVENTION 
8.1 
Identity of lnvestigational Products (treatment/ medical device) 
8.1.1 
Experimental Intervention (treatment/ medical device) 
Name: MagPro R30 with theta burst option 
Manufacturer: MagVentrue, Inc. Atlanta GA, USA 
The device is CE certified according to ISO-Norm 13485:2003 and approved for clinical use. 
Active stimulation: 1 Hz stimulation of 17 mins over left SMA, 15 sessions in total (5 per week) 
8.1.2 
Control Intervention (standard/routine/comparator treatment I medical device) 
All stimulations are delivered with the same device. The stimulation sites are the same (left SMA) for 
all groups. The iTBS protocol is shorter (3 mins), the placebo protocol will be delivered with a specific 
placebo-coil that looks identical, makes identical sounds but produces no magnetic pulses. 
Placebo control: 1 Hz stimulation of 17 mins over left SMA without magnetic emission, 15 sessions in 
total (5 per week) 
Active control: iTBS stimulation over left SMA, 21 mins per session, 15 sessions in total (5 per week) 
Waiting list: no intervention during the first three weeks, afterwards active stimulation: 1 Hz 
stimulation of 17 mins over left SMA, 15 sessions in total (5 per week) 
8.1.3 
Packaging, Labelling and Supply (re-supply) 
Not applicable. 
8.1.4 
Storage Conditions 
TMS devices are stored in the institution (translational research center at the University Hospital of 
Psychiatry, Bern) according to internal regulations and the device manual. 
8.2 
Administration of experimental and control interventions 
8.2.1 
Experimental Intervention 
The application of the TMS device follows the published guidelines 
1
· 2 and the device manual. Before 
each session, the resting motor threshold is determined to identify the individual intensity of 
stimulation. The position for the coil placement is left SMA, which is determined either via 
neuronavigation using individual brain anatomy or 3 cm anterior of the leg motor area, which is 
individually determined through single pulse stimulations causing leg movements. 
Both experimenter and participants will wear earplugs for auditory safety. 
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Active experimental protocol: 
Lf-rTMS at 1 Hz will be used with 1 '000 pulses at an intensity of 110% of the resting motor threshold 
(approximate duration 17 minutes). The protocol is identical to that of our previous study and a study 
in Parkinson's disease77. 15 sessions in total (5 per week) 
8.2.2 
Control Intervention 
Placebo control: 1 Hz stimulation of 17 mins over left SMA without magnetic emission, using the 
Placebo-coil. 15 sessions in total (5 per week) 
Active control: Stimulation parameters for iTBS will follow those of Huang et al. 100, including 600 
pulses at 50 Hz (stimulation in 2 sec trains every 1 O sec for 190 sec in total). To increase the effect, 
we will deliver two iTBS series in one session separated by 15 min with a total of 1200 pulses. During 
the experiment, iTBS pulse intensity is adjusted to 80% of the motor threshold. iTBS stimulation of 21 
mins over left SMA, 15 sessions in total (5 per week) 
Waiting list: same protocol as active experimental protocol but only between week 3 and 6. 
8.3 
Dose I Device modifications 
ln case of intolerable side effects, the study will be discontinued for the participant. No dose or device 
modifications are planned. 
8.4 
Compliance with study intervention 
Investigators have to document the order of stimulation. This will be checked for consistency with the 
group allocation. No further strategies are needed. Participants are always under observation during 
the rTMS sessions and the planned assessments. Non-compliance on the side of the participant 
would lead to study discontinuation for this person. Use of concomitant medication will be retrieved 
from the medical files of the patients and transferred to the CRF. 
8.5 
Data Collection and Follow-up for withdrawn participants 
If participants withdraw their consent, they will be contacted immediately to clarify whether there were 
intolerance issues with the study. See section 9.2.5 for safety follow-up measures. ln case of 
withdrawal the data will be analyzed and stored encrypted as all the data of the other participants. 
However, we will remove the encryption key for the participants who withdrew consent and therefore it 
will not be possible to identify the subjects from encrypted data. Patients who withdrew consent will be 
invited for the 6 month follow-up interview using their preferred way of contact (Email, letter). 
8.6 
Trial specific preventive measures 
No specific preventive measures are needed. 
8.7 
Concomitant Interventions (treatments) 
Current medication will be recorded in the CRF at study entry and throughout the 3 week intervention 
period. Patients are expected to comply with the treatment they are receiving from their treating 
physicians. 
Because this is an add-on treatment, we expect relevant changes from concomitant interventions. 
Therefore, we apply placebo, waiting-list, and an active control group. 
8.8 
Study Drug I Medical Device Accountability 
Not applicable. 
8.9 
Return or Destruction of Study Drug I Medical Device 
The TMS devices are already in use in the clinic. No study specific procedures are intended. 
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9. 
STUDY ASSESSMENTS 
9.1 
Study flow chart(s) / table of study procedures and assessments 
Flow charts are distinct for controls and patients, because controls receive no intervention. 
Furthermore, three patient groups will start interventions immediately (lf-rTMS, iTBS, and Placebo; i.e. 
groups 1-3), but one group will be waiting for 3 weeks and then enter the intervention phase (waiting 
group; i.e. group 4). 
