A Multi-center, Patient-blinded and Investigator-blinded, Randomized, Parallel-group, Superiority Study to Compare the Efficacy of Four Sessions of Amygdala fMRI-BOLD Neurofeedback With Yoked Sham-control Neurofeedback in the Treatment of Dysregulated Affect in Borderline Personality Disorder
Phase: PHASE1
Conditions: Borderline Personality Disorder
Sponsor: Central Institute of Mental Health, Mannheim

CIP Code: BrainSTEADy 
BfArM Nr.: DE-24-00015271 
Clinical Investigation Plan 
Version 03, 24.11.2025 
Page 1 of 75 
Version for publication on 
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 based on appendix SOP-PM03-A-Protocol-MDR/MPDG V002 
CLINICAL INVESTIGATION PLAN 
BrainSTEADy 
 
Title of Clinical Investigation: 
A 
multi-center, 
patient-blind 
and 
investigator-blind, 
randomized, parallel-group, superiority study to investigate a 
neurobiological mechanism of affect instability, comparing four 
sessions of amygdala fMRI-BOLD neurofeedback with sham-
feedback in Borderline Personality Disorder 
Sponsor Name and Address: 
Central Institute of Mental Health, J5, 68159 Mannheim 
 
 
BfArM-Kennnummer: 
DE-24-00015271 
Registry Number of the 
Clinical Investigation: 
ClinicalTrials.gov Identifier: NCT06626789 
Modification No. / CIP Date 
and Version: 
Version 03, 24.11.2025 
 
Modification History: 
Modification No. Date of Approval 
Modification Type 
Version 02 
10.03.2025 
‘Concluding questionnaire’ added to assessments (adapted 
sections: Schedule of assessments, 6.10. Assessments, section 
6.6 Clinical Investigation Visits). 
Version 02 
10.03.2025 
fMRI-task was removed due to time constraints (adapted sections: 
Schedule of assessments, previous section 1.5. Learning and 
transfer of Neurofeedback, section 2.2.1 Main Investigation, 
section 6 Clinical Investigation Visits, Figure 5 Patient Time Flow, 
Figure 6 Decision tree of missed/interrupted MR visits). 
Version 02 
10.03.2025 
DTI measurement added to V2b and V5, removed DTI from V4 
(adapted sections: Schedule of assessments, section 6 Clinical 
Investigation Visits). 
Version 03 
21.11.2025 
Protocol improvement: Herbal or homeopathic remedies, and 
nutritional supplements not required in assessment of medical 
history (section 6.10 Assessments) 
Version 03 
21.11.2025 
Correction: Blind check-questionnaire should be assessed in V5b, 
not V5a (changed Schedule of Assessments, c.f. 6.6 Clinical 
Investigation Visits). 
Version 03 
21.11.2025 
Clarification, excl. crit. #7, added phrase (here in italics for review): 
Treatment with any neurofeedback other than investigational 
device three months prior to or during the study participation 
(changed Synopsis, Section 4.4 Exclusion Criteria) 
Version 03 
21.11.2025 
Adapted trial duration (Synopsis) 

CIP Code: BrainSTEADy 
BfArM Nr.: DE-24-00015271 
Clinical Investigation Plan 
Version 03, 24.11.2025 
Page 2 of 75 
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 based on appendix SOP-PM03-A-Protocol-MDR/MPDG V002 
Version 03 
21.11.2025 
Added 2 more trial sites (changed Synopsis, Section 4.1 Number 
of Subjects and Sites) 
Version 03 
21.11.2025 
Clarification: Interviews and assessments of the screening phase 
should be collected on the same day as the informed consent is 
given or within 7 days thereafter (changed Section 6.1). 
Version 03 
21.11.2025 
Correction, excl. crit. #13.c (here in italics for review): Any suicidal 
ideation of type 4 or 5 in the C-SSRS in the past 3 months prior to 
randomization screening or during screening period. 
Version 03 
21.11.2025 
Correction, Appendix 2, p. 75 (sentence removed; WOCBP do not 
need to do pregnancy test at screening visit; c.f. Schedule of 
Assessments). 
Version 03 
21.11.2025 
Correction, Patient Time Flow (Figure 5): Minimum time period 
between Baseline EMA and V2 Baseline questionnaires is 4 
instead of 5 days. 
Version 03 
21.11.2025 
Clarification, section 6.3: AE/SAE are to be assessed following 
randomization, in beginning of each visit. Additional AE 
assessment to be done in the end of V2, V3, V4, V5a. 
Version 03 
21.11.2025 
Protocol improvement: If Neurofeedback 3 cannot be 
administered, the Survey of NF transfer (questionnaire) can be 
skipped (changed Figure 6). 
Version 03 
21.11.2025 
Correction to achieve consistency with DSM-5 diagnostic 
instrument and protocol change to allow mild substance use 
disorder: Excl. crit. #2 (here in italics for review): Current moderate 
or severe alcohol or substance dependence use disorder within 1 
month prior the initial screening 
 
CONFIDENTIAL: This Clinical Investigation Plan contains confidential information and is intended solely 
for the guidance of the clinical investigation. This Clinical Investigation Plan may not be disclosed to parties 
not associated with the clinical investigation or used for any purpose without the prior written consent of 
the principal investigator. 
 
 

CIP Code: BrainSTEADy 
BfArM Nr.: DE-24-00015271 
Clinical Investigation Plan 
Version 03, 24.11.2025 
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 based on appendix SOP-PM03-A-Protocol-MDR/MPDG V002 
CIP SIGNATURE PAGE 
The present clinical investigation plan was subject to critical review and has been approved in the 
current version by the persons undersigned. The information contained is consistent with: 
 
the current risk-benefit assessment of the investigational medicinal device, 
 
the moral, ethical, and scientific principles governing clinical research as set out in the 
latest relevant version of Declaration of Helsinki, the principles of the ISO 14155:2020(E) 
and the applicable legal and regulatory requirements. 
Investigators will be supplied with details of any significant change of the benefit-risk-assessment 
of the clinical investigation. 
It will be ensured that the first subject is enrolled only after all ethical and regulatory requirements 
are fulfilled. Written consent from all subjects is received after detailed oral and written information 
and according to the requirements of local law (MPDG). According to MPDG §29 (1) it will be 
confirmed that all clinical investigation subjects will be informed on the type of encoding their 
personal data (pseudonymization) and who receives or has access to such data. Subjects who 
do not agree to this data encoding and transfer will not be enrolled into the clinical investigation. 
In this context it will be assured (according to Annex 15, Chapter II, 4.5 MDR 2017/745) that all 
investigational sites comply with the local regulatory requirements for data protection. 
According to §47 (1,4.) MPDG the Sponsor states that it is not planned to include subjects in a 
relationship of any dependence to the investigators or sponsor. 
Via current versions of the clinical investigation plan and the investigator’s brochure it will be 
ensured that all investigators are informed about the applicable general safety and performance 
requirements according to Annex I MDR. This includes the technical and biological safety testing 
and pre-clinical evaluation regarding the benefits and risks of the clinical investigation, as well as 
provisions in the field of occupational safety and accident prevention, taking into consideration 
the state of the art (MDR, Article 62 (4l)).  
 
Date: 
_________________ 
Signature: 
________________________ 
 
 
Name (Print Name): 
________________________ 
 
 
Function: 
Sponsor Representative  
 
 
 
 
Date: 
_________________ 
Signature: 
________________________ 
 
 
Name (Print Name): 
 
 
 
Function: 
Biometrician 
 
 
 
 
Date: 
_________________ 
Signature: 
________________________ 
 
 
Name (Print Name): 
 
 
 
Function: 
Author (Principal Investigator) 
 
 

CIP Code: BrainSTEADy 
BfArM Nr.: DE-24-00015271 
Clinical Investigation Plan 
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 based on appendix SOP-PM03-A-Protocol-MDR/MPDG V002 
INVESTIGATOR SIGNATURE PAGE 
I have read the above-mentioned clinical investigation plan and confirm that it contains all 
information to conduct the clinical investigation. I pledge to conduct the clinical investigation 
according to the clinical investigation plan, the principles of the ISO 14155:2020(E) and the 
applicable legal and regulatory requirements. 
I will enroll the first subject only after all ethical and regulatory requirements are fulfilled. I will 
obtain written consent for participation in the clinical investigation from all subjects after detailed 
oral and written information and according to the requirements of local law (MPDG). According to 
MPDG §29 (1), I declare that all clinical investigation subjects will be informed on the type of 
encoding their personal data (pseudonymization) and who receives or has access to such data. 
Subjects who do not agree to this data encoding and transfer will not be enrolled into the clinical 
investigation. In this context I confirm (according to Annex 15, Chapter II, 4.5 MDR 2017/745) that 
my investigational site complies with all local regulatory requirements for data protection. 
Furthermore, I declare (according to §47 (1,4.) MPDG) that to the best of my knowledge no 
subjects in a relationship of any dependence to the investigators or sponsor will be included. 
I know the applicable requirements for accurate notification of serious adverse events and I 
pledge to document and notify such events as described in the clinical investigation plan. 
I declare that I am informed about the applicable general safety and performance requirements 
according to Annex I MDR. This includes the technical and biological safety testing and pre-
clinical evaluation regarding the benefits and risks of the clinical investigation, as well as 
provisions in the field of occupational safety and accident prevention, taking into consideration 
the state of the art (MDR, Article 62 (4l)) by reading the description in the clinical investigation 
plan and in the current version of the investigator’s brochure (IB). I ensure that all investigators / 
relevant staff at my site will be informed of these results and possible new risks that are forwarded 
by the sponsor later on (e.g. via new version of the investigator’s brochure).  
I confirm that every staff will be adequately trained to guarantee compliance to the clinical 
investigation plan incl. subsequent modifications, the clinical investigation procedures and 
investigation specific duties and tasks. I will maintain a list specifying the tasks delegated to each 
team member. 
I will retain all investigation-related documents and source data as described. I will provide a 
Curriculum Vitae (CV) before start of the investigation. I agree that the CV and the Declaration of 
Interest may be submitted to the responsible EC. 
As the clinical investigation and the results have to be published in a clinical investigation register 
and forwarded to the EC and competent authority I agree that my name and clinic address will be 
part of this clinical investigation (summary) report / public register and are disclosed pursuant to 
§64 (3) MPDG. 
Date: 
_________________ 
Signature: 
________________________ 
 
 
Name (Print Name): 
________________________ 
 
 
Function: 
________________________ 
 
 
Investigational Site 
(Address) 
 
________________________ 
 
 
 
________________________ 
 
 
 
________________________ 
 
 

CIP Code: BrainSTEADy 
BfArM Nr.: DE-24-00015271 
Clinical Investigation Plan 
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 based on appendix SOP-PM03-A-Protocol-MDR/MPDG V002 
INVOLVED PARTIES 
Contact information of all parties involved, incl. all principal investigators, participating sites and 
institutions can be found in a central list. Relevant contact information will be provided to each 
site in the Investigator Site File.   
 
 

CIP Code: BrainSTEADy 
BfArM Nr.: DE-24-00015271 
Clinical Investigation Plan 
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 based on appendix SOP-PM03-A-Protocol-MDR/MPDG V002 
ADMINISTRATIVE INFORMATION 
 
Table of Content 
CIP SIGNATURE PAGE ............................................................................................................................... 3 
INVESTIGATOR SIGNATURE PAGE .......................................................................................................... 4 
INVOLVED PARTIES ................................................................................................................................... 5 
ADMINISTRATIVE INFORMATION ............................................................................................................. 6 
TABLE OF CONTENT .................................................................................................................................. 6 
CIP SYNOPSIS ............................................................................................................................................ 9 
SCHEDULE OF ASSESSMENTS .............................................................................................................. 14 
ABBREVIATIONS ....................................................................................................................................... 16 
1. 
INTRODUCTION ............................................................................................................................... 18 
1.1 
Neurofeedback-approach to Borderline Personality Disorder (BPD) ............................................ 18 
1.2 
Preclinical investigation ................................................................................................................. 18 
1.3 
Clinical investigation ...................................................................................................................... 19 
1.4 
Relevance of Neurofeedback RCTs (Randomized Controlled Trials) for Evidence of Specificity 19 
1.5 
Health economic effects of neurofeedback treatment in Borderline ............................................. 20 
1.6 
Neuroplasticity: Alterations of white matter structure .................................................................... 20 
1.7 
Dissociation in the Context of Amygdala-Neurofeedback ............................................................. 21 
1.8 
Neurofeedback and non-response to standard therapy ................................................................ 21 
1.9 
Clinical Investigation Rationale ..................................................................................................... 21 
1.9.1 
State-of-the-Art BPD treatment ............................................................................................. 21 
1.9.2 
Justification for this trial ........................................................................................................ 22 
1.9.3 
Expected Clinical Benefits .................................................................................................... 23 
1.9.4 
Expected Adverse Device Effects......................................................................................... 23 
1.9.5 
Residual Risks Associated with the Investigational Product ................................................ 23 
1.9.6 
Risks Associated with the Participation in the Clinical Investigation .................................... 24 
1.9.7 
Possible Interactions with Concomitant Medical Treatments ............................................... 24 
1.9.8 
Control or Risk Mitigation Strategies .................................................................................... 24 
1.9.9 
Justification of the Positive Risk-Benefit-Ratio ..................................................................... 24 
2. 
OBJECTIVES AND ENDPOINTS OF THE CLINICAL INVESTIGATION ......................................... 25 
2.1 
Primary Objective and Primary Endpoint ...................................................................................... 25 
2.2 
Secondary Objectives and Secondary Endpoints ......................................................................... 25 
2.2.1 
Main Investigation ................................................................................................................. 25 
2.2.2 
Accompanying Research ...................................................................................................... 26 
3. 
DESIGN OF THE CLINICAL INVESTIGATION ................................................................................. 27 
3.1 
Overall Clinical Investigation Design ............................................................................................. 27 
3.2 
Planned Interim Analysis ............................................................................................................... 28 
3.3 
Overall Duration of the Clinical Investigation ................................................................................ 28 
3.4 
Duration of Clinical Investigation for each Subject ........................................................................ 28 
3.5 
Definition of End of Investigation ................................................................................................... 30 
3.6 
Patient Involvement ....................................................................................................................... 30 
3.7 
Measures to Minimize Bias ........................................................................................................... 31 
3.7.1 
Randomization and blinding ................................................................................................. 31 
3.7.2 
Breaking the Blind ................................................................................................................. 31 
4. 
SUBJECT SELECTION ..................................................................................................................... 32 
4.1 
Number of Subjects and Sites ....................................................................................................... 32 
4.2 
General Criteria for Subjects’ Selection ........................................................................................ 32 
4.3 
Inclusion Criteria ............................................................................................................................ 32 
4.4 
Exclusion Criteria ........................................................................................................................... 32 
4.5 
Lifestyle Considerations ................................................................................................................ 33 
4.6 
Subject Assignment ....................................................................................................................... 33 
4.6.1 
Identification Numbers .......................................................................................................... 33 
4.6.2 
Screening Failures ................................................................................................................ 34 

CIP Code: BrainSTEADy 
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5. 
INVESTIGATIONAL DEVICE ............................................................................................................ 34 
5.1 
Description of the Investigational Device ...................................................................................... 34 
5.2 
Supplies of Investigational Device ................................................................................................. 34 
5.3 
Device Accountability and Traceability .......................................................................................... 34 
5.4 
Use of the Investigational Device .................................................................................................. 34 
5.5 
Specific Medical or Surgical Procedure Involved .......................................................................... 34 
5.6 
Comparative Devices .................................................................................................................... 34 
6. 
CLINICAL INVESTIGATION VISITS AND INVESTIGATIONS / ASSESSMENTS ........................... 35 
6.1 
Screening Visit / Baseline (T0), V1 ................................................................................................ 35 
6.2 
Baseline Visit (T0) continued, V2a ................................................................................................ 35 
6.3 
Neurofeedback 1-3 (V2b, V3, V4) ................................................................................................. 36 
6.4 
Interim weeks between Neurofeedback 3 (V4) and Neurofeedback 4 (V5a) ................................ 37 
6.5 
Neurofeedback 4, Post-assessment visit (T1), V5a ...................................................................... 37 
6.6 
Post-assessment visit (T1) continued, V5b ................................................................................... 37 
6.7 
Follow-up assessment 1 visit (T2), FUP1...................................................................................... 38 
6.8 
Follow-up assessment 2 visit (T3) ................................................................................................. 38 
6.9 
Planned Treatment after End of Investigation Participation .......................................................... 38 
6.10 Assessments ................................................................................................................................. 38 
7. 
DISCONTINUATION AND EARLY TERMINATION .......................................................................... 41 
7.1 
Temporary Discontinuation from Treatment .................................................................................. 41 
7.2 
Permanent Discontinuation from Treatment ................................................................................. 41 
7.3 
Discontinuation from the Clinical Investigation .............................................................................. 42 
7.3.1 
Withdrawal of Consent .......................................................................................................... 42 
7.3.2 
Loss to Follow-Up ................................................................................................................. 42 
7.4 
Temporary Halt .............................................................................................................................. 42 
7.5 
Early Termination of the Clinical Investigation .............................................................................. 43 
7.6 
Premature Closure of a Site .......................................................................................................... 43 
8. 
ADVERSE EVENTS .......................................................................................................................... 43 
8.1 
Definitions ...................................................................................................................................... 43 
8.1.1 
Adverse Event....................................................................................................................... 43 
8.1.2 
Serious Adverse Event ......................................................................................................... 44 
8.1.3 
Adverse Events of Special Interests ..................................................................................... 45 
8.1.4 
Device Deficiency ................................................................................................................. 45 
8.2 
Expectedness / Anticipatedness ................................................................................................... 45 
8.3 
Characteristics of Adverse Events ................................................................................................ 45 
8.3.1 
Grading of AEs...................................................................................................................... 45 
8.3.2 
Causal Relatedness .............................................................................................................. 45 
8.3.3 
Outcome of AEs .................................................................................................................... 47 
8.3.4 
Countermeasures ................................................................................................................. 47 
8.4 
Period of Observation and Documentation ................................................................................... 48 
8.5 
Investigator’s Vigilance related Reporting Obligations .................................................................. 48 
8.5.1 
Reporting of Serious Adverse Events ................................................................................... 48 
8.6 
Sponsor’s Vigilance related Reporting Obligations ....................................................................... 48 
8.6.1 
Sponsor’s Assessment (Second Assessment) ..................................................................... 48 
8.6.2 
Expedited Reporting to the National Competent Authority ................................................... 49 
8.6.3 
Periodic Reporting to the German Competent Authority (BfArM) ......................................... 49 
9. 
STATISTICAL PROCEDURES .......................................................................................................... 50 
9.1 
Definition of Population to be analyzed in the Clinical Investigation ............................................. 50 
9.2 
Analysis Variables ......................................................................................................................... 50 
9.3 
General Considerations ................................................................................................................. 50 
9.4 
Primary Analysis ............................................................................................................................ 50 
9.5 
Secondary Analyses ...................................................................................................................... 51 
9.6 
Interim Analyses ............................................................................................................................ 51 
9.7 
Sensitivity Analyses ....................................................................................................................... 52 
9.8 
Subgroup Analyses ....................................................................................................................... 52 
9.9 
Sample Size / Power Calculation .................................................................................................. 52 
10. 
DATA MANAGEMENT .................................................................................................................. 53 

