Central Programming in Patients With a Bionic Hand After Traumatic Brachial Plexus Injury
Conditions: Brachial Plexus Neuropathies, Traumatic Brachial Plexus Lesion, Bionic Hand Reconstruction
Sponsor: Medical University of Vienna

 
 
 
 
 
Clinical Investigation Plan (Klinischer Prüfplan), Version 1.2 
 
 
Central programming in patients with a bionic 
hand after traumatic brachial plexus injury 
“Zentrale Programmierung von PatientInnen mit einer bionischen 
Rekonstruktion nach einer Plexusparese“ 
 
 
Sponsor 
Medizinische Universität Wien, Universitätsklinik für Chirurgie 
Währinger Gürtel 18-20 
1090 Wien 
 
Principal Investigator („Prüfarzt“): 
Univ.-Prof. Dr. Oskar Aszmann 
Medizinische Universität Wien, Universitätsklinik für Chirurgie 
Klinisches Labor für bionische Extremitätenrekonstruktion 
Währinger Gürtel 18-20 
1090 Wien 
 
Lead Investigator: 
Dr. ir. Galia V. Anguelova 
Haaglanden Medical Centre 
The Hague, The Netherlands 
(Visiting Researcher at Medical University of Vienna, Austria) 
 
CIP authors: 
Oskar Aszmann 
Galia Anguelova 
Agnes Sturma 
Anna Bösendorfer 
Mehmet Salih Yildirim 
Victor Schmidbauer 
Gregor Kasprian 
 

 
 
2 
 
 
 
 
 
Index 
Abstract 
3 
Introduction 
4 
Research questions 
5 
Hypothesis 
5 
Design 
5 
Risk-benefit assessment 
9 
Experimental subjects: informed consent procedure 
9 
Discontinuation/withdrawal of participants from study 
10 
Duration and scale 
10 
Procedure for handling study results 
10 
Compensation 
11 
Safety reporting and insurance 
11 
Agreements on publication 
11 
Funding statement 
11 
References 
11 
 
 

 
 
3 
 
 
 
 
Abstract 
Traumatic brachial plexus lesions may lead to permanent impairment of hand function 
despite brachial plexus surgery. In selected cases the affected forearm can be 
amputated and replaced by a bionic hand. It is unclear how cortical activation patterns 
change after the injury and after acquisition of the hand prosthesis considering the 
complex changes in sensory and motor feedback. 
 
The aim of the study is to measure cortical activity with fMRI during actual and imagery 
movements with the affected and healthy arm in a group of patients after traumatic 
brachial plexus injury and a group in whom this was followed by replacement with a 
bionic hand. 
 
In this prospective study three groups of patients will participate: 1) 3 adult patients 
with a traumatic brachial plexus lesion eligible for a bionic arm but prior to its 
acquisition, 2) 3 patients with a traumatic brachial plexus lesion who have acquired the 
bionic arm already, and 3) 10 healthy subjects. We will measure cortical activity using 
fMRI BOLD tasks of closing the hand and motor imagery of this movement. Cortical 
activity will be compared between the three groups. Additionally, regional gray matter 
volume, resting-state, and DTI networks will be studied. Written informed consent will 
be provided prior to the investigation. The complete examination has a duration of 
approximately 45 minutes. 
 

 
 
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Introduction 
In this study we want to investigate what changes take place in the brain after a 
traumatic brachial plexus lesion followed by acquiring a bionic hand. These patients 
have acquired a global brachial plexus injury including avulsions of the lower nerve roots 
(C8-Th1), which are responsible for hand function. They have a poor hand function 
despite brachial plexus surgery. After an extensive training program these patients 
acquire a myoelectric hand prosthesis (Sensor hand speed (Otto Bock HealthCare 
Deutschland, GmbH, Germany) or similar) and their affected hand is amputated. The 
acquired bionic hand is surface EMG driven by the remaining arm muscles after nerve 
and muscle transfer, if necessary. (Aszmann, et al., 2015; Sturma et al, 2018) Thus, the 
patients have to learn how to control the bionic hand with new motor and sensory 
feedback signals. It is unclear what changes occur in the brain to succeed at this. 
 