9.1.1 
Patients of treatment groups 1-3 
Study Periods 
Scree 
Treatment, Intervention 
Follow-up 
ning 
Period 
Visit 
1 
2 
3 
4 
5 
6 
7 
Time (week) 
-1 
o 
1 
2 
3 
6 
24 
Patient Information and Informed Consent 
X 
Dernooraohìcs 
X 
CASH and SCIO (historv) 
X 
ln- /Exclusion Criteria 
X 
Physical Examination 
X 
Preonancv Test 
X 
Psvchopatnoloqv (TALO, NES) 
X 
Randomisation 
X 
Administer rTMS (5 sessions per week) 
X 
X 
X 
Primary Variable SRRS 
X 
X 
X 
X 
X 
X 
Motor scales U PORS, BFCRS, AIMS, IPAQ 
X 
X 
X 
X 
Psychopathology (PANSS, BNSS, SNS) 
X 
X 
X 
X 
Actiqraohv and coin rotation 
X 
X 
X 
X 
Posturoqraphv 
X 
X 
TMS cortical excitability 
X 
X 
X 
X 
Cerebral MRI 
X 
X 
Functional outcome (SOFAS, GAF, UPSA-brief) 
X 
X 
X 
Concomitant Therapy 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
Study events patient groups 1-3 
Visit 
Information 
Instrument used 
Expected 
time 
1 (Screening) 
Check 
inclusion I CRF 
5 min 
exclusion criteria 
Demographic data 
CRF 
5 min 
Medical history 
CRF 
10 min 
Handedness 
Edinburgh Handedness Inventory 101 
5 min 
Pregnancy test 
Urine based test 
10 min 
Diagnoses 
SCIO interview 
60 min 
ascertainment 
2 (baseline) 
Psychopathology 
Positive And Negative Syndrome Scale 90 min 
(PANSS)93 interview, CASH 102 interview, 
Brief Negative Symptom Scale CBNSS)94, 
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Page 30 of 56 

Thought 
and 
Language 
Disorder 
(TALO) 103, 
Neurological 
Evaluation 
Scale (NES) 104 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS) 105
, 
Bush 
Francis 
Catatonia Rating Scale (BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 
107 
Self Report 
Self-Evaluation of negative symptoms 
10 min 
(SNS)96
, International Physical Actitvity 
Questionnaire (IPAQ)95 
Motor tests 
Actigraphy and coin rotation 
5 min 
Posturography 
Kistler platform at Dept. of Neurology 
30 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 30 min 
stimulation 
Neuroimaging 
MRI scan including structural T1, Arterial 
60 min 
spin labelling, BOLD resting state and 
task fMRI 
Functional outcome 
Global Assessment of Functioning GAF, 
15 min 
Social and Occupational 
Functioning 
Scale SOFAS, UPSA-brief assessment 
of functional capacity 
rTMS 
5 rTMS daily sessions à 20 min 
100 min 
3 (week 1) 
Primary outcome 
SRRS 
5 min 
rTMS 
5 rTMS daily sessions à 20 min 
100 min 
Check side effects 
CRF 
5 min 
Concomitant 
CRF 
5 min 
therapy 
4 (week 2) 
Primary outcome 
SRRS 
5 min 
rTMS 
5 rTMS daily sessions à 20 min 
100 min 
Check side effects 
CRF 
5 min 
Concomitant 
CRF 
5 min 
therapy 
5 (week 3) 
Psychopathology 
Positive And Negative Syndrome Scale 30 min 
(PANSS)93 
interview, 
Brief Negative 
Symptom Scale (BNSS)94 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS) 105, 
Bush 
Francis 
Catatonia Rating Scale (BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 107 
Self Report 
Self-Evaluation of negative symptoms 
10 min 
(SNS)96
, International Physical Actitvity 
Questionnaire (IPAQ)95 
Motor tests 
Actigraphy and coin rotation 
5 min 
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Posturography 
Kistler platform at Dept. of Neurology 
30 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 
30 min 
stimulation 
Neuroimaging 
MRI scan including structural T1, Arterial 
60 min 
spin labelling, BOLD resting state and 
task fMRI 
Functional outcome 
Global Assessment of Functioning GAF, 
15 min 
Social 
and Occupational 
Functioning 
Scale SOFAS, UPSA-brief assessment 
of functional capacity 
Check side effects 
CRF 
5 min 
Concomitant 
CRF 
5 min 
therapy 
6 (week 6) 
Psychopathology 
Positive And Negative Syndrome Scale 
30 min 
(PANSS)93 
interview, 
Brief Negative 
Symptom Scale (BNSS)94 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS) 105, 
Bush 
Francis 
Catatonia 
Rating 
Scale (BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 
107 
Self Report 
Self-Evaluation of negative symptoms 
10 min 
(SNS)96
, International Physical Actitvity 
Questionnaire (IPAQ)95 
Motor tests 
Actigraphy and coin rotation 
5 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 
30 min 
stimulation 
Functional outcome 
Global Assessment of Functioning GAF, 
15 min 
Social 
and Occupational 
Functioning 
Scale SOFAS, UPSA-brief assessment 
of functional capacity 
7 (week 24) 
Psychopathology 
Positive And Negative Syndrome Scale 
30 min 
(PANSS)93 
interview, 
Brief Negative 
Symptom Scale (BNSS)94 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS) 105, 
Bush 
Francis 
Catatonia 
Rating 
Scale 
(BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 107 
Self Report 
Self-Evaluation of negative symptoms 
10 min 
(SNS)96
, International Physical Actitvity 
Questionnaire (IPAQ)95 
Motor tests 
Actigraphy and coin rotation 
5 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 
30 min 
stimulation 
Functional outcome 
Global Assessment of Functioning GAF, 
15 min 
Social 
and 
Occupational 
Functioning 
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Page 32 of 56 

Scale SOFAS, UPSA-brief assessment 
of functional capacity 
9.1.2 
Patients of treatment group 4 (waiting group) 
Study Periods 
Scree 
Treatment, Intervention Period 
Follow-up 
ning 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Time (week) 
-1 
o 
3 
4 
5 
6 
9 
24 
Patient Information and Informed Consent 
X 
Dernooraohícs 
X 
CASH and SCIO (history) 
X 
ln- /Exclusion Criteria 
X 
Physical Examination 
X 
Preonancv Test 
X 
Psvchooatholocv (TALO, NES) 
X 
Randomisation 
X 
Administer rTMS (5 sessions per week) 
X 
X 
X 
Primary Variable SRRS 
X 
X 
X 
X 
X 
X 
X 
Motor scales U PORS, BFCRS, AIMS, IPAQ 
X 
X 
X 
X 
X 
Psychopathology (PANSS, BNSS, SNS) 
X 
X 
X 
X 
X 
Actioraohv and coin rotation 
X 
X 
X 
X 
X 
Posturoqraohv 
X 
X 
X 
TMS cortical excitability 
X 
X 
X 
X 
X 
Cerebral MRI 
X 
X 
X 
Functional outcome (SOFAS, GAF, UPSA-brief) 
X 
X 
X 
X 
Concomitant Therapy 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
Study events for patients of the waiting group 
Visit 
Information 
Instrument used 
Expected 
time 
1 (Screening) 
Check 
inclusion I CRF 
5 min 
exclusion criteria 
Demographic data 
CRF 
5 min 
Medical history 
CRF 
10 min 
Handedness 
Edinburgh Handedness Inventory 
101 
5 min 
Pregnancy test 
Urine based test 
10 min 
Diagnoses 
SCIO interview 
60 min 
ascertainment 
2 (baseline) 
Psychopathology 
Positive And Negative Syndrome Scale 90 min 
(PANSS)93 interview, CASH102 interview, 
Brief Negative Symptom Scale (BNSS)94, 
Thought 
and 
Language 
Disorder 
(TALO) 
103, 
Neurological 
Evaluation 
Scale (NES) 
104 
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Page 33 of 56 

Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS)1º5
, 
Bush 
Francis 
Catatonia Rating Scale (BFCRS) 
106
, 
Abnormal Involuntary Movement Scale 
(AIMS) 
107 
Self Report 
Self-Evaluation of negative symptoms 10 min 
(SNS)96