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10.1 Data Collection and Handling ........................................................................................................ 53 
10.2 Data Cleaning and Quality Checks ............................................................................................... 53 
11. 
ARCHIVING AND STORAGE ....................................................................................................... 54 
11.1 Essential Records and Source Data ............................................................................................. 54 
11.2 Collection, Storage and Future Use of Biological Samples and Corresponding Data .................. 54 
12. 
REGULATORY, ETHICAL AND OVERSIGHT CONSIDERATIONS ........................................... 55 
12.1 Compliance Statement .................................................................................................................. 55 
12.2 Data Protection and Subject Privacy ............................................................................................. 55 
12.3 Approval of the Clinical Investigation ............................................................................................ 55 
12.4 Subject Information and Informed Consent ................................................................................... 55 
12.5 Committee Structure ...................................................................................................................... 56 
12.5.1 Data Safety Monitoring Board (DSMB) ................................................................................. 56 
12.6 Steering Committee (SC) .............................................................................................................. 56 
12.7 Insurance ....................................................................................................................................... 57 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 58 
13.1 Quality Assurance ......................................................................................................................... 58 
13.2 Monitoring ...................................................................................................................................... 58 
13.3 Source Documents ........................................................................................................................ 58 
13.3.1 Direct Access to Source Documents .................................................................................... 58 
13.4 Audits and Inspections .................................................................................................................. 59 
13.5 Deviations from the CIP (Protocol Deviations) .............................................................................. 59 
14. 
ADMINISTRATIVE AGREEMENTS .............................................................................................. 61 
14.1 Financing of the Clinical Investigation ........................................................................................... 61 
14.2 Financial Disclosure ...................................................................................................................... 61 
14.3 Publication Policy / Dissemination of Data of the Clinical Investigation ........................................ 61 
14.4 Registration of the Clinical Investigation ....................................................................................... 62 
14.5 Declaration regarding Data Sharing .............................................................................................. 62 
15. 
REFERENCES .............................................................................................................................. 63 
APPENDIX 1: LIST OF TECHNICAL AND FUNCTIONAL FEATURES OF THE INVESTIGATIONAL 
DEVICE ...................................................................................................................................................... 68 
APPENDIX 2: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................................ 72 
APPENDIX 2: INFORMED CONSENT AND RECRUITMENT PROCESS ................................................ 74 
APPENDIX 3: PROVISIONS REGARDING EXCEPTIONAL CIRCUMSTANCES .................................... 75 
 
 
 

CIP Code: BrainSTEADy 
BfArM Nr.: DE-24-00015271 
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 based on appendix SOP-PM03-A-Protocol-MDR/MPDG V002 
CIP SYNOPSIS 
Full Title 
A 
multi-center, 
patient-blind 
and 
investigator-blind, 
randomized, 
parallel-group, 
superiority 
study 
to 
investigate a neurobiological mechanism of affect 
instability, comparing four sessions of amygdala fMRI-
BOLD neurofeedback with sham feedback in Borderline 
Personality Disorder 
 
Deutsch: Eine multi-zentrische, patientenverblindete und 
prüferverblindete, randomisierte Parallelgruppen-Studie 
zur Erforschung eines neurobiologischen Mechanismus 
der Affektinstabilität, durch den Vergleich von vier 
Amygdala-fMRT Neurofeedback Sitzungen mit Sham-
Feedback bei der Borderline Persönlichkeitsstörung 
Clinical Investigation Code 
Brain Signal Training to Enhance Affect Down-regulation - 
BrainSTEADy 
Deutsch: 
BrainSTEADy 
- 
Hirnsignal-Training 
zur 
Verbesserung der Gefühlsregulation 
Rationale 
Individuals with Borderline Personality Disorder (BPD) 
experience intensive, instable negative emotions. 
Hyperactivity of the amygdala is assumed to drive 
exaggerated emotional responses in BPD. 
Neurofeedback is an endogenous neuromodulation 
method to address the imbalance of neural circuits. 
Downregulation of amygdala hyperactivation with 
neurofeedback may ameliorate dysregulated emotions in 
BPD. The BrainSTEADy trial is designed to determine 
whether amygdala-fMRI-BOLD neurofeedback has a 
specific effect on affect instability in BPD beyond 
nonspecific benefit. 
Primary Objective and Endpoint 
To 
determine 
whether 
amygdala-fMRI-BOLD 
neurofeedback has a specific effect on dysregulated affect 
in BPD beyond nonspecific benefit. The main hypothesis 
to be tested is whether downregulation training of 
amygdala activation with neurofeedback reduces the 
intensity of negative affect assessed before treatment (T0) 
as compared to after treatment (T1) and whether this 
change is greater in the treatment group as compared to 
the control group.  
Primary endpoint: 
Affect intensity, group difference of change from T0 to T1 
measured via experience sampling using ecological 
momentary assessment (EMA). 
Main Secondary Objectives and 
Endpoints 
To assess whether downregulation training of amygdala 
activation with neurofeedback reduces the intensity of 
negative affect assessed before treatment (T0) as 
compared to 3-months follow-up (T2). To assess symptom 

CIP Code: BrainSTEADy 
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severity and neural regulation success through fMRI-
neurofeedback. To investigate the reduction in health 
economic burden and an improvement in patient reported 
outcomes in terms of utilities, before treatment (T0) as 
compared to 6-months follow-up (T3). For all endpoints, 
we expect that the change is greater in the treatment 
group as compared to the control group. 
Secondary endpoints 
A) Affect intensity, group difference of change from T0 to 
T2.  
B) Borderline Symptom Severity, group difference of 
change from T0 to T1 and … 
C) … from T0 to T2, assessed with the Zanarini Rating 
Scale for BPD, interview version (ZAN-BPD).  
D) Amygdala response, group difference of change from 
T0 to T1.  
E) Amygdala self-regulation, group difference of change 
from T0 to T1 
F) Improvement in quality-adjusted life years (QALY), 
group difference of change from T0 to T3. 
Clinical Investigation Design 
Multi-centre, 
investigator-blinded, 
patient-blinded, 
placebo-controlled, randomised, parallel-group design, 
prospective study with 2 treatment groups. The individual 
treatment duration per patient is approximately 20 weeks 
from screening to 3-months follow-up, with a baseline 
visit, 4 Neurofeedback visits, and a post-assessment visit. 
A limited number of scales will be assessed at a second 
follow-up assessment 6 months after the post-
assessment. 
This is a two-staged trial with planned interim-analysis 
after inclusion of 50% of the full sample, and decision to 
continue recruitment dependent on the interim-analysis 
result. 
Sample Size 
Stage 1: 82 patients, stage 2: 82 patients 
Clinical Investigational Population Inclusion Criteria 
1. 18-65 years 
2. Diagnosis 
of 
Borderline 
Personality 
Disorder 
according to DSM-5 
3. Insufficient response to ≥2 therapies. The criterion is 
fulfilled if the patient reports: 
a) 
2 or more psychotherapy treatments with 12 
or more sessions each OR: 
b) 
2 or more psychotherapy treatments with a 
duration per treatment of at least 12 weeks 
OR: 
c) 
a 
medical 
history 
of 
2 
or 
more 
psychopharmaceutic treatments, each over 
the course of at least 4 weeks OR: 

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d) 
a combination of 2 or more treatments such 
as: 
i. 
psychotherapy with 12 or more 
sessions, 
ii. 
psychotherapy with a duration of 12 
weeks or longer, 
iii. 
psychopharmaceutic treatment over 
the course of at least 4 weeks. 
4. Sufficient German language skills to give informed 
consent to the study, to understand questions posed 
by used instruments, and capable of completing the 
fMRI tasks  
5. Ability of subject to understand character and 
individual consequences of clinical investigation 
6. Written informed consent (must be available before 
enrollment in the clinical investigation) 
7. For women of childbearing potential (WOCBP) 
adequate contraception (as defined in Appendix 2). 
 
Exclusion Criteria 
1. Treatment with benzodiazepines within 7 days prior 
the initial screening  
2. Current moderate or severe alcohol or substance use 
disorder within 1 month prior the initial screening 
3. Meeting the diagnostic criteria for a psychotic disorder 
or schizophrenia (life-time), as determined by clinical 
interview at initial screening  
4. Current or history of significant neurological condition 
(such as stroke, traumatic brain injury, space 
occupying lesions, multiple sclerosis, Parkinson’s 
disease, vascular dementia, transient ischemic 
attack) 
5. Significant visual impairment that might interfere with 
the performance of the behavioural tasks or fMRI 
tasks  
6. Change 
of 
treatment 
(psychopharmacologic, 
psychological) 2 weeks prior to or during the study 
participation 
7. Treatment with any neurofeedback other than 
investigational device three months prior to or during 
the study participation. 
8. Unable or unwilling to comply with study procedures, 
including study prohibitions and restrictions  
9. History of claustrophobia or inability to tolerate 
scanner environment 
10. Fulfilling any of the MRI contraindications on the 
standard site radiography screening questionnaire 
(e.g. history of surgery involving metal implants) 
11. Clinically relevant structural brain abnormality as 
determined by prior MRI scan  

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12. Planned medical treatment within the study period 
that might interfere with the study procedures 
13. Participants deemed to be at significant risk of serious 
violence or suicide based on any one of the following: 
a. Significant risk of committing violent acts, homicide, 
or suicide based on history, routine psychiatric 
status examination, or according to the investigator’s 
experience OR 
b. Any suicide attempt in the past 3 months (i.e., actual 
attempt, interrupted attempt, aborted attempt) prior 
to screening and during the screening period OR 
c. Any suicidal ideation of type 4 or 5 in the C-SSRS in 
the past 3 months prior screening or during the 
screening period. 
14. BMI of 16.5 or lower 
15. Participation in other clinical trials or observation 
period of competing trials, respectively 
16. Previous participation in this trial (Re-Screening 
possible, c.f. Chapter 4.6.2) 
17. Pregnancy and lactation 
18. Held in an institution by legal or official order 
19. Legally incapacitated. 
Interventions and Treatments 
Experimental intervention: Real-time fMRI neurofeedback 
from amygdala’s blood oxygenation level dependent 
(BOLD) signal + negative emotional picture viewing. 
Instruction to regulate feedback via down-regulation of 
one’s emotional response. Neurofeedback is a class I 
device manufactured by BrainInnovation (Maastricht, 
Netherlands). 
Control intervention: Yoked feedback + negative 
emotional picture viewing. Instruction to regulate 
feedback via down-regulation of one’s emotional 
response. 
Duration of intervention per patient: Four training sessions 
within 4 weeks. 
Diagnostic instruments: International Personality Disorder 
Interview (IPDE), Structured Clinical Interview for DSM-5 
(SCID-5) 
Ethical Considerations 
Risk-analysis has been conducted according to ISO 
14971 and measures mitigating identified risks have been 
implemented successfully. Risks of neurofeedback using 
the 
software 
Turbo-BrainVoyager 
MED 
Borderline 
Personality Disorder (TBV MED BPD) have been 
weighted against those from alternative treatments and 
non-treatment, 
taking 
into 
account 
benefits 
from 
neurofeedback that were identified with literature analysis. 
Overall, the result of the risk-benefit analysis is positive. 
Mitigation measures were successfully implemented by 
the software developer and are reflected in the 

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investigator’s brochure and in this document wherever 
necessary. 
Constant 
monitoring 
of 
risks 
will 
be 
implemented during conductance of the trial. Thus, the 
clinical trial is in line with ethical standards devised by ISO 
14155. 
Number of Sites 
6 
Trial duration 
Total trial duration: 
 
 
 
48 months 
Duration of clinical phase: 
 
 
36 months 
Beginning of the preparation phase:  
Q2 2024 
FSI (first subject in) stage 1:  
 
Q2 2025 
LSI (last subject in) stage 1:  
 
Q3 2026 
LSO (last subject out) stage 1: 
 
Q1 2027 
FSI stage 2:                                                  Q3 2026 
LSI stage 2: 
 
 
                       Q3 2027 
LSO stage 2:  
                                   Q1 2028 
DBL (database lock):  
 
 
Q1 2028 
Statistical analyses completed: 
 
Q2 2028 
Trial report completed: 
 
 
Q3 2028 
Financing 
Deutsche Forschungsgemeinschaft (PA 3107/4-1, SCHM 
1526/26-1) 
 

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SCHEDULE OF ASSESSMENTS 
 Week in trial 
  
0-2 
1-4 
2-5 
3-6 
4-7 
5-8 
6-10 
18-22 
30-34 
Visit 
 
 
V1 
V2a 
V2b 
V3 
V4 
 
 
 
V5a 
V5b 
FUP1 
FUP2 
Description 
Screening 
Baseline- 
assess- 
ment (T0) 
part 1 
Baseline- 
assess- 
ment (T0) 
part 2, 
Neurofeed- 
back 1 
Neurofeed- 
back 2 
Neurofeed- 
back 3 
Interim 
week 1 
Interim 
week 2 
Interim 
week 3 
Neurofeed- 
back 4, 
Post-assess- 
ment (T1) 
part 1 
Post-assess- 
ment (T1) 
part 2 
Follow-up  
(T2) 
Follow-up  
(T3) 
Procedures ↓ 
  
  
  
  
  
 
 
 
  
  
  
  
Informed consent, 
eligibility  
(incl. SCID, IPDE, C-
SSRS, medical history, 
concomitant medication), 
demography 
x 
  
  
  
  
 
 
 
  
  
  
  
Randomisation 
 
x 
 
 
 
 
 
 
 
 
 
 
Pregnancy test, if 
applicable 
 
 
x 
x 
x 
 
 
 
x 
 
 
 
Assess last menstruation, 
if applicable 
x 
 
x 
x 
x 
 
 
 
x 
x 
 
 
fMRI-neurofeedback 
  
  
x 
x 
x 
 
 
 
x 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
DTI 
  
  
 x 
x 
 
 
 
 
x  
  
  
  
EMA  
(Smartphone-based 
assessment) 
  
x 
  
  
  
 
 
 
  
x 
x 
  
AE/SAE 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 

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Questionnaires & 
interviews ↓ 
  
  
  
  
  
 
 
 
  
  
  
  
AQoL-6D 
 
x 
  
  
  
 
 
 
  
  
  
x 
BSL-23 
x  
x 
  
  
  
 
 
 
  
x 
x 
x 
BDI 
x  
 
  
  
  
 
 
 
  
x 
x 
x 
Blind check 
 
 
 
 
 
 
 
 
 
x 
 
 
CGI 
x 
 
 
 
 
 
 
 
 
x 
 
 
Concluding questionnaire 
 
 
 
 
 
 
 
 
 
x 
 
 
DERS-36 
x 
 
  
  
  
 
 
 
  
x 
x 
x 
DES 
x 
  
  
  
  
 
 
 
  
  
  
  
DSS-4 
 
 
x 
x 
x 
 
 
 
x 
 
 
 
DSS-acute 
 
x 
  
  
  
 
 
 
  
x 
x 
x 
FimPsy 
x 
 
  
  
  
 
 
 
  
  
  
x 
MSQ-NF 
 
 
x 
x 
x 
 
 
 
x 
 
 
 
PCL 
 
x 
  
  
  
 
 
 
  
  
  
  
RSQ 
 
x 
 
 
 
 
 
 
 
 
 
 
SCL-27 
x 
 
 
 
 
 
 
 
 
x 
x 
x 
Survey of NF transfer 
 
 
 
 
 
x 
x 
x 
x 
 
 
 
WPAI:GH 
x 
  
  
  
  
 
 
 
  
  
  
x 
ZAN-BPD 
x 
 
  
  
  
 
 
 
  
x 
x 
  
 
All measures are study specific. For a detailed overview of planned timing of procedures and allowed flexibility of visit scheduling and data collection 
ref. to Chapter 3.4 Figure 5, Patient Time Flow 
 

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ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADL 
Activities of Daily Living  
AE 
Adverse Event 
AESI 
AE of Special Interest 
AQoL-6D  
Assessment of Quality of Life 
ASADE 
Anticipated serious adverse device effect 
ASQ 
Ages & Stages Questionnaire 
BDI 
Beck Depression Inventory 
BOLD 
Blood-oxygenation-level-dependent 
BPD 
Borderline Personality Disorder 
BSL-23  
Borderline Symptom List, short version 
CGI 
Clinical Global Impression 
CIMH 
Central Institute of Mental Health 
CIP 
Clinical Investigation Plan 
CIOMS 
Council for International Organizations of Medical Sciences 
CRO 
Clinical Research Organization 
CRF 
Case Report Form 
CRP 
Clinically Relevant Parameter 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CV 
Curriculum Vitae 
DBL 
Data Base Lock 
DBT  
Dialectal Behavioral Therapy 
DD 
Device Deficiency 
DERS 
Difficulties in Emotion Regulation Scale 
DES 
Dissociative Experiences Scale 
DiMIS 
Diversity Minimal Item Set 
DMP 
Data Management Plan 
DSMB 
Data Safety Monitoring Board 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSS 
Dissociation-Tension-Scale 
DTI 
Diffusion Tensor Imaging 
DVP 
Data Validation Plan 
eCRF 
electronic Case Report Form 
EMA 
Ecological Momentary Assessment 
EU 
European Union 
FA 
Fractional anisotropy 
FAS 
Full Analysis Set 
FimPsy 
 Fragebogen zur Inanspruchnahme medizinischer und nicht medizinischer 
Versorgungsleistungen bei psychischen Erkrankungen (Questionnaire for the 
Assessment of Medical and non Medical Resource Utilisation in Mental Disorder) 
fMRI 
Functional Magnetic Resonance Imaging 
FSI 
First Subject In 
FUP 
 Follow-up 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICH 
International Council on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
ICH GCP 
ICH harmonized tripartite guideline on GCP 
IEC 
Independent Ethics Committee 
IFU 
Instruction for Use 
IIT 
Investigator-Initiated Trial 
INR 
International Normalized Ratio  
IPD 
Individual Participant Data 
IRB 
Independent Review Board 
ISF 
Investigator Site File 
ISO 
International Organisation for Standardisation 

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ISRCTN 
International Standard Randomized Controlled Trial Number 
ITT 
intent-to-treat 
KKS 
 Coordination Centre for Clinical Trials (Koordinierungszentrum für Klinische 
 