Functional MRI (fMRI) can identify cortical plasticity in humans. (Anastakis et al., 2005) 
Additional motor imagery tasks allow us to assess the changes in cortical areas involved 
in motor planning. (Decety and Grezes, 1999) We know that motor cortical  areas 
expand at the onset of learning a new motor skill in healthy subjects, but also in patients 
following upper extremity injury and reconstruction. (Anastakis et al., 2005) These areas 
decrease again when a skill is being mastered. (Anastakis et al., 2005) In amputees a 
higher contralateral cortical activation was found during imagined phantom hand 
movements compared to healthy subjects. (Lotze et al., 2001) It has been suggested 
that this is due to an increased central effort required for action planning. (Hotz- 
Boendermaker et al., 2008) However, motor imagery ability of the affected and 
unaffected limbs in patients with complete traumatic brachial plexus palsy has been 
shown to decrease, possibly due to long-term disuse. (Date et al., 2019) And in adults 
with an obstetric brachial plexus lesion cortical activation is increased only for 
movement planning but not actual movement. (Anguelova et al., 2017) Cortical changes 
have also been found when using the healthy arm in these patients. (Anguelova et al., 
2017) 
 
Thus, the aim of this study is to elucidate with fMRI what changes occur in cortical 
activity in patients with a traumatic brachial plexus lesion followed by forearm 
amputation and acquisition of a bionic hand. Understanding what cortical changes 
occur, may help us in the future to acquire a better patient selection for this 
intervention and possibly improve rehabilitation schemes. 
 

 
 
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Research questions 
1) Does the cortical activation increase in the contralateral hemisphere during 
movement of the corresponding affected arm after traumatic plexus lesion compared to 
healthy subjects? 
 
2) Are different cortical areas activated in the contralateral hemisphere during 
movement of the affected arm after traumatic plexus lesion than those in healthy 
subjects or does the expected area of activation expand? 
 
3) Does cortical activity increase or expand in the ipsilateral hemisphere (responsible for 
the healthy arm) during movement of the affected arm after traumatic plexus lesion? 
 
4) Does cortical activity increase or expand in both hemispheres during movement of 
the healthy arm after traumatic plexus lesion? 
 
All of the above questions will be addressed for two groups of patients: 1. patients who 
are eligible for bionic reconstruction but have not acquired it yet, and 2. patients with a 
bionic arm. 
 
Hypothesis 
Cortical activity increases and the area expands which is responsible for performing and 
planning a motor task in patients after traumatic brachial plexus lesion prior as well 
after bionic hand acquisition compared to healthy control subjects for both the affected 
and unaffected side. 
 
Design 
a) Selection of experimental subjects 
A group of 3 adult patients who acquired a bionic hand at the Medical University of 
Vienna after a traumatic brachial plexus lesion, and a group of 3 patients eligible for the 
bionic hand prior to a possible amputation will be included. The number of patients 
included is based on the rarity of the procedure and thus the very limited number of 
eligible study participants. Ten control subjects will be included for comparison. An 
inclusion criterion for all participants is an age above 18, and that they understand 
German or English. Brachial plexus surgery is not an exclusion criterium for patients. 
Patients with a bionic hand are selected who are able to open and close the hand 
prosthesis. The standard contraindications for MRI will be checked for according to 
hospital protocol (ferromagnetic devices such as clips, claustrophobia, etc.) and, if 
necessary, patients will be excluded from participation. 
 

 
 
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b) Procedure 
Cortical activation is measured with a Philips Achieva 3 Tesla MRI scanner at the 
University Department of Radiology and Nuclear Medicine of Vienna General Hospital. 
The MRI protocol will include the following sequences: T1-weighted anatomical scan, 
T2-weighted task related scans, resting-state, and DTI-sequence. 
 
Participants are requested to isometrically close their hand at the rate of 1Hz. This 
means to repeatedly squeeze their closed fist tight without an observed movement, 
thus avoiding MRI movement artifacts. This movement is selected based on a surface 
EMG signal to noise ratio higher than 3 in the patients with a bionic hand from a pilot 
study prior to this investigation. The arms are positioned in a straight position next to 
the body with the hand palm facing the body. Participants are instructed to lie still 
during the experiment. For the motor imagery task, participants are requested to 
imagine rhythmically (1Hz) performing the same movement. The tasks (execution and 
imagery) are performed by all participants (all three groups) with both arms separately. 
 