, International Physical Actitvity 
Questionnaire (IPAQ)95 
Motor tests 
Actigraphy and coin rotation 
5 min 
Posturography 
Kistler platform at Dept. of Neurology 
30 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 30 min 
stimulation 
Neuroimaging 
MRI scan including structural T1, Arterial 
60 min 
spin labelling, BOLD resting state and 
task fMRI 
Functional outcome 
Global Assessment of Functioning GAF, 
15 min 
Social and Occupational 
Functioning 
Scale SOFAS, UPSA-brief assessment 
of functional capacity 
3 (week 3) 
Psychopathology 
Positive And Negative Syndrome Scale 90 min 
(PANSS)93 interview, CASH 102 interview 
present 
part 
only, 
Brief 
Negative 
Symptom Scale (BNSS)94, Thought and 
Language 
Disorder 
(TALO) 103 
' 
Neurological Evaluation Scale (NES) 104 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS) 105, 
Bush 
Francis 
Catatonia Rating Scale (BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 107 
Self Report 
Self-Evaluation of negative symptoms 
10 min 
(SNS)96, International Physical Actitvity 
Questionnaire (I PAQ)95 
Motor tests 
Actigraphy and coin rotation 
5 min 
Posturography 
Kistler platform at Dept. of Neurology 
30 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 30 min 
stimulation 
Neuroimaging 
MRI scan including structural T1, Arterial 
60 min 
spin labelling, BOLD resting state and 
task fMRI 
Functional outcome 
Global Assessment of Functioning GAF, 
15 min 
Social and Occupational 
Functioning 
Scale SOFAS, UPSA-brief assessment 
of functional capacity 
rTMS 
5 rTMS daily sessions à 20 min 
100 min 
4 (week 4) 
Primary outcome 
SRRS 
5 min 
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rTMS 
5 rTMS daily sessions à 20 min 
100 min 
Check side effects 
CRF 
5 min 
Concomitant 
CRF 
5 min 
therapy 
5 (week 5) 
Primary outcome 
SRRS 
5 min 
rTMS 
5 rTMS daily sessions à 20 min 
100 min 
Check side effects 
CRF 
5 min 
Concomitant 
CRF 
5 min 
therapy 
6 (week 6) 
Psychopathology 
Positive And Negative Syndrome Scale 30 min 
(PANSS)93 
interview, 
Brief Negative 
Symptom Scale (BNSS)94 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS) 105, 
Bush 
Francis 
Catatonia Rating Scale (BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 107 
Self Report 
Self-Evaluation of negative symptoms 10 min 
(SNS)96, International Physical Actitvity 
Questionnaire (IPAQ)95 
Motor tests 
Actigraphy and coin rotation 
5 min 
Posturography 
Kistler platform at Dept. of Neurology 
30 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 30 min 
stimulation 
Neuroimaging 
MRI scan including structural T1, Arterial 
60 min 
spin labelling, BOLD resting state and 
task fMRI 
Functional outcome 
Global Assessment of Functioning GAF, 
15 min 
Social and Occupational Functioning 
Scale SOFAS, UPSA-brief assessment 
of functional capacity 
Check side effects 
CRF 
5 min 
Concomitant 
CRF 
5 min 
therapy 
7 (week 9) 
Psychopathology 
Positive And Negative Syndrome Scale 30 min 
(PANSS)93 
interview, 
Brief Negative 
Symptom Scale (BNSS)94 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS) 105, 
Bush 
Francis 
Catatonia Rating Scale (BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 107 
Self Report 
Self-Evaluation of negative symptoms 
10 min 
(SNS)96
, International Physical Actitvity 
Questionnaire (I PAQ)95 
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Motor tests 
Actigraphy and coin rotation 
5 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 30 min 
stimulation 
Functional outcome 
Global Assessment of Functioning GAF, 
15 min 
Social and Occupational Functioning 
Scale SOFAS, UPSA-brief assessment 
of functional capacity 
8 (week 24) 
Psychopathology 
Positive And Negative Syndrome Scale 30 min 
(PANSS)93 
interview, 
Brief Negative 
Symptom Scale (BNSS)94 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS) 105, 
Bush 
Francis 
Catatonia Rating Scale (BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 107 
Self Report 
Self-Evaluation of negative symptoms 
10 min 
(SNS)96, International Physical Actitvity 
Questionnaire (IPAQ)9
5 
Motor tests 
Actigraphy and coin rotation 
5 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 30 min 
stimulation 
Functional outcome 
Global Assessment of Functioning GAF, 
15 min 
Social and Occupational Functioning 
Scale SOFAS, UPSA-brief assessment 
of functional capacity 
9.1.3 
Control subjects 
Study Periods 
Screening 
Observation period 
Visit 
1 
2 
3 
Time (week) 
-1 
o 
3 
Proband Information and Informed Consent 
X 
Demooraohics 
X 
SCIO 
X 
ln- /Exclusion Criteria 
X 
Physical Examination 
X 
Preqnancv Test 
X 
Primary Variable SRRS 
X 
X 
Motor scales UPDRS, BFCRS, AIMS, IPAQ 
X 
X 
Actlqraphv and coin rotation 
X 
X 
Posturography 
X 
X 
TMS cortical excitability 
X 
X 
Cerebral MRI 
X 
X 
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Study events for controls 
Visit 
Information 
Instrument used 
Expected 
time 
1 (Screening) 
Check 
inclusion I CRF 
5 min 
exclusion criteria 
Demographic data 
CRF 
5 min 
Medical history 
CRF 
10 min 
Handedness 
Edinburgh Handedness Inventory 101 
5 min 
Pregnancy test 
Urine based test 
10 min 
Diagnoses 
SCIO interview 
60 min 
ascertainment 
2 (week O) 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UP DRS) 105
, 
Bush 
Francis 
Catatonia Rating Scale (BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 107 
Self Report 
International 
Phisical 
Actitvity 5 min 
Questionnaire (IPAQ) 5 
Motor tests 
Actigraphy and coin rotation 
5 min 
Posturography 
Kistler platform at Dept. of Neurology 
30 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 30 min 
stimulation 
Neuroimaging 
MRI scan including structural T1, Arterial 60 min 
spin labelling, BOLD resting state and 
task fMRI 
3 (week 3) 
Primary outcome 
SRRS92 
5 min 
Motor scales 
Unified 
Parkinson's 
Disease 
Rating 
15 min 
Scale 
(UPDRS) 105
, 
Bush 
Francis 
Catatonia Rating Scale (BFCRS) 106, 
Abnormal Involuntary Movement Scale 
(AIMS) 
107 
Self Report 
International 
Phisical 
Actitvity 5 min 
Questionnaire (IPAQ) 5 
Motor tests 
Actigraphy and coin rotation 
5 min 
Posturography 
Kistler platform at Dept. of Neurology 
30 min 
Cortical excitability 
TMS 
paradigm 
with 
paired 
pulse 30 min 
stimulation 
Neuroimaging 
MRI scan including structural T1, Arterial 
60 min 
spin labelling, BOLD resting state and 
task fMRI 
9.2 
Assessments of outcomes 
Assessors of outcome variables will be psychologists or psychiatrists of master-degree-level. All 
assessors will be trained by the Pl to use the instruments correctly and to assure interrater reliability. 
Weekly staff meetings will ensure conformity in procedures. All assessments will be conducted blind to 
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rTMS treatment. 
9.2.1 
Assessment of primary outcome 
The Salpêtrière Retardation Rating Scale (SRRS) is applied at each visit from baseline to follow-up. 