Studien) 
LDR 
Legally Designated Representative 
LKP 
Coordinating Investigator according to MPDG (Leiter der Klinischen Prüfung) 
LSLV 
Last Subject Last Visit 
MD 
Medical Device 
MDR 
Medical Device Regulation 
MPDG 
 Medizinprodukterecht-Durchführungsgesetz 
(German 
Medical 
Device 
Implementing Act) 
MSQ-NF 
Mental State Questionnaire 
NF 
Neurofeedback  
PCL  
Paranoia Checklist 
PD 
Protocol Deviation 
PI 
 Principal Investigator 
PRB 
 Patient Review Board 
PV 
Pharmacovigilance 
Q 
 Quarter (time span) 
RCT 
Randomized Clinical Trial 
RDE 
 Remote Data Entry 
SADE 
 Serious Adverse Device Effect 
SAE 
 Serious Adverse Event 
SC 
 Steering Committee 
SCID-5  
Structured Clinical Interview for DSM-5 
SMD 
Standardized Mean Difference 
SOP 
Standard Operating Procedure 
SPM 
Standard Progressive Matrices 
VAS 
Visual analogue scale  
TBV MED BPD 
Turbo-BrainVoyager MED Borderline Personality Disorder 
TMF 
 Trial Master File 
USADE 
 Unanticipated Serious Adverse Device Effect 
ePRO 
Electronic Patient-Reported Outcomes 
WM 
White matter 
WPAI:GH 
Work Productivity and Activity Impairment Questionnaire: General Health 
WOCBP 
Women of Childbearing Potential 
ZAN-BPD 
Zanarini-Rating-Scale for BPD 
 
 

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1. 
Introduction 
1.1 
Neurofeedback-approach to Borderline Personality Disorder (BPD) 
Research on the point prevalence of BPD in adults converges to a rate of 1-3 % in nonclinical 
samples1. Lifetime suicide rates are very high2. Psychotherapy programs tailored to BPD are 
effective, although there is need to increase the effectivity and stability of treatment effect 3. BPD 
is a disabling condition, associated with high individual suffering and high costs for health care 
and social security systems – comprising approximately 15% of all costs for psychiatric disorders 
in Germany4. Total societal cost-of-illness per BPD patient in the year preceding a standard 
psychotherapeutic treatment, Dialectical Behavior Therapy (DBT), amounted to 31.130 € 5. 
Individuals with BPD compared to healthy controls experience highly negative emotions6. Their 
affect is characterized by high instability 6, a decreased response threshold, and a slow return to 
baseline7. This is reflected in a hyper-response of the amygdala to pictures with emotional 
content8. Current psychobiological models of BPD postulate an imbalance between 
hypersensitive emotional brain systems such as the amygdala and hypo-active “emotion 
regulation systems”, encompassing the medial and dorsolateral prefrontal cortex. This makes 
individuals with BPD vulnerable to intense emotions, for which they compensate with 
dysfunctional regulation behaviors (e.g. non-suicidal self-injury), leading to frequent medical 
treatment, social turbulences and negative emotions against the self. Accordingly, the proposed 
trial is strongly rooted in current psychobiological theory. While patients lie in the MRI machine 
and view pictures with aversive content, they see a live-display of their neural response, called 
NF. Changing neural response patterns via NF training may change dysfunctional behaviors that 
arise from abnormal neural functioning. We suppose that an alteration of a neural process, i.e. 
amygdala hyper-responding, will have effects on the related psychological process, i.e. emotion 
processing, and change affective experience. We therefore ask the question: Does NF improve 
affect intensity via the modulation of neural responding to emotional cues? 
1.2 
Preclinical investigation 
148 of the 365 original research publications used Turbo-BrainVoyager (TBV), with 94 of these 
studies targeting healthy participants and 54 studies targeting clinical populations. Two of the 
clinical publications using fMRI neurofeedback focused on BPD. TBV is used in 41% of the 365 
original studies. In 8 of the 148 studies (5%) using TBV, side effects have been reported (Table 
7 of the Literature Search Report provided by BrainInnovation, version BPD-CE-REC-Literature-
search-report-TBV-Med-BPD_20240709). This is slightly below the percentage of side effects 
found in all studies (6%: 23 of 365). In all cases, the side effects are mild and did often occur in 
the non-experimental group as well or only in the control group. 
In most cases, light side effects were due to the use of MRI; the mentioned effects were for 
example sleepiness, fatigue, headache, nausea, drowsiness and, for some tinnitus patients, 
concern about noise. Another category of side effects were slight increase of symptoms 1) in 
low/non-responders, like motor decrease in Parkinson’s Disease patients 2) after a certain period 
(worse mood on 3rd day in schizophrenia patients) 3) when targeting the wrong region-of-interest 
(intraparietal region for depressed patients) 4) in the control group, for example self-injurious 
behaviour in PTSD patients. Finally, there were unrelated side effects, such as a case of non-
lethal overdose of paracetamol in the control group (alcohol dependence patients) or “frustration 
with the questionnaire”, which is not relevant to either the use of TBV MED BPD, neurofeedback 
or MRI. No side effects seem to have been observed where the amygdala served as target region. 
The reported side effects and adverse events demonstrate that it is a safe, risk-free device. The 
reported results also show that it is a beneficial device. 

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1.3 
Clinical investigation 
While NF is an established medical procedure used for decades for treating mental disorders, 
real-time fMRI has only become available for NF training around the turn of the millennium9. More 
and more studies investigate the utility of fMRI-NF to train emotion regulation, both in healthy 
samples and in patient populations10. The amygdala has been targeted by a number of NF studies 
to treat disorders of emotion and mood in BPD11,12, Posttraumatic Stress Disorder13,14 and MDD15. 
A meta-analysis assessed amygdala 
regulation across nine studies that 
compared amygdala-NF to a control 
treatment16. The results show a high 
aggregated 
effect 
size 
(Cohen’s 
d=0.75, Figure 1) confirming improved 
amygdala 
regulation 
in 
treatment 
groups compared to control groups. 
Due to the novelty of the real-time fMRI-
NF method, clinical RCTs are still an 
exception in this field. BPD pilot studies 
indicate that NF has the potential to 
change emotion processing at several 
levels, 
including 
psychophysiology, 
behavior and subjective experience. In 
a four-session fMRI amygdala-NF 
training, administered to eight female patients with BPD, we had observed down-regulation of 
amygdala activation and increased functional connectivity between the amygdala and prefrontal 
cortex11. While this study demonstrated feasibility and was well tolerated by patients who 
participated in a DBT-based psychotherapy program in parallel, the second study extends 
previous findings12. In this study we investigated which aspects of emotion dysregulation would 
be malleable by NF. Twenty-five female BPD patients participated in three NF sessions and were 
tested again six weeks later. For inclusion, patients needed to be on constant medication or 
outpatient treatment throughout the study period. Emotion regulation was assessed on the 
physiological, behavioral and self-report level. After training, patients reported reduced negative 
affect intensity (Cohen’s d=0.71, P<0.05). BPD symptoms were reduced, too (ZAN BPD, d=0.65, 
P<0.05). In the psychophysiology lab, patients revealed improved emotion regulation skills after 
training, indicated by decreased startle responses to negative pictures (P<0.05). This study 
revealed significant improvement in emotion regulation and reductions in affective intensity in 
daily life after fMRI-NF in BPD.To retain stability of training effects, additional ‘booster’ sessions 
may be beneficial. Conclusions are limited due to the lack of control groups in these studies. An 
ongoing open-label, preregistered trial (NCT04333888) aims to assess feasibility and training 
effects in a psychotherapy setting including a no-NF control group. This research will inform 
potential clinical effects, but is not designed to show specificity of amygdala NF (vs. feedback 
from another bio-signal). A blinded RCT is needed to confirm efficacy. 
1.4 
Relevance of Neurofeedback RCTs (Randomized Controlled Trials) for 
Evidence of Specificity 
The assumed mechanism of NF is that changing a neural process will change related cognitions 
and behaviors. While this model is widely accepted, non-specific effects may mediate NF 
treatment outcomes as well17. The current state of evidence is best represented by a synthesis-
model of both NF specific and non-specific factors accounting for psychosocial and placebo 
mechanisms18. To show that amygdala-NF is effective, it is necessary to control for non-specific 
factors in a RCT design. A widely used approach in NF trials is not to provide participants in the 
 
Figure 1. Meta-analysis of amygdala regulation with 
neurofeedback. 

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control group with their own feedback signal. Instead, a signal of another participant (‘yoked 
feedback’) is presented19. Advantages of yoked feedback: a) the matching of the amount of 
reward received by both groups and b) unforeseen training effects are excluded that could be 
induced by other, conservative control conditions such as the training of alternative signals (e.g. 
different brain region). Although the risk of patient unblinding with non-contingent feedback has 
been raised and will be monitored in this project, many studies found that participants remained 
unaware that they had received yoked feedback19.  
1.5 
Health economic effects of neurofeedback treatment in Borderline 
BPD is one of the burdensome and costly illnesses in the German health care system. The total 
annual costs of BPD (including loss of productivity) amounted to €31,130 per person22. BPD 
causes higher treatment costs than other mental disorders, combined with higher utilization of 
healthcare services23. The individual burden of illness in BPD is very high and is characterized by 
a marked tendency towards hospitalization, increased somatic comorbidity, increased mortality 
and severe constraints on the social integration, on the employment and occupational situation. 
Therefore, it is important to evaluate the impact of different therapeutic treatments on costs and 
effects for people with BPD. Currently, knowledge of health economic effects of therapeutic 
procedures in BPD is very limited. We aim to assess the health economic impact of 
neurofeedback in BPD from a societal perspective. Therefore, we measure utilization of 
healthcare services, medication, remedies (direct cost), loss of productivity (indirect costs) and 
estimate costs of neurofeedback treatment (micro-costing) and measure utilities (i.e. quality 
adjusted life years, QALY) to calculate incremental cost-effectiveness ratios (ICER) and the net-
monetary benefit (NMB).  
1.6 
Neuroplasticity: Alterations of white matter structure  
Alterations in functional and structural connectivity have been found to play an important role in 
the development of borderline personality disorder (BPD)24–26. To date, only few and mostly small 
diffusion tensor imaging (DTI) studies have been conducted investigating white matter (WM) 
microstructure or connectivity in patients with BPD27,28. Although the results of previous studies 
are not universally consistent, there is some converging evidence of differences in WM pathways 
of the prefronto-limbic system including the orbitofrontal and anterior cingulate regions as well as 
the corpus callosum and fornix29–38. These results are interpreted as supporting the fronto-limbic 
dysfunction hypothesis of BPD35,36 and were found to be related to BPD-related symptoms such 
as anger or affective instability31. 
A fronto-limbic disconnection would explain the observed deficits in emotion and amygdala 
regulation38,39 and may be partly responsible for the hyperreactivity of the amygdala to negative 
affective stimuli in BPD, as reported in various studies including a meta-analysis8,40. 
We therefore hypothesize that differences in the WM structure of fronto-limbic pathways in 
individuals with BPD may have an impact on their emotion regulatory abilities and consequently 
on their individual success in affect regulation following amygdala neurofeedback training. This 
project will be conducted as a sub-project of the BrainSTEADy clinical trial. 
In addition to differences in DTI measures that may be predictive of treatment success, DTI allows 
tracking of learning-related neuroplasticity41. Effects on functional amygdala-prefrontal 
connectivity following neurofeedback training have been reported earlier42. However, it remains 
unknown what neuroplastic effects neurofeedback training has on the targeted structure 
(amygdala) itself as well as on structures that exert a regulatory influence on the amygdala (e.g. 
prefrontal regions and hippocampus). A recent neurofeedback study43 on regulating the activity 
of sensorimotor cortices showed rapid effects on WM structure measured with DTI. In a sham- 
controlled neurofeedback study, healthy individuals performed a motor imagery task (1 h) and 
showed increased fractional anisotropy (FA) in sensorimotor segments of corpus callosum. 

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Changes in the mean diffusivity (DTI) of grey matter structures are well-established in memory 
research, where plasticity sets in rapidly after learning41,44,45 and is known to persist for at least 
several days. 
1.7 
Dissociation in the Context of Amygdala-Neurofeedback 
If the main project confirms that fMRI-NF is an efficacious tool for treating BPD symptoms it will 
be important to define its role in BPD care. In particular, it will be interesting to see whether i) 
fMRI-NF works for patients who do not respond well to traditional treatments such as DBT and ii) 
to study the potential of a rational combination of psychotherapeutic approaches and fMRI-NF.  
High levels of dissociation emerged as a predictor of poor response to psychotherapies 
addressing BPD46,47 and in naturalistic studies including BPD patients (e.g., 48). Furthermore, 
there seems to be a subgroup of patients who tend to show consistent dissociation during DBT 
sessions49. However, it is unknown whether dissociation moderates the outcome to fMRI-NF. As 
successful fMRI-NF relies on learning which is known to be hampered by dissociation50 it is 
plausible that patients who tend to dissociate profit less from fMRI-NF than those who tend to 
show less or no symptoms of dissociation. On the other hand, fMRI-NF is targeting mechanisms 
associated with dissociation while circumventing elements of psychotherapies that might trigger 
dissociation. Hence, fMRI-NF might emerge as a much needed tool for diminishing dissociation 
proneness in a difficult to treat subgroup of patients. Actually, previous studies 11,12 found medium 
(not significant) to large (statistically significant) reductions of dissociation after amygdala fMRI-
NF. However, this finding is awaiting confirmation from an RCT. While of clinical relevance, the 
interplay between dissociation and amygdala fMRI-NF has not sufficiently been investigated.  
1.8 
Neurofeedback and non-response to standard therapy 
Woodbridge et al.51 identified factors contributing to non-responding to psychotherapy in patients 
with a diagnosis of BPD. They found attachment style and high levels of paranoid symptoms to 
be indicators of therapeutic success. Patients with preoccupied attachment patterns in their adult 
relationships were more likely to be non-responders regarding BPD symptoms after 12 month of 
psychotherapy and were more likely to be non-responders regarding general psychological 
distress at follow up. Patients with a high baseline level of paranoia and a dismissive adult 
relationship style had a higher risk of being non-responders with regard to global functioning51. 
Landes et al.52 examined predictors of dropout from Dialectical Behavior Therapy (DBT), which is 
currently the gold standard of treatment, in a community mental health setting. Results of a logistic 
regression showed that younger age, higher levels of baseline distress, and a higher level of 
baseline non-acceptance of emotional responses were significantly associated with dropout52. It 
is comprehensible, that those factors make it difficult to establish a reliable attachment in the 
psychotherapeutic setting or to follow a psychotherapy continuously. Hence, an alternative 
treatment might be of special value for patients fulfilling those criteria for a high risk of not 
responding to psychotherapy or not completing DBT.  
1.9 
Clinical Investigation Rationale 
1.9.1 
State-of-the-Art BPD treatment 
Psychotherapy is the first-choice treatment of BPD53. Treatment with BPD-specific psychotherapy 
programs is more effective as compared to standard psychotherapy treatment for the 
improvement of symptom severity, psychosocial functioning, self-injurious behavior and suicidal 
behavior. Evidence-based treatments are structured programs that have been tailored to meet 
the specific needs of persons suffering from BPD. They are based on Cognitive Behavior Therapy 
(CBT) and psychodynamic psychotherapy. Pivotal aspects to consider in BPD therapy as 
compared to the treatment of other mental disorders is the focus on the therapeutic relationship 

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and the treatment of self-injurious behavioral tendencies including suicidal behavior. Dialectical 
Behavior Therapy (DBT) and Mentalisation Based Therapy (MBT) are the most researched 
diagnosis-specific treatment programs for BPD. The treatment period is between 6 months and 2 
years. About one third of patients reached the state of remission after 12 months in BPD-specific 
treatment. Those with BPD presenting strong self-injurious behavior (including suicidal as well as 
non-suicidal self-injury) should be treated with DBT or MBT. Usual treatment plans include at least 
one session per week. As in DBT, group psychotherapy sessions are part of the treatment plan 
and are to be given additionally to single therapy sessions. In case no single-therapy is available, 
patients should be offered to start treatment with BPD-specific group sessions (e.g. Skills-
Training).  
There is not sufficient evidence for the effectiveness of medication on BPD symptoms. Patients 
with BPD should not be treated primarily with medications. However, medications may be used 
to treat comorbid mental disorders or psychiatric symptoms in line with current guidelines as part 
of a coherent treatment plan. For example, on-demand medication may be prescribed for suicidal 
crises, when psychotherapeutic treatment alone is not sufficient. The risk of substance 
dependence and overdosing should be considered critically when determining the type of 
medication. Psychotherapy should not be replaced by medication as standard treatment of BPD. 
Other symptoms or comorbid psychiatric disorders need to be considered during BPD treatment 
and should be integrated in the treatment plan.  
Outpatient treatment is preferable, although short-term in-patient treatment may be necessary for 
crisis intervention. Alternatively, patients may seek a residential BPD-specific treatment program 
if outpatient treatment is not available or if the in-patient setting is deemed preferable. However, 
longer in-patient clinic treatments without a structured, BPD-specific treatment program should 
be avoided. Care givers and teams who treat patients with BPD should be trained in an empirically 
validated BPD-specific program and should be supervised regularly. 
1.9.2 
Justification for this trial 
As reviewed above, previous NF-studies with BPD showed promising improvements in symptoms 
and emotion regulation skills. Adverse device-related effects have not been reported. Access to 
effective BPD treatment is limited, because the capacity of qualified therapists and of clinical 
settings meeting above mentioned specific requirements is limited. As a result, patients wait half 
a year and sometimes even longer until they can start therapy sessions. If effective, 
neurofeedback could be offered to patients during this waiting phase. Otherwise, neurofeedback 
could be integrated in the treatment plan to support the training of emotion regulation skills or to 
reduce the general stress level of patients. As emotion regulation training is a major building block 
of BPD-specific treatment programs such as DBT, neurofeedback could be offered to patients 
that will likely benefit from extra-sessions – for example, patients with pronounced dissociation 
tendencies or patients with difficulty engaging in therapeutic lessons. If supported by research, 
neurofeedback could be a treatment option for patients who did not benefit from other treatment. 
The low dosage required for fMRI-NF (clinically significant changes after 2 sessions of NF training 
were observed in a previous RCT15) speaks in favor of future usage in health care. Treatment 
costs are competitive (about 350 € per fMRI session and 3-4 sessions per treatment, if they can 
help to significantly reduce costs for residential as well as outpatient psychotherapy treatment. 
Although availability of MRI scanners is still limited, an increasing number of psychiatric hospitals 
have access to MRI. Hence, fMRI-NF may become a treatment option for many psychiatric 
patients in Germany in the near future. While the precise role of fMRI-NF in standard BPD care 
will be determined in clinical practice, it may be especially suited for treatment resistant patients. 
Therefore, the proposed project will focus on patients who have not responded sufficiently to prior 
conventional treatments. Taken together, fMRI-NF is assumed to be low-risk, demonstrably 
precise and fast acting, and arguably provides a positive cost-benefit ratio. Amygdala-NF could 

