Microelectrode Brain-Machine Interface for Individuals With Tetraplegia
Phase: NA
Conditions: Tetraplegia, Spinal Cord Injury
Sponsor: Michael Boninger

IStudy Official:  Michael L Boninger, MD    
Study Principal Investigator 
University of Pittsburgh 
 
 
Microelectrode Brain-Machine Interface 
for Individuals With Tetraplegia 
 
ClinicalTrials.gov #: NCT01364480 
IRB #: STUDY19030235 
FDA IDE #: G100298 
 
  
IRB STUDY19030235 closure date: 11/26/2022 
FDA IDE G100298 study closure date: 11/22/2022 
 
• IDE G100298 Investigational Plan (protocol) 

IDE G100298 / S013 
 
University of Pittsburgh / Michael Boninger 
IDE G100298 / S013 
CLEAN COPY 
 
This is an updated clean version of the IDE.  Note that only section E was modified. 

 
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INVESTIGATIONAL DEVICE EXEMPTION (IDE) SUPPLEMENT 
G100298, S013, January 15, 2014 
 
TABLE OF CONTENTS 
 
Item 
Description 
Page 
E. 
Investigational Plan 
1.0 Purpose of the Investigation 
1.1 Name of investigational device 
1.2 Intended use of the investigational device 
1.3 Objectives of the clinical investigation 
1.4 Anticipated duration of the clinical investigation 
2.0 Clinical Protocol (Core Study) 
2.1 Title of clinical protocol 
2.2 Study design 
2.3 Subject selection 
2.4 Study procedures 
2.5 Study outcome evaluations 
3.0 Clinical Protocol (Extension Study) 
3.1 Title of clinical protocol 
3.2 Study design 
3.3 Subject selection 
3.4 Study procedures 
3.5 Study outcome evaluations 
4.0 Risk Analysis 
4.1 Anticipated risks 
4.2 Adverse event recording/reporting 
4.3 Withdrawal of subjects due to adverse effects 
5.0 Monitoring Procedures 
6.0 Labeling 
7.0 Consent Materials 
8.0 IRB Information 
9.0 Other Institutions 
10.0 Additional Records and Reports 
10.1 Data handling and record keeping 
10.2 Record maintenance and retention 
2 
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2 
2 
3 
4 
4 
4 
4 
6 
8 
22 
26 
26 
27 
27 
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E.  Investigational Plan 
1.0 Purpose of the Investigation 
1.1 Name of investigational device 
Blackrock Microsystems NeuroPort Microelectrode Array System (Neuroport Array) 
1.2 Intended use of the investigational device 
In the proposed study, the efficacy of using NeuroPort Arrays (K070272) for chronic 
(>30 days) recording of neural signals in humans will be investigated.  No modifications 
are being made to the Arrays as part of this investigation. 
 
We will implant 2 NeuroPort Arrays in the motor cortex of individuals with limited or no 
ability to use both hands due to cervical spinal cord injury or brainstem or spinal stroke.  
The NeuroPort Arrays will be implanted for 1 year (+/- 30 days).  Study participants will 
learn to control their neural signals (brain electrical activity) recorded from the NeuroPort 
Arrays in order to control a variety of external devices including virtual reality objects,  a 
motorized prosthetic limb and a robotic arm exoskeleton in a safe environment.  
Demonstration of successful control of these devices will support our hypothesis that 
implantation of two NeuroPort Arrays allows for recording of sufficient neural 
information to control a complex BMI that can augment impaired motor functions.  
 
For the proposed extension study, we are requesting a supplement to this IDE to allow for 
implantation duration of up to 5 years.  This extension study will allow us to quantify 
BMI performance and signal quality over a longer duration. 
 
The 510(k) approval for the NeuroPort Arrays describes the indications for use as: 
“The intended use of the Cyberkinetics Neurotechnology Systems, Inc. NeuroPort 
Microelectrode Array System is for temporary (<30 days) recording and monitoring 
of brain electrical activity”.  This 510(k) was purchased by Blackrock Microsystems 
from Cyberkinetics Neurotechnology Systems, Inc. 
 
For the proposed investigation, the investigational indication for use would be:  
“For chronic (>30 days) recording and monitoring of electrical activity from the 
motor cortex, in individuals with cervical spinal cord injury or stroke, to control 
external devices such as computers, assistive devices, and potentially robotic 
devices”. 
The neural signals will be processed and recorded by the NeuroPort System as indicated 
by the current 510(k) approval (K090957). The NeuroPort System includes a patient 
cable which connects to the percutaneous pedestal connector of the NeuroPort Array, a 
neural signal processor, a front end amplifier/digitizer, and a computer and display 
monitor.  The indications for use of the NeuroPort System are:  
“The Blackrock NeuroPort Biopotential Signal Processing System supports 
recording, processing, and displaying of biopotential signals from user supplied 

 
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electrodes.  Biopotential signals include: Electrocorticography (ECoG), 
electroencephalography (EEG), electromyography (EMG), electrocardiography 
(ECG), electrooculography (EOG), and evoked potential (EP).” 
 
Because the NeuroPort System will be used as indicated by the 510(k), the IDE focuses 
solely on the NeuroPort Arrays. 
1.3 Objectives of the clinical investigation 
The proposed clinical investigation is a feasibility study directed toward: 
Specific Aim 1:  Investigate the safety and efficacy of using NeuroPort Arrays for 
chronic recording of neural activity from the motor cortex of individuals with upper limb 
impairments.   
 Specific Aim 1a:  Document the safety of using the NeuroPort Arrays for chronic 
recording of neural activity.  Monthly neurological and physical examinations will be 
conducted and documented for the duration of the trial.  Any serious adverse events 
that occur as part of this investigation will be reported in accordance with the FDA’s 
expedited reporting requirements. 
 Specific Aim 1b:  Characterize signal quality recorded with the NeuroPort Array 
during long term implantation in the motor cortex of individuals with tetraplegia. 
Primary measurements of signal quality include the number of units recorded by the 
array and the firing rate of single neurons measured during specific tasks (such as 
imagined hand movement) [6, 45, 46].   
Specific Aim 2: Demonstrate that individuals with tetraplegia can learn to successfully 
control a variety of external devices and computer-driven tasks using signals recorded 
with two NeuroPort Arrays. We aim to achieve high-dimensional control of complex 
systems including both a virtual and robotic dexterous hand and arm to perform grasping 
and reaching tasks which are essential for activities of daily living.  This will be 
measured over the duration of implantation by computing success rate for a given task as 
well as the amount of computer assist that is required.  
Specific Aim 3: Use MEG to localize areas of the brain that can be voluntarily 
modulated.  These results will be compared to pre-surgical mapping results with fMRI 
and provide additional information for planning the location of electrode implantation.   
 