Task based fMRI will be applied using a block-design-paradigm to assess cortical 
activation patterns. Task instructions are represented by a visual and an audio cue. The 
visual cue is an image of a hand, either left or right corresponding to the task, which is 
presented on a computer screen using SensaVue and projected onto a mirror above the 
eyes of the subject. The audio cue indicates to either execute or imagine isometrically 
closing the hand and states which side to use (left or right). The audio instructions are 
given by the investigator through the MRI intercom before the start of the task. A 
crossed hand indicates rest (baseline). A thirty second baseline block is presented 
followed by a thirty second task block, comprising one cycle. A cycle is repeated five 
times during a total of five minutes. A total of four conditions is used in the same order 
for all participants: 1. execution left arm, 2. execution right arm, 3. imigary left arm, 4. 
imigary right arm. Subjects are given a break to rest (not scanning) between the four 
conditions, until they indicate they are ready to continue, to minimize the effects of 
(muscle) fatigue. 
 
A 10 minute fMRI resting-state sequence will be acquired to assess ongoing functional 
communication between brain regions during rest. For this sequence participants are 
instructed to think of nothing in specific while keeping the eyes closed. An 8 minute DTI- 
sequence will be acquired to assess the structural/anatomical brain connectivity; thus, 
no specific task is requested form participants. 
 

 
 
8 
 
 
 
 
An electromyography (EMG) training session prior to MRI scanning is used to assure the 
tasks are executed as requested. EMG is measured with electrodes placed over the 
muscle belly of the flexor digitorum superficialis and profundus in control subjects, the 
healthy arm in all patients, and the affected arm in patients who have not undergone 
amputation and prosthetic fitting yet. (Hermens et al., 1999) For the patients who have 
acquired a bionic hand already, the position of the electrode used for “hand close” 
within their prosthetic fitting is used. During MRI measurement the bionic hand is 
placed outside the MRI scanner as it is not MRI compatible but could be observed by the 
patients during the EMG training session. During the training session participants 
observe their EMG activity during the tasks on a screen. They are instructed to aim for 
activity in the agonist and reduce activity in the antagonist as much as possible during 
execution and not to activate both agonist and antagonist during imagery squeezing of 
the fist. Responses are acquired using a band pass filter of 20 Hz–2 kHz and recorded 
over a minimum of 100 s using. For recording the surface EMG either the MyoBoy in 
combination with the PAULA Software (both from Ottobock Health Care GmbH, 
Duderstatt, Germany) or the TeleMyo 2400T G2 System with myoMUSCLE Master 
software (both from Noraxon, Scottsdale, US) will be used. Both systems are CE-certified 
medical products. 
 
b) Analysis 
Cortical activity is compared between patients and control subjects as follows. 
fMRI data will be preprocessed with the SPM12 software package (Wellcome 
Department of Cognitive Neurology, Institute of Neurology, University College London, 
UK) in the MATLAB R2017a programming environment (MathWorks, Inc.; Natick,MA, 
USA). The following processing steps are applied: motion correction (Jenkinson et al., 
2002), removal of non-brain tissue, (Smith, 2002) spatial smoothing using a Gaussian 
kernel of 8 mm full width at half maximum, grand-mean intensity normalization of the 
entire 4D dataset by a single multiplicative factor and high-pass temporal filtering 
(Gaussian-weighted least-squares straight line fitting, with a 128 s cut-off). To register 
fMRI scans to standard space, functional scans of an individual are registered to the 
corresponding T2-weighted images, which are registered to the T1-weighted images, 
followed by registration to MNI-152 standard space (T1 standard brain averaged over 
152 subjects; Montreal Neurological Institute, Montreal, QC, Canada) images (Jenkinson 
and Smith, 2001; Jenkinson et al., 2002). Preprocessed MRI data of patients with an 
affected left arm are mirrored with respect to the midsagittal plane (Ward and 
Frackowiak, 2003). In this way the hemisphere corresponding with the affected hand is 
on the same (left) side for all patients and the right hemisphere corresponds with the 
unaffected hand. This is also done for the healthy subjects: the hemisphere responsible 
 

 
 
9 
 
 
 
 
for the non-dominant hand will, if necessary, be mirrored to be on the left side. Patients 
will be asked for how many days of the week and how many hours a day on avarage 
they have used the prosthesis in the past two weeks, as a possible correction factor 
(independent variable) for the amount of motor cortex activation. Additionally, resting-
state networks, DTI data and regional gray matter volume will be compared between 
patients and healthy subjects. 
 