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be used to change neural patterns associated with psychopathological states, to meet special 
needs of patients with emotion dysregulation. 
1.9.3 
Expected Clinical Benefits 
The following clinical benefit is claimed for medical device software TBV MED BPD. For some of 
the BPD patients, psychopathology, emotion dysregulation, and affective instability may improve. 
This includes self-reported experience in everyday life12. Other research found that 37% (of a very 
small sample) of the BPD patients were able to downregulate the right amygdala11; it is also 
possible that the connectivity between the amygdala and lateral prefrontal cortex is modified; 
additionally, a `lack of emotional awareness' score may decrease. 
Schmahl, Niedtfeld & Herpertz54 indicate that BPD occurs frequently, with 15-20% of patients in 
psychiatric hospitals consisting of BPD patients, and up to 15% of visits made by BPD patients. 
Also, Babaskina et al55 mention that psychotherapy for patients with personality disorders can be 
challenging “because of their unstable emotions, anger, impulsivity, and poor interpersonal skills“. 
Therefore, even though more evidence is needed, it may be good not to exclude fMRI 
neurofeedback as supplement on beforehand due to lack of evidence. 
At the same time, although side effects of NF for BPD patients have not occurred, researchers 
need to explicitly focus on any potential side-effects, due to the high mortality rate (8-10%) from 
suicide of people with BPD56. 
Personalization might be a strategy to improve the effectiveness of the treatment, since 
Babaskina et al55 expect that personalization will increase the success of neurofeedback training 
for personality disorders, with the suggestion that machine learning methods could be used for 
personalizing neurofeedback protocols. 
We conclude that TBV MED BPD can be a beneficial supplement for treatment of Borderline 
Personality Disorder. 
1.9.4 
Expected Adverse Device Effects 
None 
1.9.5 
Residual Risks Associated with the Investigational Product 
Clinically relevant parameters (CRPs) are established to be able to demonstrate the general 
safety and performance of the device as well as the claimed benefit of the device and to prove 
the device-specific claims. 
1.9.5.1 
Safety Parameters 
Based on the Literature Search Report (provided by BrainInnovation, version BPD-CE-REC-
Literature-search-report-TBV-Med-BPD_20240709), we formulate the clinically relevant 
parameters (CRPs) concerning safety as based on patient health and device safety. The CRPs 
that demonstrate the safety of TBV MED BPD are as follows: 
• 
Mortality (pre-clinical data): 0 reported 
• 
Amount of light adverse events, mostly related to MRI and less to neurofeedback itself: 
6% (see elsewhere in text) 
• 
Amount of severe adverse events: 0 reported 
• 
Device malfunctions per year: 0 or close to 0 
1.9.5.2 
Performance Parameter 
The CRP that demonstrate the performance of TBV MED BPD is as follows: 

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• 
Minimally relevant difference (MIREDIF). For BPD symptom severity the current 
version of the Cochrane Review „identified a MIREDIF of −3.0 points on the ZAN-
BPD”3. 
1.9.6 
Risks Associated with the Participation in the Clinical Investigation 
Based on the extensive analysis of potential adverse events (see 1.2 Preclinical investigation), 
there has been no reports of worsened symptoms or any other severe adverse events. 
1.9.7 
Possible Interactions with Concomitant Medical Treatments  
Interactions of neurofeedback with medications have not been reported systematically in the 
literature. It can be assumed that medications that can potentially affect attention, learning and 
memory could have a disadvantageous effect on the neurofeedback training outcome.  
1.9.8 
Control or Risk Mitigation Strategies 
To mitigate potential medication interactions, ongoing treatment with Tranquilizers and with 
substances that were proven to inhibit dopamine functioning in the brain are prohibited in this trial. 
1.9.9 
Justification of the Positive Risk-Benefit-Ratio 
The safety CRPs indicate that the expected mortality risk, risk of adverse events and device 
malfunction are very low when using TBV MED BPD. The performance CRP suggests that BPD 
patients may either not respond to this supplementary treatment, but will in that case not 
experience harmful effects, or BPD patients do experience beneficial effects. These beneficial 
effects can consist of decreased activity of the amygdala, possibly increased connectivity in 
circuits where the amygdala is involved and possible reduction of BPD symptoms. 
Since the total clinical population was small, consisting of about 34 patients, it is not clear how 
these results extrapolate to a wider patient population, but thus-far the results for BPD patients 
seem slightly promising for neurofeedback by TBV MED BPD. 
Based on the findings from literature, pre-clinical data as well as risk analysis, it can be inferred 
that the probability of a patient experiencing benefit when using TBV MED BPD outweighs the 
probability of suffering harm due to a residual risk of the device. Therefore it can be concluded 
that TBV MED BPD represents a safe addition to the portfolio of available treatments for 
Borderline Personality Disorder symptoms as a potential additional or supporting non-first-line 
approach. Due to the potential costs of this additional MRI neurofeedback treatment, further 
research would be beneficial in determining individuals who would benefit most of this treatment. 
Also, due to the high risk of self-harm (suicide 8-10%56), carefully monitoring the treatment is of 
utmost important, especially for the non-responders, since in non-responders of some other 
patient groups (disruptive behaviour) symptoms worsened (increased agression). Given the 
challenges providing psychotherapy to patients with personality disorders55 and the 
empowerment by neurofeedback and enhancement of motivation that it provides57, 
neurofeedback still offers a viable supplement to regular treatment. Therefore, the benefits 
participants could experience with TBV MED BPD outweigh the potential harm. 

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2. 
Objectives and Endpoints of the Clinical Investigation 
2.1 
Primary Objective and Primary Endpoint 
To determine whether amygdala-fMRI-BOLD neurofeedback has a specific effect on dysregulated 
affect in BPD beyond nonspecific benefit. The main hypothesis to be tested is whether 
downregulation training of amygdala activation with neurofeedback reduces the intensity of 
negative affect assessed before treatment (T0) as compared to after treatment (T1) and whether 
the change is greater in the treatment group as compared to the control group.  
Primary Endpoint: Affect intensity is measured via behavioral sampling using EMA over four 
days, 9 am to 10 pm, with 12 hourly smartphone prompts (+ jitter to avoid prompt anticipation). 
EMA data on affect will be assessed with widely used measures that were recently harmonised 
in a Delphi process with more than 50 EMA experts from the German Center for Mental Health.  
2.2 
Secondary Objectives and Secondary Endpoints 
2.2.1 
Main Investigation  
A) Affect intensity assessed via behavioural sampling (EMA), group difference of change from T0 
to T2. 
B/C) Borderline Symptom Severity change (B: T0 to T1, C: T0 to T2) will be measured with the 
Zanarini Rating Scale for BPD (ZAN-BPD) and compared between groups. ZAN-BPD is a 
structured clinician-administered interview and established for assessment of BPD 
psychopathology in clinical trials58. 
D) Amygdala response, group difference of change from T0 to T1. Improvement will be quantified 
based on the first neurofeedback run (i.e., initial 4 ‘View’-trials of session number 1) and the last 
neurofeedback run (i.e., last 4 ‘View’-trials of session number 4). 
E) Amygdala self-regulation, group difference of change from T0 to T1. Improved self-regulation 
of amygdala activity, change from T0 to T1. Improvement will be quantified based on the first 
neurofeedback run (i.e., initial 4 ‘Regulate’-trials of session number 1) and the last neurofeedback 
run (i.e., last 4 ‘Regulate’-trials of session number 4). 
F) Improvement in quality-adjusted life years (QALY), group difference of change from T0 to T3. 
We hypothesize that the application of amygdala-fMRI-BOLD neurofeedback is cost effective 
compared to the control treatment. All changes in terms of utilization of mental health care, work 
productivity and utilities were measured  from T0 to T3. Especially, we expect  a reduction in 
inpatient treatment days and an improvement in quality-adjusted life years (QALY) in favor of the 
intervention group. We anticipate gaining insight into the potential health economic benefits of 
neurofeedback to society. 
 
To measure resource use of health services, productivity loss, and QALYs, both groups fill in the 
same questionnaires before the intervention group receives the first neurofeedback session, and 
six months after the last session. The three questionnaires that are provided via individualized 
online access are: the FIMPsy59, the WPAI:GH60, and a preference-weighted generic instrument, 
the AQoL-6D61. We will analyze health care utilization, productivity loss and its associated direct 
and indirect costs between groups from a societal perspective. We will calculate incremental cost-
effectiveness ratios (ICER), defined as the ratio between net total costs and net effects (i.e. the 
net costs for averting an additional inpatient treatment day and to gain an additional QALY). In 
addition, we will quantify the average costs of a single fMRI neurofeedback session using micro 
costing by consulting a specialist. With such costs at hand, we will calculate the net monetary 
benefit (NMB) of the neurofeedback treatment. To confirm the uncertainty around the ICER, non-
parametric bootstrapping is performed and presented in cost-effectiveness diagrams with 95% 
confidence intervals (sampling uncertainty). Willingness-to-pay thresholds are presented as cost-

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effectiveness acceptability curves. Consequences of uncertainty are visualized using value of 
information (VOI) curves. These analyses should inform stakeholders in health care (i.e. payers 
– health insurance companies - and service provider) about reimbursement decisions.  
2.2.2 
Accompanying Research 
In sub-studies to the main trial, we investigate following research questions/hypotheses:  
 
Predictive value of white matter structure for neurofeedback response: Differences in 
white matter microstructure, as assessed using DTI before the neurofeedback training at 
V3, will predict the response to neurofeedback training in individuals with borderline 
personality disorder (BPD), as measured by a reduction in affect intensity from pre-training 
(T0) to post-training (T1). 
 
  Impact of neurofeedback training on neuroplasticity: Neurofeedback training will induce 
changes in neuroplasticity, observed as a decrease in mean diffusivity (MD) in DTI 
measures between pre-training  and post-training (V3 and V4), compared to a control 
group undergoing a yoked feedback condition. These changes are hypothesized to be 
detectable not only in the amygdala but also in other emotion-regulatory brain structures 
such as the prefrontal cortex. 
 
Relationship between white matter structural and functional connectivity: Structural 
connectivity, as assessed with DTI (using a global fiber tracking approach) will correlate 
with functional connectivity, particularly between emotion-regulation networks and the 
amygdala during the fMRI tasks. 
 
Is response to fMRI-NF moderated by the level of patients’ dissociation? 
 
Is fMRI-NF improving (i.e. lowering) levels of patients’ dissociation? 
 
Criteria for probably not responding to psychotherapy are assessed such as attachment 
style, paranoid symptoms, younger age, baseline distress, higher baseline non-
acceptance of emotional response, to test whether they can successfully be treated with 
neurofeedback. High risk non-responders identified with the respective tools (attachment 
style measured with the Relationship Scales Questionnaire (RSQ), paranoid symptoms 
measured with the Paranoia Checklist (PCL), higher baseline non-acceptance of 
emotional response measured with the Difficulties in Emotion Regulation Scale (DERS) 
will be compared with the patients not fulfilling those criteria with regard to change in levels 
of distress (measured with CGI) and Borderline Symptom Severity change (measured with 
the Zanarini Rating Scale for BPD (ZAN-BPD) from T0 to T2.  
 

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3. 
Design of the Clinical Investigation  
3.1 
Overall Clinical Investigation Design 
This is a randomized controlled, patient-investigator-biometrician blinded, multi-center trial to 
assess superiority of fMRI-NF compared to sham-control feedback with indication of BPD. The 
study is designed to confirm effects of the treatment on affect instability and emotion dysregulation 
that were previously found to be changed following the treatment. Further aims of the investigation 
are to assess neurocognitive mechanisms of response to NF, socioeconomic effects, and the 
influence of pathological states such as dissociation that may influence treatment response. 
Comparator/control group: The assumed mechanism of NF is that changing a neural process will 
change related cognition and behavior. While this model is widely accepted, non-specific effects 
may mediate NF treatment outcomes as well17. The current state of evidence is best represented 
by a synthesis-model of both NF specific and non-specific factors accounting for psychosocial 
and placebo mechanisms18. To show that amygdala-NF is effective, it is necessary to control for 
non-specific factors in a RCT design. Participants in the control group are not provided with their 
own feedback signal. Instead a signal of another participant (‘yoked feedback’) is presented, 
which is an established standard in NF trials. Advantages of yoked feedback: a) the matching of 
the amount of reward received by both groups and b) unforeseen training effects are excluded 
that could be induced by other, conservative control conditions such as the training of alternative 
signals (e.g. different brain region)19. Although the risk of patient unblinding with non-contingent 
feedback has been raised and will be monitored in this project, many studies found that 
participants remained unaware that they had received yoked feedback19.  
Trial design: 
 
Figure 2. Trial design.  
 
 
 

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Trial Time Flow: 
 
Figure 3. Trial Time Flow. Phases marked with * depend on decision to continue recruitment 
following interim-analysis. 
3.2 
Planned Interim Analysis 
The interim analysis is scheduled when 82 of the included subjects in the full analysis set have 
been reached. If the clinical investigation continues without adaptation, the final analysis will be 
performed after inclusion of 82 further subjects. For details see chapter 9.6. 
Trial allocation and (interim-) analysis design 
 
Figure 4. Allocation and analysis design 
 
3.3 
Overall Duration of the Clinical Investigation  
The clinical investigation will be conducted over a period of approximately 4 years. The duration 
of the clinical investigation may be extended and additional sites may be added depending on the 
observed rate of recruitment. 
3.4 
Duration of Clinical Investigation for each Subject 
The investigation consists of: 
 
one day of Screening, 

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 
a 1 month treatment period, 
 
a 6-months post-treatment follow-up period. 
In total the duration of the clinical investigation for each subject is expected to be 7-8 months.  
Patient time flow: 
 

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Figure 5. Patient Time Flow. Above the arrows the time periods are given to complete tasks per 
protocol, e.g. “1-7 (+14) days” (bold: time period per protocol). Exceeding these time periods is a 
protocol deviation and should be documented accordingly in the eCRF. The patient can stay in 
the study as long as the maximum tolerable delay given in brackets is not exceeded e.g. “1-7 
(+14) days” (bold: maximum tolerable delay). If visit/procedure cannot be completed in time, the 
subject is to be terminated. An exemption of this rule is when Neurofeedback visits V3 and/or 
V4 cannot be conducted according to protocol within the given time: As long as patients 
have a valid Neurofeedback visit V2b AND are able to complete the Neurofeedback 4 (Booster-
Neurofeedback) V5a visit, they remain in the study. With other words, a lower-than-envisaged 
training dose is acceptable, as long as the first and the last neurofeedback session can be 
conducted according to protocol. In case of missed session V3 or V4, V5a has to be scheduled 
28-35 (+14) days after the last Neurofeedback visit that was completed according to protocol. 
Although a lower training dose is acceptable, missed treatment is a protocol deviation. Trial staff 
should motivate patients to receive the full training dose of 4 neurofeedback sessions whenever 
possible. 
* Count from first day of EMA data sampling 
** Online questionnaire to be completed after the last day of EMA data sampling and before fMRI-
scan begins. It is possible that subject (begins to fill or) completes online-questionnaires remotely 
before the V2a on-site visit. 
*** Online questionnaires should be completed on same day of interview and must be completed 
within 7 days following interview. Questionnaires must not be filled during EMA data sampling. 
# Online questionnaires should be completed on same day as the interview is taking place. Patient 
can begin to fill questionnaires 7 days before the interview day. 
Figure legend: 
 = On-site interview, 
= interview conducted on-site or remotely 
= 
ePRO questionnaire, 
= Ecological Momentary Assessment (EMA), 
 = MR scan. 
3.5 
Definition of End of Investigation 
The end of clinical investigation is defined as “last subject last visit” (LSLV). In case of an early 
termination of the investigation (see chapter 7.5), the date of the early termination will be the date 
for end of investigation. 
3.6 
Patient Involvement 
We consulted with the “Advisory Board of Affected Persons” (Betroffenenbeirat) of the Central 
Institute of Mental Health (CIMH) about the design and recruitment aspects of the project. Main 
outcomes from the meeting: 
 
Endpoints can be considered relevant. 
 
Questionnaires and interviews seem adequate, reasonably focused and concise. 
 
In case patients terminate participation of the trial early, the investigator should document 
the reasons. 
 
Participation should be acknowledged and patients should be informed e.g. by a newsletter 
about completion status of the trial and the general outcomes. More details could be 
provided for interested patients via a website. Therefore, it has been decided decided to 
budget costs for a trial website. 
 
BB will support the investigators during the recruitment process. 
The perspective from the Betroffenenbeirat representatives was helpful to confirm attractiveness 
to participate in the trial and to confirm adequacy and relevance of measures for the patients’ 
needs. Their reflections on design aspects such as inclusion criteria, public relations and patient 
information were helpful to conceptualize the study. Subject involvement during trial phase: A 

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patient review board consisting of 4 patients/affected persons will be formed. Tasks of the board 
are: participation in PPI training courses, the definition of the board’s tasks and goals, support in 
the development of the homework-part, co-development of informed consent and the patient 
instructions, involvement in interpretation and dissemination of results, co-authorship on paper. 
3.7 
Measures to Minimize Bias 
3.7.1 
Randomization and blinding 
Randomization and blinding will be used as primary methods to prevent bias. Participants will be 
randomized 1:1 to receive either the experimental or the control condition. In line with the 
CONSORT Statement62, GCP-compliant randomization software will assure concealed 
assignment to avoid a potential selection bias on the part of the study members involved in 
enrollment. Stratified permuted block randomization with trial site as a stratum will be applied. 
Within each stratum, block sizes will be variable to protect concealed assignment. The protocol 
conceals group allocation from patients and staff involved in data processing and statistical 
analysis. The source of feedback will be selected automatically (amygdala or yoked feedback), 
based on a priori randomization, without revealing group assignment to staff. To minimize the risk 
to unblind the biostatistician, patient randomization will be managed by the CRO. The dataset 
transferred to the biostatistician will not include the variable coding for group assignment. The 
data analysis syntax of the primary endpoint will be written by the biostatistician, but the interim 
analysis including the variable coding for group assignment will be run by the CRO. Descriptive 
statistics from interim analysis will be disclosed at the end of the trial. 
The randomization list will be kept in safe and confidential custody at the KKS Heidelberg. 
The DSMB remains unblinded and will be provided a unblinding list. 
3.7.2 
Breaking the Blind 
3.7.2.1 
Unblinding in the end of the trial 
At the end of the study and after data verification and database lock, the assigned blinded codes 
are broken for the final analysis of study data. Detailed instructions on randomization, blinding 
and breaking the blind are distributed to the respective authorized personnel prior to the start of 
the study. Patients are informed that they can´t receive any information by the clinical project 
management or the principal investigator about the treatment they had been administered during 
the study until the entire study has been completed. 
Blinded parties: Patients, investigators, biostatisticians 
3.7.2.2 
Emergency unblinding 
Allocation of a patient to treatment vs. sham-control group does not have any consequences for 
the immediate treatment of patients in case of (serious) adverse events during this trial. Therefore, 
emergency unblinding is not applicable. If unblinding becomes necessary for regulatory reasons 
before the end of the trial, the unblinding is possible based on the randomization list kept by the 
KKS. 
 