 Specific Aim 3a:  At the optional follow-up MEG visits, we will use the same 
paradigms to localize areas of the cortex that can be voluntarily modulated to 
determine if BMI training has induced neuroplasticity.  We expect the areas of cortex 
responsible for voluntary movement will be more strongly activated with more 
localized responses. 
Specific Aim 4: Conduct a sleep study to measure the quantity and quality of sleep each 
night for a specified period of time to help clarify the role of sleep in motor learning.  

 
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This study will include a sleep diary and brain activity measured during sleep using EEG 
and/or intracortical recordings from the NeuroPort electrode arrays. 
 
The aims remain the same for the proposed extension study, however we will have the 
opportunity to investigate these aims during the 1-5 year post-implant period.  We also 
expect that we may see a decline in BMI performance over time as signal quality 
declines. This will be an opportunity to see if neuroplasticity, or novel training methods, 
can compensate for this degredation in performance.   
 
1.4 Anticipated duration of the clinical investigation 
It is expected that the study will last 3 years.  If participants choose to enroll in the 
extension study, their total participation time could be up to 6 years.   
2.0 Clinical Protocol 
This section describes the core clinical protocol as already approved by the FDA and 
University of Pittsburgh IRB.  Section 3.0 describes the clinical protocol for the proposed 
extension study. 
2.1 Title of clinical protocol 
Microelectrode Brain-Machine Interface for Individuals with Tetraplegia 
2.1.1 Protocol number 
University of Pittsburgh, PRO10080021 
2.1.2 Version number and date  
Version 10, November 12, 2013 (Exp Date: November 11, 2014) 
2.2 Study design 
2.2.1 General study design 
This study is a prospective, non-randomized, open-label feasibility study that will 
be conducted at the University of Pittsburgh.   
2.2.2 Study design schematic 
Figure 2 illustrates the proposed study design.  All procedures are discussed in 
detail in Section E 2.4. 

 
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Figure 2: Study Design Schematic 
 

 
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2.3 Subject selection 
2.3.1 General characteristics of the proposed subject populations(s) 
The subjects for this study will be individuals between the ages of 18-70 with 
limited or no ability to use both hands due to cervical spinal cord injury or 
brainstem or spinal stroke.  Participants will be screened for a number of co-
morbities to ensure their safety during participation.  We are using adult subjects 
because this is a greater than minimal risk study and we want to ensure that the 
subject is mature enough to understand the tasks, as well as the risks involved in 
this study.  Further, we want to ensure that the neuromotor system is fully 
developed prior to enrolling in this study.  We will not be recruiting military or 
civilian personnel working for the Department of Defense (DOD). 
2.3.2 Anticipated number of research subjects 
A maximum of 10 participants will be enrolled in order to implant a maximum of 5 
subjects.  It is anticipated that we will implant no more than 1 subject every 6 
months.  Recruitment rates will be monitored by our DSMB.  Because it is possible 
that a subject may enroll and then be determined to be ineligible for anesthesia 
and/or surgery, the maximum number of subjects enrolled may exceed the number 
implanted.  Subjects will be enrolled as necessary to maintain the target number of 
subjects implanted.  Recruitment will not begin until we have received IRB 
approval. 
2.3.3 Inclusion criteria 
1) limited or no ability to use both hands due to cervical spinal cord injury or 
brainstem or spinal stroke; The subjects must have less than or equal to grade 4 
muscle strength in elbow extension and wrist extension and less than grade 2 
strength in finger flexor and abduction on the contralateral side to the implant 
[47].  We will include both complete and incomplete subjects 
2)  subjects must report that they are unable to perform functional activities with the 
hand contralateral to implantation. 
3)  subjects must be over 1 year post-injury at time of implantation. In addition, 
subject must report no change in neurologic status (strength or sensation) for the 
previous 6 months.  
4)   age 18-70 years old.  Participants outside this age range may be at an increased 
surgical risk and increased risk of fatigue during BMI training. 
5) live within 1 hour of the University of Pittsburgh and be willing to travel to the 
University of Pittsburgh once per week for BMI training 
6) expect to stay within 1 hour of and be willing to travel to the University of 
Pittsburgh for at least 18 months after enrollment 
7) ability to communicate with the investigators verbally in English because of the 
need to follow instructions of the study team 

 
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8) show an understanding of the study goals and the ability to follow simple 
directions as judged by the investigators 
9) have normal results on neuropsychological and psychosocial assessment (e.g., 
Wechsler Test of Adult Reading (WTAR) with a score of 90 or above and Brief 
Symptom Inventory (BSI-18) with a T-score less than 70); the WTAR measures 
intellectual functioning and the BSI-18 measures mental health; psychosocial 
health and support will be assessed by interview with the psychologist  
10) able to activate distinct cortical areas during imagined or attempted movement 
tasks (i.e. hand movement and speaking or moving the mouth); this will be 
evaluated with functional magnetic resonance imaging (fMRI) as part of 
screening  
11) must have a stable psychosocial support and caregivers who are able to perform 
the necessary daily care of the participant’s skin and pedestal site; This requires 
that the subject identify a caregiver and a back up who have been in place for 
greater than 6 months and are able to provide needed physical and psychosocial 
support. This will be assessed by the study PI and neurosurgeon. 
12) have a life expectancy greater than 12 months as assessed by the study 
investigator and neurosurgeon sub-investigator 
13) documentation of informed consent is obtained from the participant or their 
legal representative  
 