The scale is described in section 5.1. Raters will be trained to use the scale and blind to rTMS 
treatment. The score of each of the 15 items is recorded in the CRF. 
9.2.2 
Assessment of secondary outcomes 
9.2.2.1 
Clinical outcomes 
The change in motor syndromes from baseline is assessed at several visits (see 9.1 ). Trained raters 
blind to treatment will assess motor behaviour in standardized examinations with clinical rating scales. 
Parkinsonism is assess with the Unified Parkinson's Disease Rating Scale (UPDRS)1º5, of which we 
will only assess part lii, the current motor behaviour. Catatonia will be assessed with the Bush Francis 
Catatonia Rating Scale (BFCRS) 
106
, an 24 item rating scale specifically designed for this purpose. The 
timeframe of observation is the last week. Finally, dyskinesia will be monitored with the standard rating 
scale for this issue, the Abnormal Involuntary Movement Scale (AIMS) 107, a 7 item scale following a 
standardized examination. All motor rating scales are the gold standard of their kind. 
The change of general schizophrenia symptoms is assessed with the Positive And Negative 
Syndrome Scale (PANSS)93
. The 30 item scale is the widely used standard assessment following a 
standardized clinical interview. Chan~e in negative symptoms is specifically assessed with the Brief 
Negative Symptom Scale (BNSS)
9 
, which allows monitoring relevant dimensions of negative 
symptoms such as apathy and diminished expression. Furthermore, we will apply the self-evaluation 
of negative symptoms (SNS)96, a valid and reliable 20 items questionnaire to capture the subjective 
experience of negative symptoms. 
9.2.2.2 
Behavioral outcomes 
Objective gross motor behaviour will be assessed using continuous wrist actigraphy for 24 hours. The 
actigraphs (empathica e4) will be worn on the wrist of the non-dominant arm. Data is stored as logged 
electronic file. This measure is sensitive to altered motor behaviour and has been successfully applied 
in many studies of Prof. Walther's team27
· 35
· 49
· 50
· 
108-111. Patients will fill a sleep activity protocol to 
enable separation of sleep from wake periods during recording. This also allows to check data for 
consistency and plausibility, because measurements are continuously performed also in periods when 
participants are not observed. 
The fine motor performance is assessed with the coin rotation task. ln this task, participants are asked 
to rotate a .50 CHF coin between thumb, index and middle finger as fast as possible for a total of 30 
seconds. The performance is recorded on video and later analysed offline. Analysis includes the 
number of half turns and the number of coin drops according to a validated formula51· 52
• 112. 
Self-ratings of physical activity will be conducted with the 7-item International Physical Activity 
Questionnaire (IPAQ)95
, which has a German Version and has great psychometric properties. The 
ratings cover the past 7 days and allow calculating the energy expenditure and total activity. 
9.2.2.3 
Physiological outcomes 
Measures of cortical excitability will be assessed as one of the important physiological outcome 
parameters. Measurements will be conducted with a MagPro R30 (MagVentrue, Inc. Atlanta GA, USA). 
Single pulse and paired pulse TMS protocols will be conducted to measure short-interval intracortical 
inhibition (SICI) at 1 msec interstimulus interval (ISi) and 3msec ISi, intracortical facilitation (ICF) at 7 
msec ISi and 15 ms ISi, restin~ motor threshold (RMT), and 1 mv motor evoked potential (MEP), 
according to standard protocols" · 113 
Posturography will be conducted at the Department of Neurology (Prof. Roger Kalla). The 
assessments of postural sway will be scheduled immediately before or after the MRI acquisition, 
because this is also located at the Inselspital Bern. Mean postural sway will be calculated as outcome 
variable for postural stability53
' 
114. The Kistler platform will be used to calculate of the pressure 
dependent fluctuation (x-, y-, z- axis) of the bodies' centre of gravity 115. Participants will be measured 
standing with eyes open and eyes closed according to standard procedures. 
9.2.2.4 
Neuroimaqing outcomes 
Neuroimaging will be acquired twice, at baseline and week 3. MRI acquisition will be performed at a 
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3T Siemens Magnetom Trio scanner at the Institute of Diagnostic and lnterventional Neuroradiology, 
Bern (local collaborator Prof. Dr. med. Roland Wiest). The 64-channel head coil will be used for all 
MRI images. First, high-resolution T1-weighted MR images will be obtained using a 3D magnetization- 
prepared rapid two-gradient-echo with 2 inversion times (MP2RAGE) sequence. fMRI will be 
performed using a multi-slice multi-band T2*-weighted echo planar imaging (EPI) sequence for resting 
state and during task execution. Prior to the fMRI images a BO will be acquired for corrections of 
putative field inhomogeneity. Afterwards, we will perform acquisition of cerebral blood flow (CBF) at 
rest using a pseudo-continuous arterial spin labelling (pCASL) sequence. Moreover, we will acquire a 
MO image (MO equilibrium magnetization of water signal) for the quantification of CBF and a BO for 
corrections of putative field inhomogeneity. Finally, a set of diffusion-weighted images (DWI) that will 
allow reconstructing fiber tracts using the model based on diffusion tensor imaging (DTI). 
Anatomy (MP2RAGE) The optimized acquisition parameters were as follows: 176 sagittal slices, 256 
x 224 matrix (with a non-cubic field of view (FOV) of 256 x 224 mm2, yielding a nominal isotropic 
resolution of 1 mm3), 5000 ms repetition time (TR), 2.98 ms echo time (TE), 700 ms and 2500 ms 
inversion time (Tl), flip angle 4º and 5º, GRAPPA acceleration factor 3 and a 8:22 min total acquisition 
time. 
BO-map - The 48 EPI interleaved axial oblique slices will be positioned exactly like the fMRI slices with 
exactly the same slice geometry. Two amplitude and a phase image will be recorded in each subject 
(TR= 520 ms, TE1 = 4.92 ms, TE2 = 7.38 ms). The acquisition time will last 1 min 40 sec. 
fMRI - The 48 EPI interleaved axial oblique slices will be positioned in-line with the bi-commissural 
axis with the following parameters: TR = 500 ms, TE = 30 ms, FA= 90, slice thickness = 3.6 mm, gap 
thickness = O mm, matrix size = 64 x 64 mm, FOV 230 x 230 mm2 resulting in a iso-voxel dimension 
of 3.6 mm x 3.6 mm x 3.6 mm. The sequence is driven in a 3D PACE mode (Siemens Erlangen) to 
enable prospective motion correction. With these sequence parameters we will cover the whole brain 
including the cerebellum. ln total, first 720 dynamic scans will be collected for resting state fMRI (total 
of 6 mins) and subsequently 1200 dynamic scans will be collected during the conduction of the task 
(total of 10 mins). The task will consist of four blocks including two active paced blocks, a passive 
listening block and rest. All blocks except rest will be paced with a continuous 2Hz auditory cue. The 
two active blocks are right hand finger tapping (index finger vs. thumb) and sequential finger- 
thumb opposition (all fingers of the right hand vs. thumb). These tasks have produced reliable 
activation of SMA, M1, basal ganglia, and cerebellum in healthy subjects and are easy enough to be 
performed by schizophrenia patients with PS62
· 64
· 65
· 116
· 117. During one run, we will alternate active and 
passive blocks, i.e. finger tapping - listening - sequential finger opposition - rest. Each block will last 
for 15 s and each run takes 1 min. We will alternate the active blocks between runs. A total of 1 O runs 
will be conducted. Instructions will be presented on a video goggle system. Cue tones will be delivered 
via headphones. Participants will be instructed and trained on the task outside the scanner. 