 

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4. 
Subject Selection 
4.1 
Number of Subjects and Sites 
A total of 164 subjects will be enrolled in the clinical investigation, i.e. 82 subjects per treatment 
group (see chapter 9.9). 
The clinical investigation will be multicenter. The clinical investigation will take place at 6 sites in 
Germany: CIMH Mannheim; Tübingen University, Dept. of Psychiatry; Gießen University, Dept. 
of Psychiatry; Freiburg University, Dept. of Psychiatry; Hamburg University, Dept. of Psychiatry; 
Halle University, Dept. of Psychiatry. 
If enrollment is delayed, additional sites may be recruited. Screening of subjects for this clinical 
investigation is competitive, i.e. screening for the clinical investigation will stop at all sites at the 
same time once a sufficient number of subjects has been recruited. Investigators will be notified 
about screening completion and will then not be allowed to screen any more subjects. Subjects 
already in screening at this time will be allowed to continue to randomization if eligible and will be 
added to the analysis set. 
4.2 
General Criteria for Subjects’ Selection 
As there will be no preferences on the selection of gender to be included, it is anticipated that the 
clinical investigation results will give a representative gender distribution, which should reflect the 
natural gender distribution in the underlying disease.  
4.3 
Inclusion Criteria 
Subjects meeting all of the following criteria will be considered for enrollment in the clinical 
investigation: 
1. 18-65 years 
2. Diagnosis of Borderline Personality Disorder according to DSM-5 
3. Insufficient response to ≥2 therapies. The criterion is fulfilled if the patient reports: 
a) 
2 or more psychotherapy treatments with 12 or more sessions each OR: 
b) 
2 or more psychotherapy treatments with a duration per treatment of at least 12 
weeks OR: 
c) 
a medical history of 2 or more psychopharmaceutic treatments, each over the course 
of at least 4 weeks OR: 
d) 
a combination of 2 or more treatments such as: 
i. 
psychotherapy with 12 or more sessions, 
ii. 
psychotherapy with a duration of 12 weeks or longer, 
iii. 
psychopharmaceutic treatment over the course of at least 4 weeks. 
4. Sufficient German language skills to give informed consent to the study, to understand 
questions posed by used instruments, and capable of completing the fMRI tasks  
5. Ability of subject to understand character and individual consequences of clinical investigation 
6. Written informed consent (must be available before enrollment in the clinical investigation) 
7. For women of childbearing potential (WOCBP) adequate contraception (as defined in 
Appendix 2). 
4.4 
Exclusion Criteria 
Subjects presenting with any of the following criteria will not be included in the clinical 
investigation: 
1. Treatment with benzodiazepines within 7 days prior the initial screening  

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2. Current moderate or severe alcohol or substance use disorder within 1 month prior the initial 
screening 
3. Meeting the diagnostic criteria for a psychotic disorder or schizophrenia (life-time), as 
determined by clinical interview at initial screening  
4. Current or history of significant neurological condition (such as stroke, traumatic brain injury, 
space occupying lesions, multiple sclerosis, Parkinson’s disease, vascular dementia, 
transient ischemic attack) 
5. Significant visual impairment which might interfere with the performance of investigation 
procedures  
6. Change of treatment (psychopharmacologic, psychological) 2 weeks prior to or during the 
study participation 
7. Treatment with any neurofeedback other than investigational device three months prior to or 
during the study participation. 
8. Unable or unwilling to comply with study procedures, including study prohibitions and 
restrictions  
9. History of claustrophobia or inability to tolerate scanner environment 
10. Fulfilling any of the MRI contraindications on the standard site radiography screening 
questionnaire (e.g. history of surgery involving metal implants) 
11. Clinically relevant structural brain abnormality as determined by prior MRI scan  
12. Planned medical treatment within the study period that might interfere with the study 
procedures 
13. Participants deemed to be at significant risk of serious violence or suicide based on any one 
of the following: 
a. Significant risk of committing violent acts, homicide, or suicide based on history, routine 
psychiatric status examination, or according to the investigator’s experience OR 
b. Any suicide attempt in the past 3 months (i.e., actual attempt, interrupted attempt, 
aborted attempt) prior to screening and during the screening period OR 
c. Any suicidal ideation of type 4 or 5 in the C-SSRS in the past 3 months prior to screening 
or during the screening period. 
14. BMI of 16.5 or lower 
15. Participation in other clinical trials or observation period of competing trials, respectively 
16. Previous participation in this trial (Re-Screening possible, c.f. Chapter 4.6.2) 
17. Pregnancy and lactation 
18. Held in an institution by legal or official order 
19. Legally incapacitated. 
4.5 
Lifestyle Considerations 
No alcohol, drugs or not-prescribed medications to be consumed 24 hours before an MRI 
measurement. Patients should try to get sufficient sleep in the night before each MRI 
measurement. Patients should follow their regular activities during EMA data sampling. 
4.6 
Subject Assignment 
4.6.1 
Identification Numbers 
All screened subjects receive a screening number. Subjects included in the clinical investigation 
(all inclusion criteria and none of the exclusion criteria met) are assigned a consecutive subject 
number. 
Each number will be assigned only once. For allocation to a treatment arm see section 3.7.1. No 
subject will be allowed to participate in this clinical investigation more than once. 

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4.6.2 
Screening Failures 
Subjects, who evidently do not meet inclusion criteria or meet exclusion criteria prior to enrollment 
are considered screening failures. Screening failures will be recorded on the screening list, but 
will not be provided with a subject number. Minimal information to be obtained from screening 
failures include screening failure details and eligibility criteria. 
Re-screening is also allowed provided that the reasons for screening failure were reversible and 
have been resolved, based on investigator judgement. A subject is considered a “re-screener” if 
he/she was not eligible for the clinical investigation initially and is subsequently re-screened, going 
through the informed consent process for a second time, receiving a new unique number and 
repeating the screening assessments. 
5. 
Investigational Device  
5.1 
Description of the Investigational Device 
The investigational software in this clinical investigation: 
Product Name  
Purpose 
Manufacturer 
Classification 
Used Software Versions 
TBV MED BPD 
Real-time fMRI 
BOLD-signal 
tracking in the 
brain. 
BrainInnovation 
Oxfordlaan, 55 
6229EV, Maastricht 
Niederlande 
1 
- 
For further details regarding the device and its mode of operation please see the Investigator’s 
Brochure (IB), as well as the Instructions for Use (IFU).  
On the effective date of this CIP version, the software is not CE certified as medicinal product 
with indication BPD. 
5.2 
Supplies of Investigational Device 
The sponsor will provide a laptop with pre-installed investigational software and valid license for 
the trial period to site. 
5.3 
Device Accountability and Traceability 
Not applicable. 
5.4 
Use of the Investigational Device 
Sponsor will train trial staff how to operate the software. Instructions for Use will be distributed to 
sites. 
5.5 
Specific Medical or Surgical Procedure Involved 
No specific medical or surgical procedure is performed for use of the investigational device. 
5.6 
Comparative Devices 
No comparator device will be used in this clinical investigation. 

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6. 
Clinical Investigation Visits and Investigations / Assessments  
This section describes the procedures and tests specific for the clinical investigation required to 
be performed at specified visits as outlined in the schedule of assessments. Also refer to section 
3.4, Figure 5, Patient Time Flow, for more information on timing of visits and procedures. For 
details on the individual assessments please refer to sections 6.10. 
6.1 
Screening Visit / Baseline (T0), V1 
During the Screening Phase, the following assessments are conducted and recorded in the 
source documents and the eCRF: 
1. Informed consent 
2. Suicidality assessment (using C-SSRS) 
3. Review of inclusion/exclusion criteria 
4. BPD-diagnosis according to DSM-5 (using IPDE) 
Not mandatory for screening failures: 
5. Medical history (prior and concomitant diseases) 
6. Previous and ongoing medication, psychotherapy treatment, neurofeedback treatment 
7. Demography (age, sex/gender: DiMIS Table 2, race/ethnicity: DiMIS Table 1 Item 6d, 
education: DiMS Table 1 Items 3a,b) 
8. Last menstruation (to assess potential effects of cycle phase on self-regulation and 
outcomes) 
Interviews/assessments conducted during the on-site screening visit: 
1. CGI-S (State version) 
2. ZAN-BPD 
3. FIMPsy (patient self-report via ePRO with investigator assistance if needed) 
Interviews and assessments of the screening phase should be collected on the same day as the 
informed consent is given or within 7 days thereafter. 
Questionnaires to be filled during screening visit or later. The questionnaires have to be 
completed one day before the first scheduled day of EMA sampling. The subjects receive a link 
to the ePRO platform where they can fill in the online questionnaires on their own electronic 
device. The subject can pause and save interim entries (by actively clicking the “save” button on 
the ePRO site), and resume the answering of questionnaires later. 
1. BSL-23 
2. BDI 
3. DERS-36 
4. DES 
5. SCL-27 
6. WPAI:GH 
6.2 
Baseline Visit (T0) continued, V2a 
Cave: Patients are randomized only after EMA data collection was confirmed. Before 
patients come in for the on-site part of this visit, they accomplish EMA and online 
questionnaires at home. In the beginning of the on-site part of this visit, the investigator 
has to confirm that EMA data has been recorded as described below. 
The smartphone for EMA data sampling is prepared during the Screening visit. EMA is conducted 
on four consecutive days including 2 days at the weekend. The first day of EMA sampling should 
always be a weekday (i.e., Thursday or Friday) so that trial staff is able to check that the recording 

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is going well and that trial staff is available for patients if any problems and questions come up in 
the beginning of EMA. 
EMA data sampling can begin the day after V1 earliest, but should not begin later than 7 days 
after V1. 
The subjects fill the questionnaires below remotely in the ePRO system during this time: Earliest, 
they can begin 1 day after EMA data sampling and they have to complete questionnaires 7 days 
thereafter. Study staff should plan sufficient time in the beginning of Visit V2a to allow the patient 
to complete questionnaires that may not have been completed at this time. All questionnaires 
have to be completed before the first MR-scan. 
1. AQoL-6D 
2. BSL-23 
3. DSS-acute 
4. PCL 
5. RSQ 
Before the patient can continue with on-site part of this visit, trial staff needs to confirm whether 
the patients answered the minimum number of EMA prompts of 50%. If the minimum number 
of EMA prompts was not made, the patient cannot be randomized to the trial.  
At the day of MR-scan: 
 
To exclude any fetotoxic risk of participation in an MR-study, “WOCBP should only be 
included after a confirmed menstrual period and a negative highly sensitive urine or serum 
pregnancy test” (ref. HMA-CTFG Contraception guidance Version 1.2, 2020-06-14). The 
result of the test is to be documented in the patient source documents.  
 
If applicable, the day of the last menstruation should be recorded.  
Patients receive instructions for the neurofeedback training.V2a should be combined with V2b 
(Neurofeedback 1) in the same MR-session. 
6.3 
Neurofeedback 1-3 (V2b, V3, V4) 
AE/SAEs are assessed following randomization.  The first AE assessment is conducted on V2b 
when the MR session has been completed. In the following visits, AE/SAE are assessed in the 
beginning of each visit (to detect AE/SAE since the last visit). Additionally, AE are assessed in 
the end of each Neurofeedback visit (to detect AEs related to the MR session). Assessment of 
potential pregnancy with a pregnancy test is mandatory for WOCBP in the beginning of each MR 
session. 
MR safety criteria are checked. Patients are positioned in the MR-tube following guidelines in the 
Investigator’s Brochure. Patients receive a refresher of neurofeedback instructions. As part of the 
MR session, technical and anatomical scans are acquired. MR-scans of the neurofeedback visits: 
- 
fMRI neurofeedback (BrainSTEADy training implemented in TBV MED software, in all 
visits) 
- 
Questionnaire assessment in the end of each visit: 
o DSS-4 
o MSQ-NF 
- 
DTI scans: 
o V1, V4: A series of 4 scans (each 1.5 min) is conducted before and after the 
Neurofeedback. 
o V3: Two 9-min-scans are conducted after Neurofeedback. 

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In the end of visit 3, patients are instructed to fill the Survey of NF transfer provided in the next 
weeks. 
6.4 
Interim weeks between Neurofeedback 3 (V4) and Neurofeedback 4 (V5a) 
Patients receive a weekly email prompt with a link to the Survey of NF transfer presented via the 
ePRO platform. The prompts are sent 7, 14 and 21 days after Neurofeedback 3. The link should 
be valid 2 days. Patients should be informed about the importance to fill in the questionnaire. 
6.5 
Neurofeedback 4, Post-assessment visit (T1), V5a 
 
The Survey of NF transfer is conducted a last time in the beginning of the visit. 
 
AE/SAEs are assessed before and after the MR session.  
 
Assessment of potential pregnancy with a pregnancy test is mandatory for WOCBP in the 
beginning of each MR session. 
 
The day of the last menstruation should be assessed, if applicable. 
 
MR safety criteria are checked. 
 
Patients receive a refresher of neurofeedback instructions. Patients are positioned in the 
MR-tube following guidelines in the Investigator’s Brochure. As part of the MR session, 
technical and anatomical scans are acquired.  
 
fMRI neurofeedback is conducted (BrainSTEADy training implemented in TBV MED 
software, in all visits) 
 
DTI scan is conducted (see above) 
 
Questionnaire assessment in the end of the visit: 
o DSS-4 
o MSQ-NF 
EMA is conducted as described above on 4 consecutive days including a weekend. EMA data 
sampling can begin the day after V5a and should not begin later than 7 days after V5a. 
6.6 
Post-assessment visit (T1) continued, V5b 
One week after the end of EMA data sampling (i.e., 11 days after the beginning of EMA) earliest, 
but no later than 2 weeks thereafter (i.e., 18 days after the beginning of EMA), clinical interviews 
are conducted on-site or remotely via phone or via safe internet application: 
1. CGI-I (Improvement version) 
2. ZAN-BPD 
3. If applicable, the day of the last menstruation should be assessed 
4. The patients will be asked questions for checking the blind (blind check). An investigator-
version and a NF-trainer version of the blind-check questions are to be completed by trial 
staff. 
5. Concluding questionnaire to be filled by patient. 
Preferably on the same day as the interview the patient fills in (and completes) questionnaires in 
the ePRO system. It is also possible that the patient fills the questionnaires before or after the 
interview. Questionnaires must be completed during this time: One week after EMA data sampling 
(i.e., 11 days after the beginning of EMA) until 2 weeks after EMA data sampling (i.e., 18 days 
after the beginning of EMA). 
1. BSL-23 
2. BDI 
3. DERS-36 
4. DSS-acute 
5. SCL-27 

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6.7 
Follow-up assessment 1 visit (T2), FUP1 
FUP1 is to be scheduled 3 months (+/- 2 weeks) after Post-assessment (T1) EMA. 
The patient can fill in the questionnaires in the ePRO system one week before the interview and 
must complete the questionnaires no later than at the day of the interview: 
1. BSL-23 
2. BDI 
3. DERS-36 
4. DSS-acute 
5. SCL-27 
The ZAN-BPD interview is conducted on-site or remotely via phone or via safe internet 
application. If applicable, the day of the last menstruation should be assessed. 
EMA data sampling begins 1-7 days after the interview. 
6.8 
Follow-up assessment 2 visit (T3) 
Subjects receive a link to ePRO platform where they can fill in the online questionnaires on their 
own electronic device. The subject must complete the questionnaires within 7 days. 
1. AQoL-6D 
2. BSL-23 
3. BDI 
4. DERS-36 
5. DSS-acute 
6. FIMPsy 
7. SCL-27 
8. WPAI:GH 
6.9 
Planned Treatment after End of Investigation Participation  
After the end of the investigation no further treatment of patients is necessary. 
The investigator will continue to observe all subjects (also withdrawals) because of intolerable 
AEs / SAEs until any findings have been clarified or became stable. 
6.10 
Assessments 
AEs 
AEs will be asked for at each contact between the responsible 
investigator and the subject. Furthermore, new pathological and 
clinically relevant findings or aggravation of pre-existing symptoms in 
examinations will be documented as AEs. AEs will be reported with 
subject ID, start and end date, description, grading, seriousness, 
relatedness, action taken and outcome 
AQoL-6D 
The Assessment of Quality of Live Mark 2 instrument (AQoL-6D51) is 
a multi-attribute utility instrument that measures health-related quality 
of life. The instrument contains of 20 items grouped into five 
dimensions (illness, independent living, social relationships, physical 
senses and psychological wellbeing). The instrument provides 
weighted and unweighted age- (16 to 74 years) and gender-specific 
norms. Utility scores, i.e. QALYs, are elicited via time-trade off-
derived (TTO) formulas51. The questionnaire will be filled in at visit 

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V1 and again six months after the last neurofeedback session. The 
AQoL-6D is used for health economic analyses (sub-project by Höll). 
BDI-II 
Depressivity is measured with the Beck Depression Inventory (BDI-
II63), which is a widely established 21-items self-report questionnaire. 
Items are rated on a scale from 0 to 4, a total score is received by 
averaging across all items. Higher values indicate higher depressivity 
Blind check 
An in-house developed questionnaire. Subjects are asked about their 
belief in what experimental condition they were randomized (i.e., 
amygdala-feedback or sham-feedback). There is a version for 
patients and a version for trial staff. 
BSL-23 
The Borderline Symptom List short version (BSL-2364) is an 
established self-rating questionnaire to assess Borderline symptom 
severity within a 1-week time frame. It is composed of 23 items. Each 
item is rated on a scale from 0-4 (0=not at all to 4=very strong/several 
times a day). Total score is received by averaging across the 23 items. 
The scale will be administered at visits V1, V5 and FUP. 
Concluding 
questionnaire 
An in-house developed, single-page self-report questionnaire asking 
the patient to rate their experience with the treatment after V5.  
C-SSRS 
The C-SSRS (https://cssrs.columbia.edu/) is a semi-structured, 
investigator-rated interview, developed by clinical experts in 
cooperation with the FDA, assessing both suicidal behavior and 
suicidal ideation. It does not give a global score but provides some 
categorical and some severity information specifically for behavior 
and ideation. 
DERS 
The Difficulties in Emotion Regulation Scale65, is a 36-item self-report 
measure. Items are rated on a scale of 1 (almost never) to five (almost 
always). Higher scores indicate more difficulty of emotion regulation. 
DES 
In order to better characterize the sample with respect to dissociation, 
we will assess trait dissociation at baseline based on the most widely 
used assessment instrument, i.e. the DES66 (28 items). 
DSS-4 
To investigate whether state dissociation during the fMRI-NF might be 
detrimental to the effect of the fMRI-NF-intervention, a brief 
assessment of state dissociation (5 items) following each fMRI-NF-
session will be administered. 
DSS-acute 
To investigate whether fMRI-NF is improving patients’ dissociation a 
comprehensive assessment of state dissociation, the DSS-acute67 
(22 items) will be assessed. 
FIMPsy 
The “Fragebogen zur Inanspruchnahme medizinischer und nicht 
medizinischer 
Versorgungsleistungen 
bei 
psychischen 
Erkrankungen” (FimPsy59) assesses health care resource use 
(including outpatient and inpatient medical care, intake of medication, 
informal care, psychiatric counselling, psychosocial care, social 
participation, vocational (re-)integration,) in patients with mental 
disorders over the previous six months. The FimPsy facilitates health 
economic evaluations by collecting type, frequency or duration of 
health care utilization. 