2.3.4 Exclusion criteria 
1) visual impairment such that extended viewing of a computer monitor would be 
difficult even with ordinary corrective lenses 
2) presence of other serious disease or disorder that could affect ability to 
participate in this study (verified during pre-op anesthesia evaluation to 
determine surgical risk status) 
3) recent history of pressure sores that could be exacerbated by 1-2 days of bed 
rest 
4) metallic implants that would prohibit the subject from having a fMRI scan; 
spinal fixators are generally non-ferrous and would not exclude someone from 
participating in the study 
5) individuals who have any type of implantable generator such as a pacemaker, 
spinal cord stimulator, cochlear implant, deep brain stimulator, vagus nerve 
stimulator, or defibrillator 
6) women of childbearing age who are pregnant, lactating, or plan to become 
pregnant during the next 25 months 
7) allergy to contrast medium or kidney failure that could be exacerbated by 
contrast agent (for MRI)  
8) receiving medications (such as sedatives) chronically that may retard motor 

 
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coordination and cognitive ability 
9) individuals who require routine MRI, therapeutic ultrasound, or diathermy 
10) individuals with osteomyelitis 
11) having a severe skin disorder that causes excessive skin sloughing, lesions or 
breakdown of the scalp 
12) history of myocardial infarction or cardiac arrest or with intractable cardiac 
arrhythmias 
13) individuals with an implanted hydrocephalus shunt 
14) individuals who have had a stroke cause by a surgical procedure 
15) active infection(s) or unexplained fever (verified during pre-op anesthesia 
evaluation to determine surgical risk status) 
16) consuming more than 1 alcoholic beverage per day on average 
17) receiving chronic oral or intravenous steroids or immunosuppressive therapy 
18) active cancer within the past year (other than adequately treated basal cell or 
squamous cell skin cancer) or require chemotherapy 
19) uncontrolled insulin dependent diabetes mellitus 
20) uncontrolled autonomic dysreflexia (for those with spinal cord injury) 
21) history of seizures 
22) attempted suicide in the past 12 months 
23) individuals who are immunosuppressed or who have conditions that typically 
result in immunocompromise (including, but not limited to: ataxia-
telangiectasia, cancer, Chediak-Higashi syndrome, combined immunodeficiency 
disease, complement deficiencies, DiGeorge syndrome, HIV/AIDS, 
hypogammaglobulinemia, Job syndrome, leukocyte adhesion defects, 
malnutrition, panhypogammaglobulinemia, Bruton disease, congenital 
agammaglobulinemia, selective deficiency of IgA and Wiscott-Aldrich 
syndrome)  
24) individuals with implanted drug delivery pumps 
2.4 Study procedures 
2.4.1 Screening procedures 
We will recruit subjects from two University of Pittsburgh Institutional Review 
Board (IRB) approved registries developed by the Human Engineering Research 

 
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Laboratories (VA IRB #01185) and the Department of Physical Medicine and 
Rehabilitation (IRB #0304069). All members of the registry have agreed to 
participate in the registry, and have given permission to be contacted for future 
research. The recruitment letter for this study will be provided to the registry 
investigators to distribute to potential subjects according to the procedures 
established in the registry IRB approved protocols. The recruitment letter will be 
accompanied by a letter from the registry PI/coordinator stating why they are 
receiving information about our study.  In response to the recruitment letter, 
potential subjects will directly contact the research team if interested in 
participating. We may also post the recruitment letter on websites affiliated with our 
laboratory or the University of Pittsburgh, Department of Physical Medicine and 
Rehabilitation. Clinicians in the Department of Physical Medicine and 
Rehabilitation who are knowledgeable about our study may distribute the letter to 
their patients if they think they may be eligible.  Finally, we have another IRB-
approved protocol at the University of Pittsburgh (PRO10010043) which is an 
online survey related to BMI technology. Participants in that study have the option 
of providing their contact information if they would be interested in participating in 
future research.  We may contact these individuals by phone, or by sending them a 
recruitment letter.  Individuals may contact our study team directly in response to 
the clinicaltrials.gov website, scientific publications, media, or other means besides 
our planned recruitment methods. 
An initial screening will be conducted to review the study procedures and 
inclusion/exclusion criteria.  The initial screening can be conducted over the phone, 
or in person, for the individual’s convenience.  All but three eligibility criteria 
(muscle strength, fMRI and neuropsychological exam) will be reviewed during the 
screening and assessed via self-report.  A urine pregnancy test will also be given for 
females during the pre-op labs.  If the subject is interested in participating, we will 
collect his or her contact information and set up a meeting with the study team.  We 
can also mail the consent form ahead of time to potential participants to allow them 
time to read the form before meeting with the study team.  At the meeting with the 
study team, the potential participant will have a chance to gather more details about 
the study and ask additional questions.  This also allows the study team to meet the 
potential participant to make sure that they meet the inclusion criteria which include 
showing an understanding of the study and ability to follow directions.  Prior to 
consenting for the study, the subject will meet with research staff including the 
neurosurgeon on this project.  After the subject has met with the study team, and 
agreed to participate in the study, they will be consented by the principal 
investigator.  We may visit the participant's home to ensure that there is sufficient 
space for conducting in-home BMI training. 
Careful consideration of the risks/benefits and the informed consent process is 
required in this study both because of the invasive and investigational nature of the 
device, the chronic care (home) time commitment involved in utilization of the 
device, as well as the potential vulnerability of the intended subject population. 
Because the device will be utilized in the subject’s chronic care environment, which 
may be the subject’s home, an understanding of the requirements of participation is 