pCASL - The 30 EPI interleaved axial oblique slices will be positioned in-line with the bi-commissural 
axis and acquired in sequential order with the following parameters: TR= 3000 ms, TE= 12 ms, FA= 
90, slice thickness = 8.0 mm, gap thickness = O mm, matrix size = 64 x 64 mm, FOV 256 x 256 mm2 
resulting in a voxel dimension of 4.0 mm x 4.0 mm x 8.0 mm. the sequence will additionally have the 
following parameters: bolus duration = 700 ms, inversion time = 2200 ms. ln total 100 images will be 
acquired lasting in total 6 min. 
9.2.3 
Assessment of other outcomes of interest 
Measures of social and community functioning as described in section 5.3. 
9.2.4 
Assessment of safety outcomes 
9.2.4.1 
Adverse events 
After every rTMS session, participants are asked about new occurrence of adverse events. As 
example, they are inquired about sensations associated with the stimulation or headaches. The 
answers are recorded in the CRF. Furthermore, at each study visit during the intervention phase, i.e. 
after 5 rTMS sessions, patients will be inquired about adverse events using a standard questionnaire 
in the CRF2
. 
ln case the adverse event is not limited to stimulation, the participants will be asked at the next 
session (24 hours later), whether the adverse event still continues or when it was resolved. The 
frequency and type of adverse events will be reported in the publication of results. 
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9. 2. 4. 2 
Laboratory parameters 
No laboratory parameters will be taken. 
9.2.4.3 
Vital signs 
No routine measurement of vital signs is planned. If patients report dizziness, clinical routines will 
include measurement of blood pressure and heart rate. 
9.2.5 
Assessments in participants who prematurely stop the study 
Participants who prematurely stop the study will be immediately assessed for adverse events. ln case 
of adverse events reports, a physical examination will be conducted and results will be recorded 
accordingly. Follow-up examinations will be planned within the next 14 days in case of continuing 
problem related to adverse events, and these examinations will be continued every 14 days until the 
health issue is resolved. 
9.3 
Procedures at each visit 
9.3.1 
Screening visit 
• 
Check the inclusion and exclusion criteria, use CRF 
• 
Collect demographic data, use CRF 
• 
Conduct urine pregnancy test in female participants between 18 and 50 years of age 
• 
Assess diagnoses with SCIO, document results in CRF 
• 
Assess handedness with EHl1º1, document result in CRF 
• 
Assess medical history in CRF 
See table study events at 9.1 
9.3.2 
Visit 2 (baseline, week O) 
• 
Assess current psychopathology, use PANSS interview and BNSS, document in CRF 
• 
Assess formal thought disorder, use TALO interview, document in CRF 
• Assess Neurological soft signs, use NES, document in CRF 
• 
Assess psychiatric history with CASH interview in patients, document result in CRF 
• 
Assess primary outcome with SRRS scale, document in CRF 
• Assess motor behaviour with rating scales, use BFCRS, UPDRS, AIMS, document results in 
CRF 
• 
Assess functioning, use GAF, SOFAS, and UPSA-brief, document results in CRF 
• 
Hand out self-rating questionnaires SNS and IPAQ, collect and document in CRF 
• 
Conduct coin rotation test, record on video 
• 
Record gross motor activity using actigraphy 
• 
Test cortical excitability using the TMS device according to standard procedure. Record 
electronic data 
• 
Acquire MRI scans at University Institute of Diagnostic and lnterventional Neuroradiology 
• 
Acquire posturography at University Hospital, Dept. of Neurology, record electronic data 
• 
Record current medication regime in CRF 
• 
Schedule 5 rTMS sessions 
• 
Schedule next visit 
9.3.3 
Visit 3 and 4 (week 1 and 2) 
• Assess primary outcome with SRRS scale, document in CRF 
• 
Assess side effects with questions in the CRF 
• 
Record current medication regime in CRF 
• 
Schedule 5 rTMS sessions 
• 
Schedule next visit 
9.3.4 
Visit 5 (end of intervention, week 3) 
• Assess side effects with questions in the CRF 
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• 
Assess current psychopathology, use PANSS interview and BNSS, document in CRF 
• 
Assess primary outcome with SRRS scale, document in CRF 
• 
Assess motor behaviour with rating scales, use BFCRS, UPDRS, AIMS, document results in 
CRF 
• 
Assess functioning, use GAF, SOFAS, and UPSA-brief, document results in CRF 
• 
Hand out self-rating questionnaires SNS and IPAQ, collect and document in CRF 
• 
Conduct coin rotation test, record on video 
• 
Record gross motor activity using actigraphy 
• 
Test cortical excitability using the TMS device according to standard procedure. Record 
electronic data 
• 
Acquire MRI scans at University Institute of Diagnostic and lnterventional Neuroradiology 
• 
Acquire posturography at University Hospital, Dept. of Neurology, record electronic data 
• 
Record current medication regime in CRF 
• 
Schedule next visit (follow-up) 
9.3.5 
Visit 6 and 7 (follow-up, week 6 and 24) 
• 
Assess current psychopathology, use PANSS interview and BNSS, document in CRF 
• 
Assess primary outcome with SRRS scale, document in CRF 
• 
Assess motor behaviour with rating scales, use BFCRS, UPDRS, AIMS, document results in 
CRF 
• 
Assess functioning, use GAF, SOFAS, and UPSA-brief, document results in CRF 
• 
Hand out self-rating questionnaires SNS and IPAQ, collect and document in CRF 
• 
Conduct coin rotation test, record on video 
• 
Record gross motor activity using actigraphy 
• 
Test cortical excitability using the TMS device according to standard procedure. Record 
electronic data 
• 
Record current medication regime in CRF 
• 
Schedule next visit (follow-up) 
10. SAFETY 
10.1 
Medical Device Category A studies 
Device deficiencies and all adverse events (AE) including all serious adverse events (SAE) are 
collected, fully investigated and documented in the source document and appropriate case report form 
(CRF) during the entire study period, i.e. from patient's informed consent until the last protocol-specific 
procedure, including a safety follow-up period. Documentation includes dates of event, treatment, 
resolution, assessment of seriousness and causal relationship to device and/or study procedure [ISO 
14155, 6.4.1.]. 
Safety is assessed spontaneously at each stimulation session and in a structured set of questions at 
each visit during the intervention phase (after 5 stimulations). See 9.2.4. If adverse events occur, 
patients are followed-up with extra-visits after 14 days until the issue has resolved. 