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Medical history and 
underlying disease 
history 
Clinically 
significant 
diseases, 
surgeries, 
previous 
medical 
procedures, smoking history, use of alcohol and/or drug abuse, 
reproductive status, and all medications (e.g., prescription drugs, 
over-the-counter drugs) taken by the subject within 7 d prior to start 
of investigational treatment. 
MSQ-NF 
Mental strategies used by participants for amygdala downregulation 
during the neurofeedback training will be assessed using Mental 
Strategies Questionnaire for NeuroFeedback (MSQ-NF). Patients will 
determine their own mental strategy for every regulation block and fill 
out the questionnaire at the end of every neurofeedback visit (V2b, 
V3, V4, V5a) for every distinct mental strategy separately. MSQ-NF 
allows to characterize strategies across dimensions, and identify the 
features of successful mental strategies. 
[EMA] 
Smartphone-based assessment over four days, 9 am to 9 pm, with 12 
hourly smartphone prompts. When prompted, subjects will answer up 
to 15 questions about their emotions and negative events. 
IPDE 
The International Personality Disorder Exam (IPDE) is a clinician-
administered semi-structured interview used to assess personality 
disorders as defined in the DSM-5 and ICD-11. The BPD subsection 
will be used to assess for the presence of severity of symptoms 
related to BPD. It will be administered during the diagnostic interview. 
Negative affect intensity 
(based on EMA) 
The primary endpoint is based on the EMA scale measuring negative 
affect. 
PCL 
The Paranoia Checklist68 (PCL; 18 items) measuring the extent of 
paranoid symptoms, will be assessed for prediction of potential non-
response to therapy. 
RSQ 
The Relationship Scales Questionnaire69 was developed as a 
continuous measure of adult attachment. The RSQ contains 30 short 
statements on a 5-point scale ranging from "not at all like me" to "very 
much like me", participants rate the extent to which each statement 
best describes their characteristic style in close relationships. 
Survey of NF transfer 
Short questionnaire to ask patients whether they used self-regulation 
strategies learned during neurofeedback in daily life and how effective 
they were. 
SCID 
The Structured Clinical Interview for DSM-5 is a semi-structured 
clinician-administered interview for the assessment of psychiatric 
diagnosis according to the Diagnostic and Statistical Manual of Mental 
Disorders Version 5. 
SCL-27 
The SCL-27 is designed to screen for psychological complaints in 
patients with leading physical symptoms. The subscales depressive, 
dysthymic, vegetative, agoraphobic, sociophobic symptoms and 
symptoms of mistrust are formed, as well as a global severity index 
(GSI-27). 
WPAI-GH 
The General Health (GH) version of the Work Productivity and Activity 
Impairment Questionnaire (WPAI-GH50) is a questionnaire designed 
to assess presenteeism and absenteeism due to health problems and 
work or activity impairments. The WPAI:GH consists of six questions, 
which elicit the amount of productivity loss to society over the past 
seven days. The questionnaire will be filled in at visit V1 and again six 

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months after the last neurofeedback session. The WPAI-GP is used 
for health economic analyses (sub-project by Höll). 
ZAN-BPD 
Symptom severity will be assessed with the Zanarini Rating Scale for 
BPD58 (ZAN-BPD). ZAN-BPD is a structured clinical interview 
administered by trained staff, who are blinded with respect to group 
allocation. The questions are adapted from the Diagnostic Interview 
for DSM-5 Personality Disorder to reflect a 1-week time frame. Each 
criterion is rated on a scale from 0-4, yielding a total score of 0 to 36.  
7. 
Discontinuation and Early Termination  
Any subject can withdraw from the treatment or the clinical investigation verbally or in writing at 
any time without personal disadvantages and without having to give a reason. However, the 
investigator should make a reasonable effort to ascertain possible reasons, while fully respecting 
the subject's rights. Specifically, the subject must not be coerced or unduly influenced to continue 
participation. Any given reason should be specified in the subjects file and in the CRF. 
The investigator can also discontinue the investigational treatment after considering the risk-to-
benefit ratio, if he / she no longer considers the treatment justifiable. The date of and the primary 
reason for withdrawal (one primary reason must be determined), as well as the observations 
available at the time of withdrawal are to be documented on the CRF. In all subjects who 
discontinue the clinical investigation prematurely, a withdrawal examination at least with respect 
to the primary endpoint should be carried out. The subject must be asked to consent to this last 
examination. The withdrawal examination must be specified in the CRF.  
For details concerning sample and statistical considerations see 9.1. 
7.1 
Temporary Discontinuation from Treatment 
Temporary treatment discontinuation at the discretion of the investigator is defined as one or 
more applications of the investigational device not performed. 
Temporary treatment discontinuation may be considered by the investigator because of 
 
AEs/SAEs 
 
Unexpected unavailability or malfunction of the MR scanner  
 
Unexpected unavailability or malfunction of other equipment that is critical for proper 
function of the investigational device and that cannot be replaced in a timely manner 
The usage of the investigational device may be resumed under close and appropriate clinical 
and/or laboratory monitoring if according to the investigator’s medical judgment the concerned 
event is unlikely to be related to the investigational device and provided that eligibility criteria for 
the clinical investigation are still met. For all temporary treatment discontinuations, duration must 
be recorded by the investigator on the appropriate pages of the e-CRF. See section 13.5 for 
recommended treatment continuation in case of unavailability/malfunction. 
7.2 
Permanent Discontinuation from Treatment  
Permanent treatment discontinuation is any treatment discontinuation associated with the 
investigator’s or the subject’s definitive decision not to re-expose the subject to the investigational 
device. The following criteria will lead to a permanent discontinuation from investigational 
treatment: 
 
Subject’s request, i.e. withdrawal of consent for treatment, 
 
Loss to follow up, 

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 
Death, 
 
Use of illicit drugs, prohibited concomitant medications,  
 
Intolerable AEs such as critical suicidal ideation, suicide attempt, psychotic state 
 
Lack of subject’s compliance  
 
Existing or intended pregnancy or lactation. If a female subject becomes pregnant, she 
will be followed up until birth or termination of the pregnancy. 
 
Any additional diagnosis due to which, in the investigator’s opinion, participation in the 
clinical investigation may pose a risk for the subject or that may interfere with CIP 
adherence, 
 
Significant structural brain abnormality observed during MRI scan 
 
Subject did not meet one of the in-/exclusion criteria (coming to light after inclusion): 
Treatment with benzodiazepines within 7 days prior to the initial screening, current or 
history of significant neurological condition, fulfilling any MRI contraindication 
Even if the treatment is discontinued, the subjects may remain in the clinical investigation and, 
given their agreement, will undergo the procedures for early treatment discontinuation and follow-
up as outlined in the schedule of assessments and section 6. Consent for further data collection 
should be documented in the patient file. 
7.3 
Discontinuation from the Clinical Investigation 
In addition to death, the following incidents will lead to discontinuation of a subject from the clinical 
investigation: 
 
Loss to follow up 
 
Withdrawal of consent 
 
Lack of compliance 
7.3.1 
Withdrawal of Consent 
Subjects may withdraw their consent to participation in the clinical investigation at any time without 
the need to justify the decision. If a subject wants to withdraw his/her consent, the investigator 
should explain the difference between treatment discontinuation and withdrawal from participation 
in the clinical investigation, including the options for continued follow-up after treatment 
discontinuation (see section 7.2). The decision of the subject must be documented in the source 
data. In case the subject still wants to withdraw from participation in the clinical investigation, an 
early treatment discontinuation visit should be conducted as outlined in the schedule of 
assessments and section 6, if possible. 
7.3.2 
Loss to Follow-Up 
Subjects will be considered lost to follow-up if they fail to show up for visits of the clinical 
investigation and cannot be contacted by the site. Site personnel is expected to make diligent 
attempts to contact subjects who did not show up for a scheduled visit or were otherwise not 
available. These contact attempts should be documented in the subject’s medical record. 
7.4 
Temporary Halt 
A temporary halt of a clinical investigation is defined as an unforeseen interruption not provided 
in the clinical investigation plan but with the intention to resume it. If the reason for the temporary 
halt may have a negative effect on benefit-risk assessment, re-start is possible only after approval 
of a substantial modification. 

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7.5 
Early Termination of the Clinical Investigation 
Early termination is defined as the premature end of a clinical investigation before the conditions 
specified in the CIP are met.  
The following reasons or events may result in an early termination: 
 
New findings on the investigational device leads to doubt as to the benefit-risk ratio; 
 
Subject enrollment is insufficient; 
 
DSMB recommends termination of the entire clinical investigation or single treatment 
arms. 
An early end of the clinical investigation due to early inclusion of the total number of subjects is 
not considered an early termination. In the event of premature discontinuation of the clinical 
investigation for any reason whatsoever, the regulatory authorities should be informed according 
to applicable regulatory requirements. In case of an early termination of the clinical investigation, 
the date of early termination will be the date of end of trial. 
When the clinical investigation is terminated, all materials related to the clinical investigation 
(CRFs: empty, completed or partially completed; emergency envelopes etc.) must be returned to 
the sponsor. The laptop with the investigational software installed must be returned to the 
sponsor. 
7.6 
Premature Closure of a Site  
Premature closure of a single site by the sponsor may be considered for the following reasons:  
 
The investigator failed to recruit any subjects even though he/she had received the laptop 
with the investigational software, means and information necessary to perform the clinical 
investigation and had reasonable time to do so.  
 
Non-compliance with ISO 14155:2020(E), any provision of the clinical investigation plan 
or breach of the applicable laws and regulations of the investigator, sub-investigator or 
delegated staff. 
In the event of premature closure for any reason whatsoever, the regulatory authorities must be 
informed according to applicable regulatory requirements. When a site is closed, all materials 
related to the clinical investigation (CRFs: empty, completed or partially completed; emergency 
envelopes etc.) must be returned to the sponsor. The laptop with the investigational software 
installed must be returned to the sponsor. 
 
8. 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event 
According to the ISO 14155:2020(E) 3.2 and the Regulation (EU) 2017/745 Art. 2 (57) an adverse 
event (AE) means any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other 
persons, in the context of a clinical investigation, whether or not related to the investigational 
device and whether anticipated or unanticipated. 
This definition includes events related to the investigational medical device or the comparator and 
the procedures involved. For users or other persons, this definition is restricted to events related 
to the use of investigational medical devices or comparators. 

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An AE may be: 
 
New symptoms/ medical conditions, 
 
New diagnosis, 
 
Changes of laboratory parameters, 
The criteria that should be considered when determining whether an abnormal test finding 
should be reported as adverse event are as follows: 
o Test result is associated with accompanying symptoms, and/or 
o Test result require diagnostic testing or medical/surgical intervention, and/or 
o Test result lead to a discontinuation from the clinical investigation, significant 
additional concomitant drug treatment, or other therapy, and/or 
o Test result is considered clinically relevant at the discretion of the investigator or 
sponsor. 
 
Intercurrent diseases and accidents, 
 
Worsening of medical conditions/ diseases existing before start of the clinical 
investigation, 
 
Recurrence of disease, 
 
Increase of frequency or intensity of episodic diseases. 
A pre-existing disease or symptom will not be considered an adverse event unless there will be 
an untoward change in its intensity, frequency or quality. This change will be documented by an 
investigator.  
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical investigation plan and the condition(s) leading to these 
measures are not AEs, if the condition leading to the measure was present prior to inclusion into 
the clinical investigation. In the latter case the condition should be reported as medical history. 
AEs are classified as "non-serious" or "serious". 
8.1.2 
Serious Adverse Event 
In accordance with ISO 14155:2020(E) 3.45 and the Regulation (EU) 2017/745 Art. 2 (58) serious 
adverse event (SAE) means 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) hospitalization or prolongation of subject hospitalization,  
(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,  
Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
(c) fetal distress, fetal death or a congenital abnormality or birth defect including physical or mental 
impairment  

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(d) Not applicable (Note that this option is only to be selected in case of reportable device 
deficiencies that did not lead to an SAE.). 
8.1.3 
Adverse Events of Special Interests 
Not applicable 
8.1.4 
Device Deficiency 
According to the EN ISO 14155:2020 3.19 and the MDR Art. 2 (59) a device deficiency (DD) 
means any inadequacy in the identity, quality, durability, reliability, safety or performance. Device 
deficiencies include malfunctions, use errors, and inadequacy in the information supplied by the 
manufacturer including labelling. 
This definition includes device deficiencies related to the investigational device or the comparator. 
8.2 
Expectedness / Anticipatedness 
The classification of expectedness / anticipatedness should be performed by the sponsor 
according to the following definition: 
Expected / anticipated: 
an AE which by its nature, incidence, severity or outcome has 
been identified in the Investigator Brochure (IB). 
Unexpected / unanticipated: 
an unexpected / unanticipated event is one which by its nature, 
incidence, severity or outcome has not been identified in the 
current version of the risk analysis. 
In this clinical investigation IB will be used for determination of the expectedness / 
anticipatedness.  
8.3 
Characteristics of Adverse Events  
8.3.1 
Grading of AEs 
The investigator should assess the intensity as follows: 
Mild:  
signs and symptoms which can be easily tolerated. Symptoms can be ignored or 
disappear when the subject is distracted. 
Moderate: 
symptoms cause discomfort but are tolerable, they cannot be ignored and affect 
normal activity. 
Severe: 
symptoms strongly affect normal activity. 
 
If an AE shows an undulating course of intensity, it must be documented only once with 
predominant or medically most appropriate intensity.   
Clarification of the difference in meaning between "serious" and "severe": The terms “serious” 
and “severe” are not synonymous. The term “severe” should be used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor significance 
(such as severe headache). This is not the same as “serious”, which is based on the existence of 
at least one of the above-mentioned seriousness criteria. 
8.3.2 
Causal Relatedness 
The relatedness between the AE and all potential causes will be assessed. The potential causes 
are: 

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 
investigational device, 
 
comparator (sham-neurofeedback), 
 
medical procedure, 
 
underlying disease, 
 
other. 
The classification of relatedness should correspond to one of the following criteria: 
Causal relatedness: 
The adverse event is associated with the investigational device, 
comparator or with procedures beyond reasonable doubt when:  
 the event is a known side effect of the product category the device 
belongs to or of similar devices and procedures;  
 the event has a temporal relatedness with investigational device use 
/ application or procedures;  
 the event involves a body-site or organ that  
o the investigational device or procedures are applied to;  
o the investigational device or procedures have an effect on.  
 the serious adverse event follows a known response pattern to the 
medical device (if the response pattern is previously known);  
 the discontinuation of medical device application (or reduction of the 
level of activation / exposure) and reintroduction of its use (or 
increase of the level of activation / exposure), impact on the serious 
adverse event (when clinically feasible);  
 other possible causes (e.g. an underlying or concurrent illness / 
clinical condition or / and an effect of another device, drug or 
treatment) have been adequately ruled out;  
 harm to the subject is due to error in use;  
 the event depends on a false result given by the investigational 
device used for diagnosis, when applicable. 
Probable: 
The relatedness with the use of the investigational device or comparator, 
or the relatedness with procedures, seems relevant and / or the event 
cannot be reasonably explained by another cause. 
Possible: 
The relatedness with the use of the investigational device or comparator, 
or the relatedness with procedures, is weak but cannot be ruled out 
completely. Alternative causes are also possible (e.g. an underlying or 
concurrent illness / clinical condition or / and an effect of another device, 
drug or treatment). Cases where relatedness cannot be assessed, or no 
information has been obtained should also be classified as possible. 
Not related: 
Relatedness to the device, comparator or procedures can be excluded 
when:  
 the event has no temporal relatedness with the use of the 
investigational device, or the procedures related to application of the 
investigational device;  

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 the adverse event does not follow a known response pattern to the 
medical device (if the response pattern is previously known) and is 
biologically implausible;  
 the discontinuation of medical device application or the reduction of 
the level of activation / exposure - when clinically feasible - and 
reintroduction of its use (or increase of the level of activation / 
exposure), do not impact on the serious adverse event; 
 the event involves a body-site or an organ that cannot be affected 
by the device or procedure;  
 the serious adverse event can be attributed to another cause (e.g. 
an underlying or concurrent illness / clinical condition, an effect of 
another device, drug, treatment or other risk factors);  
 the event does not depend on a false result given by the 
investigational device used for diagnosis, when applicable. 
The classification of relatedness will be carried out by both the responsible investigator and the 
sponsor. 
8.3.3 
Outcome of AEs 
All subjects who have reportable AEs must be monitored to determine the outcome. The clinical 
course of the AE will be followed up until resolution or normalization of changed laboratory 
parameters or until it has changed to a stable condition. This also holds for ongoing AEs/SAEs of 
withdrawn subjects. 
The outcome of an AE at the time of the last observation will be classified as: 
Recovered / resolved: 
All signs and symptoms of an AE disappeared without any 
sequels at the time of the last interrogation, 
Ongoing: 
Signs and symptoms of an AE are mostly unchanged or worsened 
at the time of the last interrogation, 
Recovered / resolved with 
sequel: 
Actual signs and symptoms of an AE disappeared but there are 
sequels related to the AE, 
Death: 
Resulting in death. If there are more than one adverse event only 
the adverse event leading to death (related) will be characterized 
as ‘fatal‘, 
8.3.4 
Countermeasures 
The term “countermeasures” refers to the specific actions taken to treat or alleviate adverse 
events or to avoid their sequels. The following categories will be used to classify the 
countermeasures taken for adverse events: 
No 
No countermeasures / treatment performed 
Yes 
Newly-prescribed medication or other countermeasures, e.g. an 
operative procedure 

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8.4 
Period of Observation and Documentation 
AEs will be ascertained by the investigators using non-leading questions, noted as spontaneously 
reported by the subjects to the medical staff at any time during the study or observed at any of 
the clinical investigation visit.  
The observational period begins with the randomization of the patient to the trial (V2a, following 
confirmed EMA assessment) and ends with the last visit of the clinical investigation, i.e. Follow-
up Visit 2 (FUP2). Thereafter, the investigator does not need to actively monitor subjects for 
adverse events. However, if the investigator becomes aware of a serious adverse event with a 
suspected causal relatedness to the investigational device or the medical procedure that occurred 
after the end of the observational period he or she shall report the SAE without undue delay to 
the Sponsor, as long as the clinical investigation is still ongoing. These events are also to be 
documented in the eCRF. 
AEs will be documented in the subject file and in the eCRF. If applicable, all medical diagnoses 
or symptoms occurring prior to the beginning of the period of observation and documentation will 
be recorded in the eCRF as medical history.  
The following general rules apply to the documentation of the AEs and SAEs: The start date of 
an SAE must not be earlier than that of the corresponding AE. The end date of a SAE is typically 
the same as that of AE. The end date of the SAE must not be later than the end date of the 
corresponding AE. Due to limited regulatory standard outcome values, the outcome of AEs and 
SAEs that are ongoing at the time of death is documented as “ongoing”. 
All SAEs and their relevance for the benefit-risk assessment of the clinical investigation will be 
evaluated continuously during the clinical investigation and for the final report. All SAEs will be 
documented in the eCRF and in the ‘SAE form’ (see section 8.5.1). 
8.5 
Investigator’s Vigilance related Reporting Obligations 
8.5.1 
Reporting of Serious Adverse Events 
All SAEs and any device deficiencies must be reported by the investigator to the PV department 
of KKS Heidelberg immediately, but not later than 24 hours after the SAE / DD becomes 
known using the ‘SAE/DD form’. The initial report must be as complete as possible including 
details of the SAE / DD and an assessment of the causal relatedness between the event and the 
investigational device / medical procedure.   
The reporting will be performed by faxing or e-mailing (in case of technical issues) a completed 
‘SAE/DD form’ to the PV department of KKS Heidelberg,  
fax number: +49 (0)6221/56 33725  
or e-mail: pharmakovigilanz.KKS@med.uni-heidelberg.de 
8.6 
Sponsor’s Vigilance related Reporting Obligations 
8.6.1 
Sponsor’s Assessment (Second Assessment) 
All SAEs and DD will be subject to a second assessment by Sponsor’s designated persons, who 
will be independent from the reporting investigator. 
The second assessor will fill out a ‘Second Assessment Sheet’ for each SAE and each DD and 
send it back per fax or e-mail to the PV department of KKS Heidelberg within 48 hours, 
fax number: +49 (0)6221/56 33725  
or e-mail: pharmakovigilanz.KKS@med.uni-heidelberg.de 

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The ‘Second Assessment Sheet’ will contain the following information: 
 
assessment of relatedness between SAE / DD and investigational device and medical 
procedure, 
 
assessment of relatedness between SAE / DD and underlying disease (indication), 
 
assessment of expectedness / anticipatedness of SAE / DD (derived from IB), 
 
statement if the Risk Benefit Assessment for the clinical investigation did change as a 
result of SAE / DD.  
8.6.2 
Expedited Reporting to the National Competent Authority 
The sponsor shall report to the competent authorities:  
 
any SAE that has a causal relatedness with the investigational device or the medical 
procedure or where such causal relatedness is reasonably possible,  
 
DD that might have led to a serious adverse event if appropriate action had not been 
taken, intervention had not occurred, or circumstances had been less fortunate,  
 
and any new findings in relation to any event referred to in points above. 
These SAEs / DDs which indicate an imminent risk of death serious injury, or serious illness and 
that requires prompt remedial action for other patients, users or other persons or a new finding to 
it: Immediately, but not later than 2 calendar days after awareness by sponsor of a new 
reportable event or of new information in relation with an already reported event. This includes 
events that are of significant and unexpected nature such that they become alarming as a 
potential public health hazard. It also includes the possibility of multiple deaths occurring at short 
intervals.  
Any other SAEs / DDs or a new finding / update to it: Immediately, but not later than 7 calendar 
days following the date of awareness by the sponsor of the new reportable event or of new 
information in relation with an already reported event. 
The reporting format is described on the appropriate homepages of authorities. 
8.6.3 
Periodic Reporting to the German Competent Authority (BfArM) 
The sponsor shall report all SAEs (independent on causal relatedness) and all DD exclusively to 
the German competent authority (BfArM) in a summarized form quarterly.  
The quarterly safety reports consist of the following three parts:  
 
summary assessment of SAEs and DDs, 
 
table “complication rates”,  
 
statement of DSMB. 
The templates are provided on the homepage of BfArM.  
 