 
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important to the subject as well as a committed family member and/or caregiver. 
Individuals with tetraplegia require help in their day-to-day activities from someone 
other than themselves.  Because participation in the study requires at least one 
family member/primary caregiver to take an active role in the study, the informed 
consent form also requires the signature of a family member or primary caregiver.  
It is the responsibility of the principal investigator (PI) that each subject being 
considered for participation in the study be given a full explanation of the protocol. 
Informed consent is mandatory after adequate explanation of the objectives, 
methods, anticipated benefits, and potential risks of the study before any study 
specific procedures are performed. The informed consent form must include the 
required eight basic elements. Informed consent will, consistent with site 
institutional policies and FDA regulations (21CFR, Part 50), be obtained in the 
following manner. 
A meeting will be held with the investigator, potential study participant, his/her 
family member or primary caregiver, and if required (i.e., if not the family 
member/primary caregiver), the subject’s legal representative that is authorized to 
sign for the subject.  The investigator will discuss the study with all those present. 
The informed consent form will be reviewed in detail and a discussion of the nature 
and duration of the study as well as the anticipated risks and benefits will take 
place.  The subject and family member/primary caregiver will be encouraged to ask 
questions and these questions will be answered.  The subject will be encouraged to 
take additional time, if necessary, to consider participation before signing or having 
the informed consent signed by their legal representative. 
The family member/primary caregiver is agreeing to support the subject in their 
chronic care environment.  This support includes reading and following the 
instructions for daily wound monitoring and weekly cleaning designed to minimize 
the risk of infection.  The family member/primary caregiver and the subject will 
also be responsible for informing any other caregivers or nursing staff about the 
subject’s participation in the study and the steps required to minimize the risk of 
infection.  
Once written informed consent is obtained, the subject is enrolled in the study and 
is assigned a subject ID.  A physician-investigator will then verify the eligibility of 
the subject by assessing all of the eligibility criteria.  The subject’s muscle strength 
will be tested by a physician-invesigator or therapist.  Two additional screening 
procedures will be conducted after informed consent, but prior completing the study 
procedures. 
(1) Neuropsychological examination: Participants will complete a 
neuropsychological assessment with a trained psychologist. We will use the 
Wechsler Test of Adult Reading (WTAR) and Brief Symptom Inventory (BSI-18) 
to assess intellectual functioning and psychological distress. If the subject does not 
have a normal result on the neuropsychological examination, they will be excluded. 
The WTAR measures intellectual functioning and the BSI-18 measures mental 

 
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health.  Psychosocial health and support will also be assessed by interview with the 
psychologist.  This examination is expected to take less than 30 minutes and will be 
performed in University of Pittsburgh or UPMC research space. 
(2) Pre-surgical screening to localize cortical activity during imagined or attempted 
movement: fMRI will be used as the gold standard to localize the cortical area 
where the NeuroPort Arrays will be implanted. fMRI testing will be completed at 
the Magnetic Resonance Research Center at UPMC Presbyterian Hospital. Subjects 
will be asked to complete simple tasks during the fMRI scan. For example, subjects 
may be asked to view, imagine, or attempt hand and upper limb movements, 
speaking, or tongue movements.  The goal of the fMRI scan is to create a map of 
motor cortical areas in order to guide the surgical procedure.  The fMRI is expected 
to take less than 1 hour. 
2.4.2 Experimental procedures 
Pre-surgical procedures and electrode implantation will occur within 6 months after 
the subject undergoes screening procedures.  We will work with each individual to 
determine the optimal testing schedule.  We will photograph or videotape portions 
of the experimental sessions. Appropriate UPMC permission will be obtained as 
needed for any photographs or videotaping of participants.  All experimental 
procedures are described below. 
Demographic and Medical History Questionnaire: 
The subject will be asked to provide basic demographic information (age, weight, 
height, etc.) via self-report.  We will also ask questions about their medical history 
including the date of injury or diagnosis and their current level of function. Finally, 
we will ask questions related to improvement of quality of life and BMI technology. 
A complete copy of the questionnaire is included with the Case Report Forms in 
Appendix I.  This questionnaire is expected to take less than 30 minutes to complete 
and can be completed at any of the study visits. 
Pre-surgical Magnetoencephalography (MEG) Testing: 
Subjects will participate in a MEG scan prior to surgery where they will be asked to 
perform simple imagined or attempted movements which will provide additional 
data related to the ideal site for electrode implantation.  Similarly, they may be 
asked to observe actions performed by others.  These actions will be simple 
movements such as hand grasp or tongue movement.  As part of the standard 
protocol for MEG testing, we may attach additional sensors (using tape or an 
adhesive) to record head position, electroencephalography (EEG), 
electrocardiography (EKG), electromyography (EMG), or electro-oculography 
(EOG).  EEG is an additional measurement of neural activity.  The other recordings 
allow us to correct for noise sources or head movement.  MEG and all of the related 
recordings are completely non-invasive.  The MEG test allows us to measure 
cortical sources of activity with high spatial and temporal resolution.  MEG testing 