Typical adverse events to be expected by rTMS are: 
• 
Mild pain or nausea (39 %) 
• 
Mild headaches (28%) 
• 
Mild neck pain (40%) 
Rare events include hearing problems or local skin irritation. 
10.1.1 
Definition and Assessment of safety related events 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs 
(including an abnormal laboratory finding) in participants, users or other persons whether or not 
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related to the investigational medical device [ISO 14155: 3.2]. 
This includes events related to the investigational device or the comparator and to the procedures 
involved. For users or other persons this is restricted to events related to the investigational medical 
device. 
Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device [ISO 14155: 3.1 ]. 
This includes any adverse event resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, operation, or any malfunction of the investigational medical 
device. This includes any event that is a result of a use error or intentional misuse. 
Serious Adverse Event (SAE) [European regulation on medical devices 2017/745, art. 58]. 
Any adverse event that led to any of the following: 
(a) death, 
(b) serious deterioration in the health of the subject that resulted in any of the following: 
(i) life-threatening illness or injury, 
(ii) permanent impairment of a body structure or a body function, 
(iii) hospitalisation or prolongation of patient hospitalisation, 
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
(v) chronic disease, 
(c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect. 
This includes device deficiencies that might have led to a serious adverse event if a) suitable action 
had not been taken orb) intervention had not been made or c) if circumstances had been less 
fortunate. These are submitted to the EC via BASEC within 7 days. A planned hospitalisation for pre- 
existing condition, or a procedure required by the protocol, without a serious deterioration in health, is 
not considered to be a serious adverse event. 
Device deficiency 
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety or 
performance, such as malfunction, misuse or use error and inadequate labelling [ISO 14155: 3.15]. 
Health hazards that require measures 
Findings in the trial that may affect the safety of study participants and, which require preventive or 
corrective measures intended to protect the health and safety of study participants SAE [ClinO Art. 37]. 
Causal Relationship of SAE [MEDDEV 2.7/3 revision 3, May 2015]. 
A causal relationship towards the medical device or study procedure should be rated as follows: 
• 
Not related: The relationship to the device or procedures can be excluded. 
• 
Unlikely: The relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be obtained. 
• 
Possible: The relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible. 
• 
Probable: The relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably explained by another cause. 
• 
Causal relationship: The serious event is associated with the investigational device or with 
procedures beyond reasonable doubt. 
Device deficiencies that might have led to an SAE are always related to the medical device. 
10.1.2 
Reporting of (Serious) Adverse Events and other safety related events 
Reporting to Sponsor-Investigator: 
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The following events are to be reported to the Sponsor-Investigator within 24 hours upon becoming 
aware of the event: 
• 
All SAEs 
• 
Health hazards that require measures 
• 
Device deficiencies 
The Sponsor-Investigator will evaluate SAEs with regard to causality and seriousness. Device 
deficiencies are assessed regarding their potential to lead to an SAE. 
Pregnancies 
Because pregnancy tests are a prerequisite to participation and the intervention is only 3 weeks, 
pregnancies will not be further assessed or reported. 
Reporting to Authorities [ClinO Art. 42]: 
ln Category A studies, the sponsor is subject to the notification requirements specified in Art. 15 of the 
MedDO of 17 October 2011 (SR 812.213). 
lt is the Investigator's responsibility to report to the Ethics Committee via BASEC device deficiencies 
that could have led to serious adverse events if suitable action had not been taken, intervention had 
not been made, or circumstances had been less fortunate within 7 days [ClinO Art. 42]. 
Health hazards that require measures are reported to the Ethics Committee via BASEC within 2 days 
[ClinO Art. 37]. 
Periodic safety reporting: 
A yearly safety update-report is submitted by the Investigator to the Ethics Committee via BASEC. 
10.1.3 
Follow up of (Serious) Adverse Events 
If adverse events occur, patients are followed-up with extra-visits after 14 days until the issue has 
resolved. This applies to patients who continue with the study but also to patients who prematurely exit 
the study. ln case subjects are lost to followed-up, study personnel will contact the treating 
psychiatrists (or if unavailable, the general practitioners) in order to inform on serious adverse events 
and the recommendations for follow-up clinical examinations. ln cases of headaches for example, care 
would include the prescription of a non-steroidal antirheumatic drug, i.e. pain medicine, according to 
the person's preferences, medical history, or interaction with existing medication. 
11. ST A TIS Tl CAL METHODS 
A two-tailed p-value of< .05 is considered to be statistically significant in all analyses. We will also 
report effect sizes for the comparisons of primary and clinical secondary outcome variables between 
groups. 
11.1 
Hypotheses 
Aim 1: investigate the clinical and functional neural changes following 15 sessions of daily rTMS 
Hypothesis 1a (main hypothesis): 
lf-rTMS (inhibitory) will be superior over placebo or iTBS 
(facilitatory) in all clinical and motor behavioral measures, e.g. greater reduction in SRRS scores from 
baseline, greater increase in activity levels, or coin rotations. 
Hypothesis 1b: lf-rTMS will reduce aberrant functional connectivity in the motor system, e.g. between 
thalamus and M1. lf-rTMS will alter regional CBF in the motor system and increase SMA and M1 
activity during the fMRI task. No relevant changes are expected in the sham group, iTBS may 
deteriorate neural alterations. 
Hypothesis 1c: cortical excitability will be differentially changed with rTMS. Lf-rTMS will increase SICI, 
while iTBS will reduce SICI. 
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Aim 2: characterization of psychomotor slowing (PS) in schizophrenia spectrum disorders compared 
to healthy controls 
Hypothesis 2a: Patients will have poorer performance on all motor tasks, eg. reduced activity levels, 
increased postural sway, and less coin rotations 
Hypothesis 2b: Patients will have aberrant structural and functional connectivity within the motor 
system, as well as increased CBF in basal ganglia and decreased CBF in premotor/motor cortex. 
Applying network metrics, the functional motor network will be less efficient in schizophrenia. 
Hypothesis 2c: Behavioral measures of PS will be associated with aberrant motor network structure, 
perfusion, function, and connectivity. For example, patients with strong PS will have increased resting 
state functional connectivity between thalamus and M1. PS severity will be linked to reduced structural 
motor network efficiency, lower M1 and SMA activity during the fMRI task, and increased SMA 
perfusion at rest. 
Hypothesis 2d: Patients will have increased motor cortex excitability (e.g. reduced SIGI), which will 
be linked to measures of PS. 
Aim 3 characterize short term dynamics of PS 
Hypothesis 3a: in very few subjects we expect relevant spontaneous improvements in PS measures. 
The majority will have less than 20% fluctuation of motor parameters within 3 weeks 
Hypothesis 3b: we expect slight longitudinal changes in resting state functional connectivity and 
perfusion of the motor system, but no structural changes. 