 

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9. 
Statistical Procedures 
9.1 
Definition of Population to be analyzed in the Clinical Investigation 
The primary analysis will be performed for the full analysis set (FAS) which comprises all subjects 
with valid informed consent randomized into the clinical investigation. In this set, every subject is 
analyzed according to the group randomized into (i.e. intention to treat, ITT).  
The per-protocol set will comprise all subjects in the FAS who were treated according to the 
randomized treatment, as specified in the study protocol. Specifically, subjects have to be eligible 
according to in- and exclusion criteria. Before the clinical investigation team is unblinded, rules 
for selecting the per-protocol set will be selected by at least the sponsor and biometrician, who 
remains blinded at that stage.   
The safety set will comprise all subjects who have received the investigational device at least 
once, and will allocate the subjects to the treatment they actually received, regardless of 
randomization. 
Reasons for missing values (e.g., death of subject, withdrawals, missed assessments), and 
reasons for premature end of treatment, intercurrent events, reasons for screening failure, and 
protocol deviations will be recorded.  
9.2 
Analysis Variables 
The primary and secondary endpoints have been specified in detail in sections 2.1 and 2.2. 
9.3 
General Considerations 
The primary analysis will be performed on all subject data at the time the clinical investigation 
ends. The trial will be conducted within the framework of a sequential design according to Bauer 
& Köhne71 with one scheduled interim analysis. All analyses will be carried out using validated 
statistical software, in particular SAS™. 
9.4 
Primary Analysis 
The primary analysis will be performed by testing the hypothesis whether downregulation training 
of amygdala activation with neurofeedback reduces the intensity of negative affect assessed 
before treatment (T0) as compared to after treatment (T1). This hypothesis will be tested at the 
one-sided overall significance level α of 0.025. The primary endpoint will be analyzed on the full 
analysis set in stage 1 after 82 participants (n1=41 per group) have reached this endpoint 
according to the ITT principle. The effect of the intervention with respect to the primary outcome 
will be tested from the time*condition interaction of a mixed linear model with the mean score of 
negative affect as dependent variable, time as within-subject factor, condition (amygdala-NF vs 
control) as between-subject factor, trial site as a random factor, and sex as a cofactor. If the p-
value pertaining to the primary outcome in stage 1 (p1) exceeds the critical threshold of α0=0.3 
in stage 1 the trial will be stopped for futility, i.e., without rejection of the null hypothesis. If p1≤α1 
(with α1=0.0131 according to Bauer & Köhne, 1994, p. 1031) the null hypothesis (H0) can be 
rejected at stage 1 and the trial is terminated. If α1<p1≤α0 the trial will be continued (stage 2) with 
an additional sample size of n2=41 patients per group. If the trial enters the second stage, the 
null hypothesis is rejected at the final analysis if the product of the stage-wise p-values p1p2 falls 
below the critical boundary of cα = 0.0038.  
 

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9.5 
Secondary Analyses  
Secondary endpoints A), B) and C) will be analysed analogously to the primary endpoint, i.e.  from 
the time*condition interaction of a mixed linear model. Amygdala response (secondary endpoint 
D) and changes in amygdala self-regulation (secondary endpoint E) will be using mass-univariate 
GLM and region of interest analysis. Neural response will be quantified by fitting the hemodynamic 
response function to the amygdala BOLD-signal time course. Resulting values will be statistically 
analysed using analysis of variance. Secondary endpoint F) (health care utilization) will be include 
analyses of productivity loss and its associated direct and indirect costs between groups from a 
societal perspective. Statistical analyses will be performed strictly according to the ITT principle. 
Missing data will be imputed with the last observation carried forward (LOCF) method, a 
conservative approach strengthening the null-hypotheses of equal costs and effects between 
intervention and control condition. Cost data are mostly highly right-skewed. Therefore, we will 
apply generalized linear models (GLM) with gamma distribution and identity link function to 
estimate differences in health care costs between groups. We will perform a crude model 
containing randomization group as explanatory variable and an adjusted model containing 
randomization group (study site), and baseline costs as explanatory variables. As the time horizon 
of the study is one year, we will not discount costs and outcomes. 
For the cost-utility analysis, the outcome is quality-adjusted life years (QALY). QALYs are 
commonly used aggregate measures of quality and quantity of life and are used to compare the 
cost-effectiveness of a broad range of health care interventions. We will calculate QALY for V1 
and T3 using the multi-attribute utility instrument Assessment of Quality of Life (AQoL)-6D. 
Unfortunately, there are currently no German value sets with preference weights for the AQoL-
6D. Thus, we will use the established value sets and norms from Australia and the cross-walks 
for the EQ-5D-5L version to elicit QALYs. We will calculate incremental cost-effectiveness ratios 
(ICER), defined as the ratio between net total costs and net effects To satisfy the condition of 
statistical uncertainty around the ICER, we will perform non-parametric bootstrapping with 1,000 
to 5,000 replications, which will be plotted on cost-effectiveness planes. Likewise, we will calculate 
bootstrapped 95% confidence intervals (95%CI) around the ICER. Since willingness-to-pay 
thresholds are usually unknown, we will calculate the incremental (net) monetary benefit (NMB) 
of the neurofeedback treatment. While the NMB approach is a function of willingness-to-pay 
thresholds, we will use different thresholds and illustrate them as cost-effectiveness acceptability 
curves. Consequences of uncertainty are visualized using value of information (VOI) curves. 
Safety analyses will be based on AEs, SAEs, and potential deterioration in the ZAN-scale. 
9.6 
Interim Analyses 
One scheduled interim analysis will be carried out on the primary endpoint at the end of stage 1, 
i.e. after 82 participants (n1=41 per group) have reached the primary endpoint according to the 
ITT principle. If the p-value pertaining to the primary outcome in stage 1 (p1) exceeds the critical 
threshold of α0=0.3 in stage 1 the trial will be stopped for futility, i.e., without rejection of the null 
hypothesis. If p1≤α1 (with α1=0.0131 according to Bauer & Köhne, 1994, p. 1031) the null 
hypothesis (H0) can be rejected at stage 1 and the trial is terminated. If α1<p1≤α0 the trial will be 
continued with an additional sample size of n2=41 patients per group (stage 2). The interim 
analysis will be carried out by unblinded statisticians at the KKS Heidelberg. The results will be 
communicated to the DSMB. Otherwise, the results will not be disseminated inside or outside the 
clinical investigation team. The KKS will communicate the decision to STOP or to CONTINUE 
directly to the sponsor.  
For pragmatic reasons (in particular to guarantee feasibility of recruitment within the scheduled 
time) no further interim analyses are planned.  

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9.7 
Sensitivity Analyses 
In addition to the intent-to-treat analyses all analyses will be carried out per protocol. In the event 
of deviations with regard to significance the assessment of statistical significance will be based 
on the intent-to-treat analyses. 
9.8 
Subgroup Analyses 
On a descriptive level, analyses of the primary endpoint will be carried out for both men and 
women. Because the sample is relatively small, we anticipate that the case numbers for the 
gender diverse subgroup and for other races/ethnicities than Caucasian will be too small to allow 
for reliable subgroup analyses. 
 
9.9 
Sample Size / Power Calculation 
Power calculations were carried out to determine the sample size needed for achieving an overall 
power of 1-β≥0.90 for the primary outcome. This power analysis is based on the improvements 
(i.e. pre-post differences of the mean negative affect) and the pooled standard deviation of these 
improvements as observed in our pilot data12. Mean improvements were 0.37±0.52 in the group 
with amygdala-NF and 0.03±0.44 in the control group. This translates to a between-group 
difference in the improvements of 0.34 and a pooled standard deviation of 0.46, which 
corresponds to a standardized mean difference (SMD) of δ1=0.74. Despite the lack of established 
minimally relevant difference, SMDs above 0.50 are likely highly relevant because negative affect 
assessed in real life conditions is crucial for individuals with BPD and closely relates to 
dysfunctional and self-harming behaviors. The utility of an add-on intervention that can be 
combined with traditional treatment is particularly high. As suggested by the International 
Committee of Harmonization (ICH) E9 guideline, sensitivity analyses were considered when 
determining the sample sizes n1 and n2 (i.e. the n’s per group at stages 1 and 2 of the sequential 
trial). To this end, the following scenarios were investigated. Scenario (S1) based on the point 
estimates according to the pilot data analyses, i.e. an absolute group difference (AGD) of 0.34 in 
the improvement of the mean negative affect and a pre-to-post correlation (r=0.82) required for 
specifying the correlation matrix in the power analysis were complemented by scenarios (Sa-Sc) 
based on more conservative, albeit realistic values for r and the AGD. For correlation r, the lower 
end of the 95% confidence interval (i.e. r=0.73) was considered, while sensitivity analyses 
alternatively considered an AGD of 0.23 (instead of 0.34), which corresponds to a medium SMD 
of 0.50, which is both plausible according to the pilot data and still presents a clinically meaningful 
difference. Furthermore, as suggested by Pilz et al.72, we set a constraint for the minimal 
conditional power of 0.70 for stage 2 and have split n1 and n2 to minimize the expected total 
sample size. These conditions were required for all scenarios considered under H1 (i.e. S1, Sa-
Sc). Accordingly, n1=41 plus (possibly) n2=41 participants per group are needed to achieve an 
overall power of 90% in all of these scenarios. Accordingly, the maximum total sample size is 
164. 
 
 

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10. 
Data Management 
For more details refer to the corresponding data management plan (DMP). All data management 
activities will be conducted according to the current SOPs.  
10.1 
Data Collection and Handling  
In this clinical investigation the clinical data management system MARVIN by EvidentIQ Germany 
is used for data collection by using an electronic CRF (eCRF) with remote data entry (RDE).  
All entries in the CRF must be verifiable by source documents. There must be no data that are 
inconsistent between eCRF and source documents. In addition, source documents must reflect 
that the subject has been enrolled in this clinical investigation and must include all medical 
information necessary for appropriate medical care outside of the clinical investigation.  
All CIP-required information collected during the clinical investigation must be entered into the 
eCRF by the investigator or a designated representative. There must not be subject identifying 
data in the eCRF. Data corrections must always be justified. Data entry should be completed 
within 7 days after the respective investigational procedure (e.g., an examination). Any pending 
data entries have to be completed immediately after the final examination. Missing data should 
be explained. Completeness and correctness of all data entries in the eCRF have to be confirmed 
by dated electronic signatures of the responsible investigator. 
10.2 
Data Cleaning and Quality Checks 
Data entries will be checked for plausibility and consistency. The checks are defined in the clinical 
investigation specific data validation plan (DVP). In case of implausibilities, 'warnings' will be 
generated during data entry (edit checks). The responsible investigator or a designated 
representative must then either correct the entered data or confirm its correctness by giving an 
appropriate explanation. The responsible data manager will check all explanations and resolves 
the warnings if the explanation is appropriate. The responsible monitor may raise electronic 
questions (monitor queries) to the responsible investigator as well. The investigator or a 
designated representative should answer queries within 7 days. The responsible monitor will 
verify the answer and will resolve the query if the answer is appropriate. A similar query flow can 
be used by the data manager (DM query). 
All missing data or inconsistencies have to be clarified by the responsible investigator prior to 
database lock. If no further corrections in the database are required it will be declared as locked 
and used for statistical analysis. 
 

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11. 
Archiving and Storage 
11.1 
Essential Records and Source Data 
The sponsor will archive the Trial Master File (TMF), CRFs, and reports. The investigator will 
archive the Investigator Site File (ISF) as well as source data. Records and source data will be 
stored for at least 10 years after the end of the clinical investigation.  
Any change of data ownership shall be documented. All data shall be made available to relevant 
authorities on request.  
11.2 
Collection, Storage and Future Use of Biological Samples and 
Corresponding Data 
Not applicable 
 

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12. 
Regulatory, Ethical and Oversight Considerations 
12.1 
Compliance Statement 
This clinical investigation will be conducted in compliance with the clinical investigation plan and 
in accordance with the following regulatory requirements: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines, 
 
ISO 14155:2020(E), 
 
Applicable laws and regulations 
12.2 
Data Protection and Subject Privacy 
Data obtained during the clinical investigation will be handled pursuant to the EU General Data 
Protection Regulation (GDPR) and national regulatory requirements. 
To ensure confidentiality of records and personal data, only pseudonymized data will be 
transferred to the sponsor by using a subject identification number instead of the subject’s name. 
The code is only available at the site and must not be forwarded to the sponsor. In case a subject’s 
records will be forwarded e.g. for SAE processing or adjudication committees, personal data 
identifying the subject will be redacted by the site prior to forwarding. Access to the subject’s files 
and clinical data is strictly limited. Data specific for the clinical investigation generated at the site 
need to be available for inspection on request by the local participating investigators, the 
sponsor’s representatives, by the IRB / IEC and the regulatory authorities. A potential data 
security breach will be assessed regarding the implications for rights and privacy of the affected 
person(s). Immediate actions as well as corrective and preventive actions will be implemented. 
Respective regulatory authorities, IRBs / IECs and subjects will be informed as appropriate.  
Data transferred directly to the sponsor will be kept on in-house servers of the Central Institute of 
Mental Health where security measures are in place to prevent unauthorized access from outside 
the institute. Access to data directories will be limited to trial staff who is required to access the 
data to fulfill their tasks. An automatic back-up system saves data for 6 weeks to restore data 
after loss.  
Sites will inform sponsor about a potential data privacy breach in connection with the clinical 
investigation immediately when it is brought to their attention.  
12.3 
Approval of the Clinical Investigation 
This clinical investigation will be initiated only after all required legal documentation has been 
reviewed and approved by the responsible IRB / IEC and the regulatory authority has been 
notified according to national and international regulations. The same applies for the 
implementation of changes introduced through modifications.  
12.4 
Subject Information and Informed Consent 
Before being enrolled in the clinical investigation, the subject must consent to participate after 
being fully informed by an investigator about the nature, importance, risks and individual 
consequences of the clinical investigation and his/her right, to terminate participation at any time. 
The subject should also have the opportunity to consult the investigator, or a physician of the 
investigating team about the details of the clinical investigation. The investigator shall emphasize 
that subjects are completely free to participation or to withdraw later on at any time, without 
suffering consequences for future care and without the need to justify (see section 7.3.1).  

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Each subject will be informed that his/her source records may be reviewed by the local 
investigators, the monitor of the clinical investigation, a quality assurance auditor or authority 
inspector, and the IRB/EC in accordance with applicable regulations, and that these persons are 
bound by confidentiality obligations. 
After reading the informed consent document, subject and physician conducting the informed 
consent discussion must sign and personally date the informed consent form. A copy of the signed 
informed consent document must be given to the subject; the original will be filed by the 
investigator. A copy of the information about insurance must be given to the subject. 
The information process must be documented in the source records. 
Written subject information must be in a language understandable to the subject and must specify 
who informed the subject. 
If the subject is unable to write, oral presentation and explanation of the content of the informed 
consent form and of the data protection information must take place in the presence of an impartial 
witness. The witness and the physician conducting the informed consent discussions must also 
sign and personally date the consent document. The witness must not be in any way dependent 
on the sponsor of the clinical investigation, the site or any member of the investigating team (e.g. 
an employee at the site).  
The subjects will be informed as soon as possible if new information may influence his/her 
decision to participate in the clinical investigation. The communication of this information should 
be documented. 
12.5 
Committee Structure 
12.5.1 Data Safety Monitoring Board (DSMB) 
The tasks of the DSMB are to ensure the ethical conduct of the clinical investigation and protecting 
the rights and welfare of the subjects.  
 
A DSMB made up of independent experts will be set up. It consists or 3 physicians who are not 
involved in the conduct of the clinical investigation. The task of the DSMB is to oversee the safety 
of the subjects in the clinical investigation by periodically assessing the safety and efficacy of the 
investigational therapy, and to monitor the integrity and validity of the data collected and the 
conduct of the clinical investigation. The DSMB will meet on a regular basis (approx. 1x per year). 
After reviewing the data on conduct of the clinical investigation (recruitment, CIP adherence / 
protocol deviations) and safety issues, the DSMB will make recommendations to the Steering 
Committee (SC) on the further conduct of the clinical investigation (modification, continuation, 
closure). 
For further details see charter. 
12.6 
Steering Committee (SC) 
The steering committee is comprised of the coordinating investigator and his supporting co-
investigators, i.e. clinical experts not directly involved in the clinical investigation and the 
responsible biometrician. The steering committee is responsible for the scientific integrity of the 
clinical investigation plan, the quality of the clinical investigation conducts as well as for the quality 
of the final clinical investigation report. The Steering committee will decide on the 
recommendations made by the DSMB. 