 
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following the same procedure will be performed again after BMI testing is 
completed to determine if plasticity has been induced.  For example, we would 
expect the sources responsible for imagined movement to be stronger following 
BMI training.  The pre-surgical MEG session is expected to take less than 2 hours. 
All MEG scans will take place at the UPMC Brain Mapping Center at UPMC 
Presbyterian Hospital. 
For some subjects, MEG testing may be contraindicated. Reasons for 
contraindication include: having a head circumference greater than 60 cm (in order 
to fit in the MEG helmet), having metallic implants in the head or neck region, or 
being ventilator dependent. If the subject is unwilling or unable to participate in 
MEG testing, they can still be included in the study. While the MEG experiments 
would provide additional information regarding plasticity, this is not the main 
priority of this research. We can assess similar measures of plasticity using neural 
data recorded during BMI training. 
Pre-surgical Brain-Machine Interface (BMI) training: 
Study participants may complete up to 5 sessions of BMI training using 
electroencephalography (EEG) and/or MEG prior to implantation of the NeuroPort 
Arrays.  They will learn to modulate activity in the motor cortex to complete simple 
tasks (such as 1D or 2D cursor control).  While these neural recording methods will 
not allow for high dimensional control, these training sessions will allow 
participants to learn to voluntarily modulate their neural activity using non-invasive 
technology.  If participants are unable to voluntarily modulate their motor cortical 
activity during the pre-surgical BMI training, the investigators may decide to 
withdraw the participant from the study or conduct additional training with 
EEG/MEG prior to implantation. 
Pre-surgical MRI scan: 
A 3-D structural MRI of the subject’s brain and skull will be taken at a clinical 
facility at UPMC following a standard protocol for use with the image guidance 
surgical tool.  Since the structural MRI for image guidance and fMRI scan take 
place at the same facility, we may complete both during the same visit.  The scan, 
including preparation time, is expected to last less than 1 hour.  This MRI will be 
used in conjunction with image guidance technology to localize the surgical site. 
This type of scan requires the use of an FDA-approved contrast agent.  The agent is 
given through a needle (IV) placed in the arm.  The IV is placed using standard 
hospital techniques. 
Pre-operative labs and screening:  
Participants will undergo standard pre-surgical screening at the Anesthesia Pre-Op 
Clinic at UPMC.  The clinic staff will perform a medical history interview and a 
simple physical examination.  Participants will be asked to provide a blood and 
urine sample.  Standard lab tests will be run on these samples to ensure that 

 
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participants do not have risk factors that would make them an unsuitable candidate 
for surgery.  Women of childbearing age will be required to undergo a urine 
pregnancy test.  Participants will be withdrawn if it is determined that there are 
unexpected increased surgical risks.  Sometimes the clinic requires an EKG to 
monitor cardiac activity.  They may also request a chest x-ray as part of this 
screening.  If the participant has an active urinary tract infection, they will be 
required to pursue appropriate treatment (antibiotics) at their own cost prior to 
having surgery.  This visit is expected to last 1 hour and will be performed at 
UPMC Montefiore up to 30 days before the implantation surgery.  This screening 
will guide selection of anesthesia which will be selected by the anesthesiologist to 
minimize propofol infusions and benzodiazepines.  Additional tests and treatments 
may be ordered by the PI or neurosurgeon to ensure participant safety. 
Surgical Procedures: 
The NeuroPort Arrays will be implanted by our neurosurgical team at UPMC 
Presbyterian Hospital.  The subject will be fully anesthetized throughout the 
surgery. Antibiotics (1-2 grams of 1st generation cephalosporin, i.e. cefazolin) will 
be given intravenously in the operating room within 60 minutes prior to the first 
incision to minimize the risk of infection.  A different appropriate broad spectrum 
antibiotic may be used if the subject is allergic to cefazolin. 
Hair near the implantation site will be shaved to minimize the risk of infection. A 
small craniotomy (approximately 5 cm x 5 cm) will be performed over the motor 
cortical areas identified during the screening procedures.  Image-guidance 
techniques that allow the surgeon to view 3-D coordinates of a physical stylus on 
the imaging studies will be used to allow for precise positioning of the craniotomy 
and electrode arrays.  The structural MRI, fMRI, and MEG scans will be used with 
the image guidance system as needed.  A head holder (Mayfield Head Clamp) will 
be used to keep the subject’s head still during the surgery and allow for use of the 
image guidance protocol.  This clamp is fixed to the subject’s skull during surgery 
and will leave 3-4 small puncture wounds away from the site.  These sites heal 
quickly and generally do not leave scars.  The dura will be cut and elevated to allow 
for positioning of the NeuroPort Arrays.  A neurophysiologist may perform 
intraoperative mapping to further verify that the NeuroPort Array is positioned in 
the optimal location.  This involves using electrodes on the cortical surface to 
record neural activity while a nerve in the arm (typically the median nerve) is 
stimulated using surface electrodes.  This type of intraoperative mapping will be 
used only if the participant has an incomplete spinal cord injury or reports some 
level of residual motor or sensory function in the upper limb.  Impedance testing 
may also be conducted during surgery.  Impedance testing measures voltages when 
very small currents are driven to the electrodes for a short period of time.  It is an 
approved function of the array and no additional risks are expected.  The targeted 
locations for implantation will be on a relatively flat portion of a gyrus away from 
large blood vessels. 
The NeuroPort Array is implanted using a NeuroPort Inserter Assembly.  The 

 
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pneumatically-actuated inserter wand is designed for consistent and controlled 
implantation of the NeuroPort Array.  When the button on the trigger cable is 
pushed, the inserter wand applies a consistent pulse and travel distance (1.5 mm) to 
the NeuroPort Array, inserting it into the parenchyma in less than 1 millisecond.  
During surgery, the inserter assembly attaches to the Mayfield Head Clamp via the 
inserter wand holder which serves two key functions.  It firmly secures the inserter 
wand to prevent recoil during the NeuroPort Array insertion process, and it 
facilitates precision alignment of the inserter wand with respect to the back of the 
NeuroPort Array just prior to pneumatic impulse insertion. 
Each NeuroPort Array connects 
to its 
own Patient Pedestal.  The 
positioning of the Patient 
Pedestals will be chosen based 
on 
number of factors.  First, they 
will 
be positioned along the midline 
of the 
skull as this is a flat, thick area of 
bone 
and it will not interfere with the 
subject’s comfort when they are 
lying 
down.  Second, the Patient 
Pedestals will be as positioned as 
far 
away from the craniotomy site as 
possible, as this has been shown 
to 
reduce the risk of infection [48, 
49].  
The gold lead wires will be 
tunneled beneath the scalp in 
order 
to separate the craniotomy and 
Patient Pedestal sites.  This distance will be maximized while ensuring that there is 
enough slack in the gold wire bundle for strain relief.  Third, the Patient Pedestals 
will be secured to the skull at least 5 cm apart.  This allows for sufficient space to 
connect the Patient Cable which connects the Patient Pedestal to the NeuroPort 
System.  The space between the Patient Pedestals will be larger than the pedestal 
diameter to minimize the risk of necrosis.  The general rule of thumb is that a flap 
should be no longer than it is wide and when making parallel incisions the distance 
between should be equal to the length to prevent devascularization of tissue in 
between.  The Patient Pedestal will be affixed to the skull with titanium screws.  
Titanium cranial straight plates may be used to fix the gold wire bundle to the skull.  
Each NeuroPort Array has two silver reference wires that can be placed subdurally 
or epidurally.  Figure 3 shows an example of an implanted array and pedestal, 
although in our protocol, the pedestal will be positioned further away from the 
craniotomy site. 
Figure 3. Patient Pedestal and NeuroPort 
Array Placement 