EMG activity before MRI scanning is compared for the patient and control groups, and 
for each muscle and task separately. To exclude learning effects the first 50 s of the  
EMG signal for each of the four conditions (motor imagery/movement, right/left hand) 
are excluded from analysis. The EMG signal is then rectified and the sum of values 
between 50 and 100 s of the recording is calculated. The non-parametric dependent 
samples Wilcoxon’s test is used in IBM SPSS Statistics 25 with a significance threshold of 
0.05. 
 
Risk – benefit assessment 
The risk for study participation is negligible. If the experienced inconvenience turns out 
to be unexpectedly greater than estimated by the subject beforehand then participation 
in the investigation is stopped immediately. 
As no medical treatment is delivered, the benefits for the participants will be relatively 
little. For some of the amputees or participants with severe nerve injuries, it might be 
interesting to better understand how they cortically adapted to the situation. 
Additionally, participants will support basic research that might in the future have 
applications in the field of human-machine interfacing in healthy people and individuals 
with injuries and impairments. It is, however, unlikely that the cohort of participants 
supporting us within this study will ever directly benefit from the experiments. 
In summary, we do neither expect any great benefits nor any risks for the participants. 
As this is basic research, we do, however, hope to be able to use the findings to develop 
better rehabilitation technology in the future. This might include better interfaces for 
prosthetic control as well as better tools for the rehabilitation after nerve injuries. 
As we cannot guarantee that the participants will benefit from any of the possible future 
applications, we plan to compensate their time spend within the study with 10€/hour 
and reimburse their travel expenses. 
 
Experimental subjects: informed consent procedure 
Written informed consent will be required before performing the investigation. Not 
participating in the study or withdrawal from the study will not have any negative 
effects for the participants and will not affect the medical treatment of patients. 
 

 
 
10 
 
 
 
 
Discontinuation/withdrawal of participants from study 
Each participant has the right to withdraw study at any time without needing to give a 
reason for withdrawal. In addition, the investigator may discontinue a participant from 
the study at any time if the investigator considers it necessary for any reason including: 
 
• 
Ineligibility 
• 
Significant protocol deviation 
• 
Significant non-compliance with study requirements 
• 
An adverse event which makes further participation not possible 
• 
Consent withdrawn 
 
The reason for withdrawal will be recorded. If the participant is withdrawn due to an 
adverse event, the investigator will arrange for follow-up visits or telephone calls until 
the adverse event has resolved or stabilised. Only after participant approval, data 
already collected before withdrawal from the study will be included in the analysis. 
 
Duration and scale 
Participants will be contacted and scanned (training session prior to scanning included) 
from September 2020 onwards (pending ethical approval). 
Eligible participants will receive an information letter with an attached informed 
consent form and an enclosed return envelope. 
Expected time for scanning is 45 minutes. Including the time for EMG training and 
instructions before scanning, the full duration of one experiment is 1.5 to 2 hours. 
 
Procedure for handling study results 
Research data will be processed under a number for each patient. The gathered MRI 
scans will be saved and managed corresponding to that number in a file. The data are 
accessible exclusively to the involved investigators: 
- Dr. ir. Galia V. Anguelova, Haaglanden Medical Centre, The Hague, The Netherlands 
- Dr. Agnes Sturma, Medical University of Vienna 
- Anna Bösendorfer, Medical University of Vienna 
- Mehmet Salih Yildirim, Medical University of Vienna 
- Victor Schmidbauer, Medical University of Vienna 
- Dr. Gregor Kasprian, Medical University of Vienna 
- Prof. Dr. Oskar Aszmann, Medical University of Vienna 
 

 
 
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We will not share any study results with researchers outside the EU. Currently, there are 
no plans for making any data sets fully publicly available via any open data platform. If 
any data sets will be made publicly available in the future, this will happen after 
consultation of the Medical University of Vienna’s data clearing committee. 
(https://www.meduniwien.ac.at/web/ueber-uns/organisation/gremien/daten- 
clearingstelle/ ). 
 
Should incidental findings of clinical relevance occur, we will follow the 
recommendations from “Managing Incidental Findings in Human Subjects Research: 
Analysis and Recommendations” by Wolf S et al. 
 
Compensation 
Traveling expenses and time spent on the experiment will be compensated for with 
10€/hours. 
 
Safety reporting and insurance 
Any adverse events happening during the experiments will be recorded and reported to 
the Ethical Committee of the Medical University of Vienna. An insurance covers injuries 
or impairments resulting from study participation. Details in regard to the insurance can 
also be found in the participant information sheet. 
 