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12.7 
Insurance 
The insurance was taken out at HDI Global SE (insurance number: 57 010321 03010/03739). 

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13. 
Quality Control and Quality Assurance 
13.1 
Quality Assurance 
A risk-based approach is used for quality management of the clinical investigation. It is initiated 
by the assessment of critical data and processes for subject protection and reliability of the results 
as well as identification and assessment of associated risks. The rationale and strategies for risk 
management during conduct of the clinical investigation including monitoring approaches, vendor 
management and other processes focusing on areas of greatest risk will be documented. 
Continuous risk review and assessment may lead to adjustments in conduct, design or monitoring 
approaches of the clinical investigation. A quality assurance audit/inspection of this clinical 
investigation may be conducted by the sponsor, sponsor’s designees, or by IRB / IEC or by 
regulatory authorities (see section 13.4).  
13.2 
Monitoring 
Following a risk-based approach, a combination of monitoring techniques (central and on -site 
visits) will be used to monitor the clinical investigation.  
As the monitoring strategy will consider current aspects of risk-based quality management, 
frequency of monitoring activities per site will vary depending on recruitment and general 
performance, e.g. quality of documentation.  
The monitor will ensure that the clinical investigation is conducted according to the protocol and 
applicable regulatory requirements by reviewing essential records, source documents and entries 
into the CRFs (see section 0). The monitor will document the visits in a report for the sponsor. 
The site will be provided with a follow-up letter about the findings and the necessary actions to be 
taken. Details of monitoring will be defined in the monitoring plan. 
In case of critical findings during monitoring or an audit, the site might be closed prematurely by 
the sponsor (see section 7.6). 
13.3 
Source Documents 
In accordance with regulatory requirements, the investigator should maintain adequate source 
documents and investigational records including all observations / data pertinent to the 
investigation on each subject. Source data as well as reported data should follow the “ALCOA 
principles”, i.e. should be attributable, legible, contemporaneous, original and accurate. Changes 
to the data should be traceable (audit trail). All data reported on the eCRF must be consistent 
with and verifiable by the source data except for following “direct entries”: 
 
In- and exclusion criteria (yes/no checkboxes), excluding: psychiatric diagnoses listed in 
eligibility criteria, suicidality, fulfilling any of the MRI contraindications 
The current medical history of the subject may not be sufficient to confirm eligibility for the clinical 
investigation so that the investigator may need to request records on previous medical history 
and test results. In case of incompliance, any corrective action e.g. repeated instructions must be 
documented in the subject’s medical records, too. 
13.3.1 
Direct Access to Source Documents  
According to ISO 14155:2020(E), the investigator(s) / institution(s) must provide direct access to 
source data / documents for monitoring related to the clinical investigation, audits and inspections 
by regulatory authorities. Via the written informed consent each subject has agreed to grant 
monitors and auditors related to the clinical investigation and inspectors from regulatory 
authorities direct access to his/her original medical records (see section 12.4). 

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In case of electronic medical records, the monitor’s / auditor’s / inspector’s access must be 
restricted to the subjects. If this is not possible the files have to be reviewed in the presence of 
site staff. The electronic medical record should have an accessible audit trail. 
13.4 
Audits and Inspections 
Representatives of the sponsor may visit the site at any time during or after completion of the 
clinical investigation to audit compliance with applicable regulatory requirements and sponsor’s 
policies. Similarly, officials of the responsible authorities may carry out inspections either as part 
of a national GCP compliance program or to review the results of the clinical investigation in 
support of a regulatory submission. Both audits and inspections will require access to all records 
of the clinical investigation and source documents (see section 13.3.1). The investigator and site 
personnel must be available for consultation during site audits / inspections.  
The investigator should immediately notify the sponsor if he/she becomes aware of an upcoming 
inspection. 
13.5 
Deviations from the CIP (Protocol Deviations) 
Definition, categorization and examples of protocol deviations (PD) are described in the PD Log 
specific for the clinical investigation and the applicable SOPs. 
 
Figure 6 provides a decision tree how to deal with missed or interrupted MR-scans. Whenever 
the regular schedule is left (i.e., ‘no’-arm is true), a PD has to be documented. If the indicated 
time intervals are exceeded, the subject has to be discontinued (early discontinuation). 

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Figure 6. Decision-tree of missed/interrupted MR-visits. If rescheduling of a session is demanded, 
the investigator needs to make sure that the visits are done in line with the period as defined 
above. C.f. section 3.4 Figure 5, Patient Time Flow. 
 

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14. 
Administrative Agreements 
14.1 
Financing of the Clinical Investigation 
This research is funded by federal funding agency German Research Foundation (Deutsche 
Forschungsgemeinschaft, DFG), PA 3107/4-1 and SCHM 1526/26-1, project #502833016. 
Access to core facilities for Magentic Resonance Imaging (MRI) and technical services, including 
provision of servers, computers and licenses for analysis software is partly funded by DFG and 
the sponsor, Central Insitute of Mental Health.  
14.2 
Financial Disclosure 
Investigators will provide the sponsor with accurate financial information in accordance with local 
regulations allowing the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the conduct of the clinical investigation. The 
investigator agrees to update this information in case of significant changes. 
14.3 
Publication Policy / Dissemination of Data of the Clinical Investigation 
A summary of the clinical investigation data will be written after all subjects have completed the 
clinical investigation. The sponsor will submit a summary of the final results of the clinical 
investigation within 12 months after the regular completion or 3 months after early termination or 
temporary halt of the clinical investigation. The rights of the investigator and the sponsor regarding 
publication of the results of the clinical investigation are described in the investigator contract. In 
general, no results of the clinical investigation should be published prior to finalization of the 
summary. 
The results of this trial will be published as an original article in a peer-reviewed medical journal. 
As far as preprints are allowed by the target journals, the manuscripts will be submitted to a 
preprint server such as bioRxiv or medRxiv before submission to the journal. 
 
We expect following types and numbers of publications: 
Primary publications: 
• 
1 paper of the study protocol 
• 
1 main clinical trial results report presenting clinical efficacy results of primary and 
secondary outcomes 
• 
1 paper presenting neuroimaging results 
• 
1 paper describing the published dataset 
Secondary publications: 
• 
Papers from sub-projects and secondary data analysis  
Authorship will be defined according to the International Committee of Medical Journal Editors 
(ICMJ, 
https://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-
role-of-authors-and-contributors.html). Below persons qualify for authorship in primary and 
secondary publications, as long as they will have met all four ICMJ criteria at time of manuscript 
submission: 
 
Steering committee members 
 
Up to one staff of recruiting sites per paper, additionally to SC-members 
 
Miroslava Jindrová (data manager) 
 
Matthias Ruf, Gabriele Ende (ZI Mannheim) 

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 
Rainer Goebel, Michael Luehrs (BrainInnovation) 
 
Representatives from KKS Heidelberg (Clinical/project manager), biostatistician (NN) 
 
PRB members 
 
For papers from sub-projects: authors of the sub-project abstract and additional staff 
involved in the sub-project. 
One representative of each center will be included on each primary and secondary paper. The 
project leaders will lead primary publications and may assign first and senior author position 
between them. Authorships of secondary publications and order of authorship of all publications 
is to be discussed in the steering committee. The project leaders may appoint co-authors listed 
above as (equally contributing) first/senior authors if they think that this is justified by the quality 
and/or effort of the contribution. 
Other researchers that contribute significantly to secondary publications may be listed as authors 
as well. 
The results of this trial will be published with open access. The study procedures will be described 
in depth to warrant reproducibility of trial methods and data analysis. The study protocol and other 
non-proprietary, unprotected documents will be published with open access, as long as 
publication of materials does not predate the privacy of trial participants and trial staff. Study 
materials such as scripts to present experimental stimuli, experimental stimuli themselves and 
questionnaire templates will be published with open access as long as they are not IP/patent 
protected.  
14.4 
Registration of the Clinical Investigation 
Prior to the beginning of the clinical phase the study was registered at http://www.clinicaltrials.gov. 
14.5 
Declaration regarding Data Sharing  
Individual participant data (IPDs) will be made available, as far as legally possible. IPDs (including 
metadata such as data dictionaries) that underlie results concerning primary or secondary 
endpoints reported in a published scientific article will be shared on demand after deidentification. 
Furthermore, the following documents may be made available: Study Protocol, Statistical Analysis 
Plan or Informed Consent Form.  
Data will be published on the open data repository “heiDATA” with restricted access, where it will 
be citable with a DOI. HeiDATA is an institutional repository for Open Research Data from 
Heidelberg University. It is managed by the Competence Centre for Research Data, a joint 
institution of the University Library and the Computing Centre. Data from participants who do not 
consent for upload will not be shared on heiDATA. Access to the dataset on heiDATA will be 
embargoed until the primary publication of the clinical trial results is accepted for publication. 
 
 
 

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15. 
References 
Regulations and norms referred to in this CIP: 
(1) WMA Declaration of Helsinki – Ethical Principles for Medical Research involving Human 
Subjects; Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and 
amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. 
(2) ISO 14155:2020, Clinical investigation of medical devices for human subjects — Good 
clinical practice. Third Edition, 2020-07 
(3) Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 
on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 78/2002 and 
Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 
93/42/EEC; OJ L 117, 5.5.2017, p. 1–175; Current consolidated version: 20/03/2023. 
(4) EMEA/CHMP/EWP/5872/03 Corr: Guideline on Data Monitoring Committees. Effective date 
2006-01-01. 
(5) Medical Device Law Implementation Act of 28 April 2020 (Federal Law Gazette [BGBl.]) 
Part I p. 960, last amended by Article 3f of the Act of 28 June 2022 (Federal Law Gazette I 
p. 938). 
(6) Civil Code in the version promulgated on 2 January 2002 (Federal Law Gazette 
[Bundesgesetzblatt] I page 42, 2909; 2003 I page 738), last amended by Article 1 of the Act 
of 10 August 2021 (Federal Law Gazette I p. 3515). 
(7) Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 
on the protection of natural persons with regard to the processing of personal data and on 
the free movement of such data, and repealing Directive 95/46/EC (General Data Protection 
Regulation) (Text with EEA relevance); OJ L 119, 4.5.2016, p. 1–88; Current consolidated 
version: 04/05/2016. 
(8) Betäubungsmittelgesetz (narcotic act) in der Fassung der Bekanntmachung vom 1. März 
1994 (BGBl. I S. 358), das zuletzt durch Artikel 2 des Gesetzes vom 26. Juli 2023 (BGBl. 
2023 I Nr. 204) geändert worden ist. 
(9) Strahlenschutzgesetz (radiation protection act) vom 27. Juni 2017 (BGBl. I S. 1966), das 
zuletzt durch die Bekanntmachung vom 3. Januar 2022 (BGBl. I S. 15) geändert worden 
ist. 
(10) Clinical Trial Facilitation Group (CTFG) Recommendations related to contraception and 
pregnancy testing in clinical trials; Version 1.1; 2020-09-21. 
 
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Appendix 1: List of Technical and Functional Features of the 
Investigational Device 
Description below is based on document BPD-CE-REC-Clinical-Evaluation-Plan-SW-TBV-Med-
BPD_20240709 received from BrainInnovation.  
TBV MED BPD contains the following data processing and visualization functionality: 
 
Reading of EPI slices into working memory 
 
3D motion correction (report of within-run motion) 
 
3D spatial smoothing 
 
Incremental statistical analysis (RLS GLM) 
 
Drift removal via design matrix (confound predictors) 
 
Incremental event-related averaging 
 
Thresholding, clustering and color-coding of resulting statistical maps 
 
Creation of anatomical projects within TBV MED BPD (including brain extraction, B1 
inhomogeneity correction) 
 
Advanced visualizations in volume (Native, MNI) space 
 
Connectivity Feedback, i.e. Windowed Pearson and Partial Correlation 
Export to Files (RTP, ERT, BTC, Neurofeedback values) enabling link to external 
stimulation software and different feedback types (visual, auditory, tactile) and 
feedback displays 
 
Visualization of export and computation time for each volume: 
o 
Shorter than one TR 
o 
TBV MED BPD shows a warning/error message when time limit is exceeded 
during the scanning 
Restrictions: 
 
No support of plugins 
 
No Surface Space available 
 
Operating system: Windows 10 (64-bit) 
TBV MED BPD can be used with the following MRI scanner: 
 
Manufacturer: Siemens 
 
Model: Prisma (Fit) 
 
Static magnetic field (B0) strength: 3T 
 
Restrictions to specific software versions of the scanners (minimum VB17): syngo MR 
E11 
 
Image file type: restriction to DICOM 

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Further specifications: 
 
Structural sequences 
o 
T1-weighted (MPRAGE / ADNI) for Anatomy Creation 
o 
Standard resolution: 1mm3 isotropic 
 
Functional sequences 
o 
T2*-weighted 
 
Data from other sequences, such as a localizer and gradient field mapping, can be 
acquired before starting NF 
 
For each approved sequence an example dataset has to be provided 
 
Given a baseline level bl, the feedback value fb for the current time point (without/prior 
to averaging) with value val is calculated within a neurofeedback trial simply as follows: 
fb = (val - bl) / bl * 100. This results in a percent signal change (PSC) value that can be 
used for neurofeedback, e.g. by filling a thermometer display (see below). Note that if 
the detrending time course (default) option is used, the input values to the 
neurofeedback calculation are already (GLM detrended) PSC values. In this case, the 
equation simplifies to: fb = (val - bl). 
 
Installation  
The setup of TBV MED BPD in the scanner environment consist mainly of two parts: Enabling the 
real-time data export of the MRI images and the access to this exported data from another 
computer running TBV MED BPD. 
 
As shown in Figure 2 above, the MRI images are exported in real-time from the MRI console 
computer to the TBV MED BPD computer. On the TBV MED BPD computer all images will be 
read and processed from a specified directory called "watch folder" in TBV MED BPD. It is 
essential that the MRI console computer exports the images to a shared folder provided by the 
TBV MED BPD computer. Otherwise the real-time export could be decelerated because of 
multiple network queries that are necessary to read the MRI images. To ensure a fast and reliable 

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data transmission and processing the user needs to verify that all computers that are not 
necessary for the fMRI experiment are excluded from the network or turned off. The more 
computers are in the network the more likely it becomes that a prolonged (i.e. non real-time) 
transmission time occurs. It is recommended to set the power plan of the operating system (if 
available) to maximum performance. This ensures that the whole processing of the MRI images 
including online reconstruction from k-space to image space can be realized as fast as possible. 
A minimum to use a computer for TBV MED BPD that possesses a minimum of 8GB of working 
memory, powerful processor and good OpenGL capable graphics card is recommended. While 
TBV MED BPD is a highly efficient program, the usage of latest PC hardware should be favored. 
 
An example network structure is shown in Figure 3. The shared folder is provided by the TBV 
MED BPD computer and can be reached via its host name or IP. After setting up the connection 
one can define the settings and parameters in the TBV MED BPD Settings dialog. 
Setup for Neurofeedback 
TBV MED BPD supports the advanced real-time application of neurofeedback. The feedback will 
be conveyed to the subject during the experiment. A conceptional overview of a typical 
neurofeedback setup is shown in the picture below. 

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In most cases a video projector is used to convey a visual feedback to the subject in the scanner 
(but auditory or tactile information has also been used with TBV MED BPD). While TBV MED 
BPD supports custom feedback visualizations by exporting ROI data in real-time to disk, one can 
in many cases simply use the in-built neurofeedback dialog to produce feedback visualizations. 
The neurofeedback dialog allows to select the data from one or more ROIs as the source of 
feedback information for a subject during an ongoing measurement. 
Update procedure 
Updated TBV MED BPD versions can be downloaded from the Brain Innovation servers and 
installed by the IT or MRI technician in admin mode. 
Remote maintenance 
User support will be provided via an online helpdesk and by telephone. 
Specification of Control Parameters for Real-Time Analysis 
In order to run successfully, Turbo-BrainVoyager MED BPD (TBV MED BPD) needs to know 
several pieces of information about the local environment. The most important information is the 
location of the data, i.e. the location where the incoming scanned slices are to be expected. In 
order to find the data, the program looks in the MasterTBV file. The user can edit the master file 
directly or more conveniently using the MasterTBV File dialog. 
The MasterTBV file provides the highest level of control by pointing to a "TBV Watch Directory". 
This directory may contain TBV MED BPD settings files, which provide the next level of control, 
containing information about a particular run in a particular session. A TBV MED BPD settings file 
is stored in JSON format with extension ".tbvj" and contains information about the expected data 
coming from the scanner as well as settings controlling real-time analysis and visualization. There 
are also "MTBV settings files", which specify analyses across multiple runs within a session. The 
user can edit a TBV MED BPD file directly or more conveniently using the TBV MED BPD Settings 
File dialog. 
 
 

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Appendix 2: Contraceptive and Barrier Guidance 
Definition of women of childbearing potential (WOCBP): 
For the purpose of this clinical investigation, a woman is considered of childbearing potential, i.e. 
fertile, following menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
Birth control methods which may be considered as highly effective: 
For the purpose of this clinical investigation, methods that can achieve a failure rate of less than 
1% per year when used consistently and correctly are considered as highly effective birth control 
methods. Such methods include: 
 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
 
progestogen-only hormonal contraception associated with inhibition of ovulation:  
o oral 
o injectable 
o implantable1 
 
intrauterine device (IUD)1 
 
intrauterine hormone-releasing system (IUS)1 
 
bilateral tubal occlusion1 
 
vasectomized partner1,2 
 
sexual abstinence3 
Acceptable birth control methods which may NOT be considered as highly effective: 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
 
progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
 
male or female condom with or without spermicide4 
 
cap, diaphragm or sponge with spermicide4 
                                               
1 Contraception methods that are considered to have low user dependency. 
2 Vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual partner of the subject and 
that the vasectomized partner has received medical assessment of the surgical success. 
3 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the investigational treatment. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical investigation and the preferred and usual lifestyle of the subject 
4 A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also considered 
acceptable, but not highly effective, birth control methods 

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Pregnancy information: 
All menarchal females should be informed about the potential risks of pregnancy and the need to 
prevent pregnancy during the clinical investigation. It is important to be sensitive in introducing 
this issue, as understanding and comprehension of sexual activity, pregnancy and contraception 
is influenced by age, socio (educational) economic and familial background. Therefore 
consultation, monitoring and questioning regarding potential sexual contacts with the subject are 
to be performed at every visit by investigators familiar with the subject. The consultations should 
consider the socio-economic, cultural factors and religious beliefs of the subject. The investigator 
should discuss possible birth control methods and the management of the pregnancy test results 
with the subject.  
 
 

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Appendix 2: Informed Consent and Recruitment Process 
No special arrangements or processes necessary, ref. chapter 12.4. 
 
 

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Appendix 3: Provisions regarding Exceptional Circumstances 
Not applicable