 
15
The dura will be 
reapproximated before the 
bone flap is repositioned 
over 
the implantation site and 
secured using suture or 
titanium or absorbable 
miniplates.  The skin 
around the Patient Pedestal 
will 
be reapproximated and 
closed with skin sutures or 
staples.  The pedestal will 
be 
covered with the patient 
pedestal cap, which will 
remain in place anytime 
the 
Patient Cable is not 
connected (Figure 4). 
The entire surgical procedure is expected to last 4-8 hours.  
Post-Operative Hospital Stay:   
Post-operative care will depend on the participant’s condition, however we expect 
most subjects to stay in the post anesthesia care unit (PACU) for approximately 3 
hours after surgery.  They will be transferred to the neurosurgical intensive care unit 
(ICU) for approximately 24 hours before transitioning to the neurosurgical medical 
surgery recovery unit where they will stay for 1-2 days.  The PACU, ICU, and 
medical surgery recovery unit are all located at UPMC Presbyterian Hospital.  The 
participants will then stay at the UPMC Rehabilitation Institute for up to 10 days for 
post-operative rehabilitation.  The rehabilitation stay serves primarily as an 
opportunity for the participant and their caregiver to become familiar with caring 
for the Patient Pedestal while medical staff can monitor wound healing.  We may 
begin BMI training while the participants are staying at the UPMC Rehabilitation 
Institute.  The study neurosurgeon and PI will determine when the participant will 
be moved from each post-op unit.  The PI and rehabilitation team will determine 
when the individual can be discharged from the Rehabilitation Institute and sent 
home.  
Post-Operative Imaging: 
Study participants will have an x-ray and head CT after surgery to document 
placement of the NeuroPort Arrays.  Lateral and AP head x-ray views will be taken. 
These imaging procedures will take place in UPMC facilities during the 
participants' post-operative hospital stay, typically within 48 hours after surgery. 
Additional CT images will be obtained if there is a change in the subject’s 
neurological examination or the subject experiences severe headaches, nausea, 
and/or abnormal behavior.  These procedures will enable our neurosurgeon and 
their clinical team to identify infection, bleeding, edema, or neurological 
 
Figure 4. Patient Pedestal and Cap Post-Surgery 

 
16
dysfunctions as early as possible and treat them properly.  
Post-Implant Clinical Evaluation: 
A clinical investigator will perform a monthly clinical evaluation to monitor the 
participant’s neurological and musculoskeletal status.  Wound checks will also be 
performed at this visit.  If any changes in neurological status or musculoskeletal 
functioning are noted, appropriate medical care will be provided.  These clinical 
visits will likely be combined with research visits to the University of Pittsburgh or 
UPMC.  
Psychological Evaluation: 
The subject will have opportunities to talk to a psychologist throughout the study, 
either over the phone or in person.  These discussions can be scheduled regularly 
(approximately 1, 3, 6 and 9 months after implantation as well as prior to 
explantation) to discuss any concerns the subject may have.  The psychologist may 
refer the subject for additional meetings as necessary.  In addition, physician-
investigators, including the study PI and neurosurgeon, will be interacting with the 
subject on a regular basis and can refer the subject to a psychologist at their 
discretion.  If the subject has severe problems or concerns, he or she may be 
withdrawn from the study.  
Brain-Machine Interface (BMI) Training/Testing: 
Neural recording from the NeuroPort Arrays may begin as soon as the participant 
has recovered from surgery.  We expect this to take 2-3 days and the first recording 
session will be scheduled based on the medical opinion of the study neurosurgeon 
and PI and how the subject is feeling.  Neural recording will be conducted for the 
duration of implantation.  The recorded neural data will be used to operate a BMI 
system that allows the participant to control a computer cursor, virtual object, or 
assistive device.  A summary of selected configurations of this system is provided 
below.  Subject safety is ensured by the physical and electrical isolation offered by 
the NeuroPort System. 
While the NeuroPort Arrays are implanted, we will conduct BMI training for up to 
8 hours per day for up to 5 days per week.  At least 1 session per week will be 
conducted while the array is implanted.  BMI testing may occur at the University of 
Pittsburgh, UPMC, or in the participant’s home.  Rest, meals, and other breaks will 
be scheduled as needed.  We may not conduct training sessions every day.  This 
will be determined by the research staff and the subject.   
At the beginning of each BMI testing session, an investigator will connect the 
Patient Cable to the Patient Pedestal.  There are two types of behavioral tasks that 
the subjects will participate in as part of the BMI Training/Testing: 
1. Open-loop tasks: 