Agreements on publication 
Publications will take place in peer reviewed journals. No obligations by contract have 
been made. No commercial interests are at issue; manufacturers of prosthetic hands are 
not involved in data collection, analysis or interpretation. 
 
Funding statement 
Haaglanden Medical Centre (the Hague, the Netherlands) is funding the on site 
participation of dr.ir. G.V. Anguelova for the duration of four months as part of her 
neurology training. She is joining the Medical University as a Visiting Researcher. 
 
 
References 
 
Aszmann O.C., Roche A.D., Salminger S., Paternostro-Sluga T., Herceg M., Sturma A., Hofer C., Farina D. 
2015. Bionic reconstruction to restore hand function after brachial plexus injury: a case series of three 
patients. Lancet. 30;385(9983):2183-9. 
 
 

 
 
12 
 
 
Sturma A., Hruby L.A., Prahm C., Mayer J.A., Aszmann O.C. 2018. Rehabilitation of upper extremity nerve 
injuries using surface EMG biofeedback: protocols for clinical application. Front Neurosci.12:906. 
 
Anastakis, D.J., Chen, R., Davis, K.D., Mikulis, D., 2005. Cortical plasticity following upper extremity injury 
and reconstruction. Clin. Plast. Surg. 32, 617–634 (viii). 
 
Decety, J., Grezes, J., 1999. Neural mechanisms subserving the perception of human actions. Trends Cogn. 
Sci. 3, 172–178. 
 
Lotze M., Flor H., Grodd W., Labrig W., Birbaumer N. 2001. Phantom movements and pain. An fMRI study 
in upper limb amputees. Brain. 124(Pt 11):2268-77. 
 
Hotz-Boendermaker, S., Funk, M., Summers, P., Brugger, P., Hepp-Reymond, M.C., Curt, A., Kollias, S.S., 
2008. Preservation of motor programs in paraplegics as demonstrated by attempted and imagined foot 
movements. Neuroimage 39, 383–394. 
 
Date S., Kurumadani H., Yoshimura M., Fukae A., Onishi K., Hayashi J., Shinomiya R., Sunagawa T. 2019. 
Long-term disuse of the hand affects motor imagery ability in patients with complete brachial plexus 
palsy. Neuroreport. 10;30(6):452-456. 
 
Anguelova G.V., Rombouts S.A.R.B., van Dijk J.G., Buur P.F., Malessy M.J.A. 2017. Increased brain 
activation during motor imagery suggests central abnormality in Neonatal Brachial Plexus Palsy. Neurosci 
Res. 123:19-26. 
 
Brainard, D.H., 1997. The psychophysics toolbox. Spat. Vis. 10, 433–436 
 
Hermens, H.J., Freriks, B., Merletti, R., Stegeman, D., Blok, J., Rau, G., Disselhorst-Klug, C., Hägg, G., 1999. 
European Recommendations for Surface ElectroMyoGraphy, Results of the SENIAM Project. Roessingh 
Research and Development b.v. 
 
Jenkinson, M., Beckmann, C.F., Behrens, T.E., Woolrich, M.W., Smith, S.M., 2012. FSL. Neuroimage. 62, 
782–790. 
 
Jenkinson, M., Bannister, P., Brady, M., Smith, S., 2002. Improved optimization for the robust and  
accurate linear registration and motion correction of brain images. Neuroimage 17, 825–841. 
 
Smith, S.M., 2002. Fast robust automated brain extraction. Hum. Brain Mapp. 17, 143–155. 
 
Jenkinson, M., Smith, S., 2001. A global optimisation method for robust affine registration of brain images. 
Med. Image Anal. 5, 143–156. 
 
Ward, N.S., Frackowiak, R.S., 2003. Age-related changes in the neural correlates of motor performance. 
Brain 126, 873–888. 
 
Wolf, S. M., Lawrenz, F. P., Nelson, C. A., Kahn, J. P., Cho, M. K., Clayton, E. W., Fletcher, J. G., Georgieff, 
M. K., Hammerschmidt, D., Hudson, K., Illes, J., Kapur, V., Keane, M. A., Koenig, B. A., Leroy, B. S., 
McFarland, E. G., Paradise, J., Parker, L. S., Terry, S. F., Van Ness, B. Wilfond, B. S. (2008). Managing 
incidental findings in human subjects research: analysis and recommendations. The Journal of law, 
medicine & ethics : a journal of the American Society of Law, Medicine & Ethics, 36(2), 219–211.