Aim 4: to describe the short-term and medium-term clinical outcome of 3 weeks of rTMS intervention 
Hypothesis 4a: patients receiving inhibitory rTMS will have better outcome (less PS, less general 
symptom severity) shortly after the intervention (at 6 week follow-up) compared to patients receiving 
placebo or facilitatory iTBS 
Hypothesis 4b: patients receiving inhibitory rTMS will have better outcome (less PS, less general 
symptom severity) and superior function (social and global) at 6-month follow-up compared to patients 
receiving placebo or facilitatory iTBS 
Hypothesis 4c (exploratory): changes in functional connectivity within the motor system from 
baseline to week 3 will predict better outcome at week 6, particularly reduced M1-thalamus functional 
connectivity. 
11.2 Determination of Sample Size 
The main effects of the 3-week interventions on PS (SRRS scores) will be calculated in a repeated 
measures design including 2 measures (Baseline, week 3) and four groups (lf-rTMS, iTBS, sham, 
waiting group-lf-rTMS). Assuming a moderate effect size (f = 0.23) as indicated by our pilot data in a 
repeated measures ANOVA with moderate correlation between time points (0.5), a power of 0.95 and 
an alpha = 0.05, we would need 88 patients (22 per group). 
11.3 Statistical criteria of termination of trial 
No statistical stopping rules are planned. 
11.4 Planned Analyses 
11.4.1 
Datasets to be analysed, analysis populations 
All data from subjects in the intent-to-treat population, who received at least one dose of rTMS will be 
used in the analyses of rTMS effects. We will conduct sensitivity analyses in all trial-completers (see 
11.5). 
ln the analyses on biological and clinical correlates of PS, we will use all data of the baseline 
assessment, thus including data from subjects who dropped-out prior to the first rTMS session. 
11.4.2 
Primary Analysis 
The primary analysis will be a repeated measures ANOVA of SRRS scores with two timepoints (within 
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subjects: baseline and week 3) and four groups (lf-rTMS, iTBS, sham, waiting group-lf-rTMS). ln case 
of significant baseline demographic or clinical group differences, we will adjust for these in an 
repeated measures ANCOVA of SRRS. 
The analysis will be performed by the Pl and his team in SPSS using data from the RedCap database. 
11.4.3 
Secondary Analyses 
Secondary analyses focus on the secondary outcomes (see 5.2) and hypotheses (see 11.1 ). 
Crosstabs are used to calculate the proportion of responders (>=30% reduction in SRRS from 
baseline) across groups. Repeated measures ANOVAs will clarify the time-course of SRRS change 
from baseline to week 6 (including week 1, 2, 3 and 6) and differences between groups. 
Repeated measures ANOVAs will test the change of clinical and motor rating scales between baseline 
and week 3, week 6, and week 24 and differences between groups. 
Linear regression analyses will test the association between neuroimaging markers (resting state 
perfusion, connectivity, fMRI activation, ect.) and measures of PS at baseline. 
Repeated measures ANOVAs will test the longitudinal changes in neuroimaging markers from 
baseline to week 3. 
All analyses will be performed by the Pl and his team or collaborators with permission of the Pl. 
11.4.4 
Interim analyses 
Interim analyses of the primary analysis are planned after enrolment of 1 O, 20, 30, 40, 50, 60, and 70 
subjects. The scope is to estimate whether any adjustments of the treatment arms are necessary. ln 
addition, baseline data can be tested for associations between neuroimaging data and clinical/motor 
measures after enrolment of 20, 40, or 60 subjects. 
All interim analyses are optional and at the discretion of the Pl. Interim analyses are conducted by the 
Pl and his team. 
11.4.5 
Safety analysis 
The study team will provide a descriptive analysis of all reported adverse events. The analysis will 
focus on the type of event, duration, and timing and relate the number of observed events to the 
number of rTMS sessions administered. Furthermore, the frequency of adverse events will be 
compared between treatment arms of the trial. 
11.4.6 
Deviation(s) from the original statistical plan 
Any deviation from the statistical plan will be reported and justified in the methods of the study report. 
11.5 Handling of missing data and drop-outs 
We will apply the last-observation-carried-forward (LOCF) method in the final analyses. ln case a 
patient withdraws consent before the first rTMS stimulation, we will recruit an additional patient. The 
number of all patients recruited and randomized will be reported in the publications. 
Sensitivity analyses will be performed in order to establish whether premature dropout would influence 
the results. Therefore, the primary analyses will be repeated with all subjects who completed the 
interventional trial. Further tests will establish whether drop-outs differ from completers in basic clinical 
or demographic variables. 
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12. QUALITY ASSURANCE AND CONTROL 
All study personnel will be trained by the Pl to achieve consistent adherence to procedures and 
interrater reliability. Standard operating procedures will be written for the intervention and standardized 
TMS measurements. For all clinical rating scales, instructions and manuals are provided for the study 
personnel. All study personnel will have to read the manuals. 
12.1 
Data handling and record keeping / archiving 
12.1.1 
Case Report Forms 
All relevant data is documented in paper CRFs. This data includes inclusion/exclusion criteria, 
demographic data, medical history, scores of clinical and motor rating scales. Furthermore, side 
effects, concomitant treatment, reasons for discontinuation will be recorded in the CRF. Timing and 
conductance of experimental measures, such as posturography, cerebral MRI, cortical excitability, and 
actigraphy will be recorded recorded in the CRF. However, the real data of these measures is stored 
electronically outside the CRF. 
For each enrolled study participant a CRF is maintained. CRFs will be kept current to reflect subject 
status at each phase during the course of study. Participants will be coded by use of a participant 
number in combination with the year of birth. 
The paper forms of rating scales (e.g. PANSS) and the electronic data (e.g. MRI, posturography, ect.) 
are considered source documents. Furthermore, in patients the medical record of our hospital is a 
source document for the past psychiatric history and current concomitant treatment. All other data 
(participant history, side effects, ect.) are directly entered into the CRF without further source. 
The study personnel is authorized to enter data into the CRFs, the name of the entering person will be 
documented. CRF data will be recorded in an electronic database, i.e. Redcap-Database. The 
procedure will include data cross-check between electronic and paper CRF. Any deviation will be 
corrected by consensus and consulting the CRF forms. Redcap-Database has individualized logins 
for each member of the study team and provides logs for data entry. 
The electronic database for the non-CRF data will be logged via a secure Dropbox folder, thus the 
person entering the data or changing data can be identified by individualized logins. The log also 
identifies the document changes and the time of the change. Dropbox allows for restoring each 
version of the documents within the study folder. A copy of the electronic neuroimaging data will be 
shared with Collaborator Prof. Jessica Bernard, College Station, TX, USA At her laboratory, specific 
neuroimaging analyses will be performed with a subset of the electronic data. The original electronic 
files will be stored in Bern (see 12.1.3), while the specific neuroimaging analyses data of Prof. Bernard 
will be stored encrypted at her university for 1 O years. 