 
17
In the so-called "open-loop" tasks, subjects respond (with movement or other 
action) to a simple stimulus (such as visual or audio cue).  Kinematics and muscle 
activity may be recorded using a DataGlove (a wearable glove that measures the 
finger joint movement), EMG electrodes, or motion tracking system. These tasks 
are used to identify associations between the user's action and neural activity in the 
brain.  The type of data that will be recorded will be dependent on the participant’s 
injury level and completeness.  Some participants may not have any residual motor 
or sensory function in the upper limb and may not perform these tasks.  In some 
cases the kinematic or EMG data will be used to verify that no overt movement is 
occurring. 
Examples of sensory inputs include: 
 Visual cue (e.g. prompt on a computer screen) 
 Audio cue (e.g. tone or spoken word) 
 Somatosensory 
o Passive movement of a limb 
o Peripheral nerve stimulation: Here a small metal disc electrode is placed on 
the arm or leg to deliver an electrical stimulus which results in an evoked-
potential in the brain. The stimulus level will be adjusted so that the subject 
is able to feel the stimulation, but is not uncomfortable. 
o Vibrotactile feedback 
Examples of user responses include: 
 Real, imagined, or observed movement (e.g. opening and closing the hand, 
tapping fingers, or protruding the tongue)  
 Cognitive response (e.g. describing an object or saying a word) 
 Interaction with a human interface device (e.g. mouse, joystick, or DataGlove)  
2. Closed-loop tasks 
In the so-called "closed-loop" tasks, the computer cursor (or other output signal) is 
controlled by neural signals recorded and processed by the BMI system. The subject 
is trained to willfully modulate their neural signals to achieve the desired output. 
We have the capability to provide “computer-assist” which blends the neural signals 
with an optimal control signal in order to ensure some level of successful 
completion.  This will facilitate learning and keep the participant motivated.  The 
assist level will be documented and the goal is to reduce the assist level to 0% so 
that the participant has full neural control over the output signal. 
There are three main categories of tasks that a subject may complete: 
 Basic paradigms (e.g. controlling a computer cursor or virtual hand) 

 
18
 Interaction with computer and computer games (e.g. typing, icon selection, or 
playing a video game) or a virtual reality environment 
 Controlling external devices (e.g. prosthetic limb, robotic arm or exoskeleton) 
Neural and behavioral data will be recorded during each BMI session in order to 
address the Specific Aims.  At the beginning of each session (or at least weekly) 
spike-sorting will be used to identify single-units that are recorded from each 
electrode.  We will track the number of units recorded over the duration of 
implantation.  Further, by comparing the amplitude and shape of the recorded action 
potential, it is possible to identify whether the single-unit recorded by a given 
electrode is different from that recorded on a previous day.  Spike data (recorded 
action potentials) along with the calculated firing rate for each neuron will be 
recorded during the behavioral tasks and compared over the duration of the implant.  
Behavioral and neural data that is recorded during closed-loop control will be used 
to address Specific Aim 2.  Behavioral data may include kinematics of a cursor, 
virtual object, robotic arm, etc.  We will also compute the success rate achieved by 
the participant for a given task over a number of sessions.  In addition, part of the 
training paradigm involves initial control being achieved with computer assistance. 
We expect that the amount of computer assistance will decrease over time as 
success rates with a task improve or stay constant.  The amount of computer 
assistance needed is an easily measured variable that we will track as an indicator of 
success.  Impedance measurements will be collected during BMI testing sessions 
throughout the study.  Impedance testing is an approved function of the NeuroPort 
recording system and can be used to assess array function and encapsulation. 
We will also document volunteered or observed adverse events at least weekly as 
part of the BMI training sessions as a measure of device safety.  Monthly 
neurological and physical examinations will be conducted for the duration of 
implantation and will likely be conducted at the same visit as a BMI training 
session.   
At the end of each session, an investigator will remove the Patient Cable and clean 
the device.  At a minimum, the Patient Pedestal should be cleaned every 7 days by a 
family member, caregiver, medical professional, or study team member.  We will 
provide detailed cleaning instructions to the participant and anyone who may assist 
with the cleaning.  Sterile procedures will be followed and an antiseptic solution, 
such as ChloraPrep, will be used to wipe the outside of the Patient Pedestal, the 
surrounding skin, and the first 8-10 inches of the Patient Cable.  An antimicrobial 
dressing, like the BioPatch, will be placed around the Patient Pedestal.  The 
Pedestal Cap will remain in place whenever the Patient Cable is not connected.  The 
Patient Cable can be cleaned using alcohol or an antiseptic solution. 
We will monitor the subject’s temperature once per day (on days that BMI testing 
occurs) as this can be an early indicator of infection.  We will instruct the subject to 
monitor and record their own temperature daily as well.  A family member or 
caregiver will be asked to inspect the Patient Pedestal sites on a daily basis to 

 
19
identify any changes that may indicate an infection such as erythema, drainage, 
ecchymosis, pain, or unusual redness along the lead tunnel or pedestal.  The study 
neurosurgeon and PI will train the research team and family member or caregiver in 
how to monitor wound healing.  
Explantation of the electrodes: 
Subjects will undergo a second surgery at UPMC Presbyterian Hospital 
approximately 1 year after implantation of the NeuroPort Arrays.  It is possible that 
the NeuroPort Arrays may be explanted earlier due to technical problems, clinical 
complications, investigator-initiated withdrawal, or subject-initiated withdrawal.  
The participant will go through standard pre-operative screening procedures which 
may include a blood draw. The subject will be fully anesthetized throughout the 
surgery and will receive antibiotics intravenously as with the implantation surgery. 
The hair will be clipped in the area of the planned surgery.  A skin incision will be 
made from the Patient Pedestal to the area of the craniotomy.  It is possible that 
fibrous tissue will have formed around the wire bundles and NeuroPort Arrays and 
this will be dissected away prior to explantation.  Impedance testing may also be 
conducted during surgery. Impedance testing measures voltages when very small 
currents are driven to the electrodes for a short period of time.  It is an approved 
function of the array and no additional risks are expected.  The bone flap will be 
dissected from the dura and lifted and the dura will be opened.  The NeuroPort 
Arrays will most likely be encased in a membrane that appears to be continuous 
with the arachnoid.  The membrane will be cut open and the NeuroPort Arrays will 
be removed with forceps.  The bone flap will be repositioned and secured with 
titanium or absorbable miniplates.  The skin will be repositioned and closed with 
skin sutures or staples.  The entire surgical procedure is expected to take 
approximately 3 hours. 
Post-operative care will depend on the participant’s condition, however we expect 
most subjects to stay in the post anesthesia care unit (PACU) for approximately 3 
hours after surgery.  They will be transferred to the neurosurgical intensive care unit 
(ICU) for approximately 24 hours before transitioning to the neurosurgical medical 
surgery recovery unit where they will stay for 1-2 days.  The PACU, ICU, and 
medical surgery recovery unit are all located at UPMC Presbyterian Hospital.  The 
participants will then stay at the UPMC Rehabilitation Institute for up to 3 days for 
post-operative rehabilitation.  The rehabilitation stay serves primarily to ensure that 
the participant is ready to resume normal daily activities while medical staff can 
monitor wound healing.  The study neurosurgeon and PI will determine when the 
participant will be discharged and sent home. 
2.4.3 Follow-up procedures 
Post-surgical MEG testing: 
We will ask the subject to come back for up to 3 MEG sessions within 6 months 
after completion of the BMI training. The follow-up MEG sessions are optional 