12.1.2 
Specification of source documents 
As described in 12.1.1. most data in the CRFs is source data. Furthermore, Informed consent form, 
specific rating scales and electronic data (such as MRI, actigraphy or posturography) are source data. 
ln patients, the medical record of the hospital may contain source data on the psychiatric history. All 
CRFs and paper source data will be kept in folders. Any extra examination in case of additional safety 
assessments will be documented on paper and kept as source data in the same folders as CRF and 
other source data. 
12.1.3 
Record keeping/ archiving 
All study data will be archived for 1 O years after study termination or premature termination of the trial 
at the translational research center of the University Hospital of Psychiatry, Bern. ln addition, the data 
of specific neuroimaging analyses performed at Prof. Bernard's laboratory, will be stored encrypted for 
10 years at Texas A & M University, College Station, TX, USA Thus, source data are kept in Bern, 
and all further handled data will be stored under identical conditions in Bern or Texas Station. 
12.2 Data management 
Data of all participants will be encrypted and analysis will be performed using encrypted data only. 
Unblinding of participant-specific data is only possible after consent has been given by the participants 
and the sponsor. Data of all participants will receive a numerical identification. The key to this 
encryption code will be stored in a single file at the address below, and it will be accessible only by the 
sponsor and the principal investigator. 
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Office of the Pl: University of Bern, University Hospital of Psychiatry, Murtenstrasse 21, 3008 Bern, 
Office 01-132 
12.2.1 
Data Management System 
Describe what system (also software) is being used and who is responsible and how it is tested before 
the trial (may include a description of where the system is hosted). 
12.2.1.1 Neuroimaging data 
MRI data are anonymized digital data of appr. 1 GB per subject and scan, we will aim for 278 scans, 
i.e. total of 300 GB. MRI data sets include the dicom files of the planned sequences fMRI task, fMRI 
rest, ASL rest, DTI and T1 anatomy. MRI data sets will be safely stored in encrypted formats at the 
server of the translational research center, university hospital in Bern. Data will be logged with 
personal logins, such that any change to the files is reproducible. Data analysis will be performed 
locally in computers of the institute's network. Some analyses are planned to be performed on 
encrypted data at computers of the study collaborator Prof. Bernard. All files generated during data 
processing and analysis will be stored. Total data volume is approximately 2 TB. Neuroimaging data 
will be stored at a dropbox-folder, which is encrypted by Boxcryptor Software and owned by the 
Translational Research Center, University Hospital of Psychiatry, Bern. The system has been 
effectively used in several studies. Access to the folder and files is secured by personal login and 
password. The log of the Dropbox folder enables the identification of data entry/data change according 
to the logins used. The log will inform on which data has been changed when by whom. Dropbox 
allows for restoration of each file version, thus each change can be tracked. 
12.2.1.2 motor behavioral/instrumental data 
Data from actigraphy, posturography, TMS-MEP experiments as well as video recordings of coin 
rotation will be stored encrypted in digital format. As neuroimaging data, storage will comply with the 
federal human research act and will be conducted at standard facilities of the translational research 
center with encrypted and logged server storage. Data access is granted upon personal logins, such 
that any change to the files is reproducible. Each dataset includes several measures across 4-5 time 
points for one study participant. We expect appr. 1 GB per subject, total of 130 GB. 
12.2.1.3 clinical and demographic data 
Clinical data including outcome measures with observer based rating scales or patients' history will be 
collected. This data is transferred to paper case report forms and will later be anonymously transferred 
to a red cap data base, hosted by the CTU Bern. Data access is only available to study staff with 
personalized logins. During the longitudinal assessments approximately 300 variables will be 
assessed for each participant. 
12.2.2 
Data security, access and back-up 
Only the Pl and authorized personnel with own logins and passwords will have access to the 
electronic data. The translational research center Bern runs a daily backup of the dropbox folders. The 
RedCap Database also has regular backups. 
12.2.3 
Analysis and archiving 
All analyses will be performed with a final copy of the SPSS file including all clinical data. All other 
analyses (neuroimaging, posturography, actigraphy) will be conducted with the appropriate standard 
software. Only the Pl and authorized personnel will have access to the data to perform the analyses. 
12.2.4 
Electronic and central data validation 
Data will be checked for consistency, e.g. range checks for questionnaire scores or test scores, 
checks for date entries temporal consistency. 
12.3 Monitoring 
The principal investigator will check the CRFs for completeness and internal consistency (plausibility 
of information) and external consistency (with source data) after each participant completed the study. 
ln addition an external monitoring will be performed by Dr. Peter. 
Four monitoring dates are planned. The first before the study recruitment starts, the second after the 
first three participants have been included, the third after 50% of enrolment was achieved and the final 
monitoring is planned after the last data had been collected. 
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Before first recruitment: Check whether all study assessments and instruments are ready and 
complete. 
After the first three participants: Check CRF entries and compliance with source data where possible. 
Clarify queries of data entry or study procedures. 
After the 50% enrolment: Check whether CRFs of the all collected cases are completed and data is 
consistent. 
After the final data collection: Check whether CRFs of the all cases collected after the last monitoring 
are completed and data is consistent. 
12.4 Audits and Inspections 
Not intended for this single center trial. 
12.5 Confidentiality, Data Protection 
All data will be handled strictly confidential. Direct access to the source documents will be permitted 
only for purposes of inspections (ICHE6, 6.10) by authorities such as the CEC or monitoring by the Pl. 
Only the Pl and his team will have access to the protocol, dataset and other study related information 
during and after the study. 
12.6 Storage of biological material and related health data 
No storage of biological material is planned. 
All electronic data will be archived for 1 O years (see 12.1 ). 
13. PUBLICATION AND DISSEMINATION POLICY 
Publication of results is the responsibility of the sponsor/investigator. The results of the study will be 
prepared for publication in peer-reviewed scientific journals, preferably as open-access articles. 
Authorship will follow the national guidelines. Furthermore, results will be reported at scientific 
conferences as posters or oral communications. The use of professional writers is not intended. After 
scientific publication, the results will be prepared for communication in lay man's terms in the media. 
Data sharing outside of the project is currently not planned. However, electronic data, particularly 
neuroimaging electronic data, may be later shared with national or international collaborators to 
address research questions that are currently unknown. The data storage must comply with the same 
regulations as the data storage of this study. 
14. FUNDING AND SUPPORT 
14.1 
Funding 
This study receives project funding by the Swiss National Science Foundation (grant #182469 to Prof. 
Sebastian Walther). Additional minor costs will be covered by the University Hospital of Psychiatry in 
Bern. 
14.2 Other Support 
Consumables and further material support is provided by the host institution, the Translational 
Research Center of the University Hospital of Psychiatry, University of Bern, Switzerland. 
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15. INSURANCE 
No special insurance due to category A 
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17. APPENDICES 
1. 
1B (according to ISO 14155) - "Produktinformation" 
2. TMS device manual 
3. 
Case Report Forms, v2 of December ia" 2018, patient version and control version 
4. 
Study Information for patients, v2 of December 13th 2018 
5. 
Study Information for healthy controls, v2 of December 13th 2018 
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