 
20
visits for the subjects.  If the subject is interested in participating, we will plan to 
schedule the visits at 2 weeks, 6 weeks, and 3 months after the explantation surgery. 
The same tasks that were completed during the pre-surgical MEG session will be 
repeated. In addition to measuring changes in single unit activity over the duration 
of the study, the MEG studies will allow us to determine if plasticity was induced 
due to BMI training in terms of volitional modulation of motor cortex activity.  
These visits are expected to last up to 2 hours each. 
Clinical follow-up: 
Follow-up visits will be scheduled in order to ensure that the bone flap and Patient 
Pedestal sites are healing properly.  These visits will be scheduled at the discretion 
of the study neurosurgeon and the subject.  We expect that each subject will have 
two follow-up visits with the study neurosurgeon and their clinical team at 1 and 4 
weeks (+/- 3 days) after explantation.  Depending on the healing process of the 
implantation site and percutaneous port, additional imaging studies (x-ray, CT scan, 
or MRI) may be performed although this is unlikely. 
Post-explant counseling: 
Subjects will be scheduled for an appointment with a licensed rehabilitation 
psychologist to assure that they have an opportunity to discuss any concerns they 
may have post explantation. 
2.4.4 Study compliance and withdrawal: 
The subject will be under medical supervision for the duration of this study. Their 
health will be the top priority and participation will be discontinued if surgical 
intervention is required. The study neurosurgeon and PI will be primarily 
responsible for evaluating the subject’s condition. Complications that could result in 
removal from the study (and having the NeuroPort Array removed) include: 
-  Treatment resistant (serious) infection at the implantation site or Patient pedestal 
-  Array technical malfunction resulting in an inability to collect data that is useful 
for brain-control tasks  
-  Serious medical complications that compromise the subject’s safety or health 
If the participant is non-compliant (e.g., unwilling to participate in BMI training 
sessions) they may be withdrawn from the study. The NeuroPort Arrays will be 
explanted and they will be strongly encouraged to attend the follow-up monitoring 
visit with the study neurosurgeon. 
Prior to implantation of the NeuroPort Array, the principal investigator may 
withdraw the participant if they do not demonstrate an understanding of the study or 
a willingness to participate.  Participants can withdraw from the study at any time. 
The NeuroPort Arrays will be explanted and they will be strongly encouraged to 
attend the follow-up monitoring visits with the study neurosurgeon. 

 
21
We will also ask for guidance from the DSMB if the research team and participant 
disagree on the decision to explant the NeuroPort Arrays (i.e., if the research team 
wishes to explant the arrays, but the participant does not). 
2.4.5 Schedule of activities (Study Table) 
Table 1 summarizes the study schedule. 
Table 1: Study Schedule 
Study Activities  
Screening 
Baseline/ Pre-
operative 
Evaluation  Implant 
Pre-
Discharge Discharge 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Month 
2-12  
Explant/
End of 
Study 
Screening Interview 
X 
  
  
  
  
  
  
  
  
  
  
Informed Consent, Eligibility 
Assessments  
X 
  
 
 
 
 
 
 
 
 
 
Neuropsychological and 
Psychosocial Examination 
(WTAR & BSI-18) 
X 
  
 
 
 
 
 
 
 
 
 
Pre-surgical fMRI Screening 
X 
  
  
  
  
  
  
  
  
  
  
Demographic and Medical 
History Questionnaire 
  
X 
  
  
  
  
  
  
  
  
  
Pre-surgical 
Magnetoencephalography 
(MEG) Testing 
  
X 
  
  
  
  
  
  
  
  
  
Pre-surgical BMI Training 
  
X 
  
  
  
  
  
  
  
  
  
Pre-surgical Structural MRI 
  
X 
  
  
  
  
  
  
  
  
  
Pre-operative Labs and 
Screening 
  
X 
  
  
  
  
  
  
  
  
  
Implantation of Two NeuroPort 
Arrays 
  
  
X 
  
  
  
  
  
  
  
  
Post Anesthesia Care Unit 
(PACU) Stay 
  
  
  
X 
  
  
  
  
  
  
  
Neurosurgical Intensive Care 
Unit (ICU) Stay 
  
  
  
X 
  
  
  
  
  
  
  
Rehabilitation Stay at UPMC 
Institute for Rehabilitation and 
Research  
  
  
  
X 
  
  
  
  
  
  
  
Head X-ray and CT  
  
  
  
X 
  
  
  
  
  
  
  
Ongoing psychological 
evaluations 
 
 
 
 
 
 
 
 
X 
X 
 
Neurological and 
Musculoskeletal Exam; Wound 
Check by Clinical Investigator 
  
  
  
  
X 
  
  
  
X 
X 
  
BMI Training/Testing; Wound 
Check/Temperature Monitoring 
by Study Team* 
  
  
  
  
  
X 
X 
X 
X 
X 
  
Pedestal Cleaning (at least 
weekly) 
  
  
  
  
  
X 
X 
X 
X 
X 
  
Daily Temperature 
Monitoring/Wound Check by 
Primary Caregiver 
  
  
  
  
  
X 
X 
X 
X 
X 
  
Explantation of NeuroPort 
Arrays 
  
  
  
  
  
  
  
  
  
  
X 
Post Anesthesia Care Unit 
(PACU) Stay 
  
  
  
  
  
  
  
  
  
  
X 
Neurosurgical Intensive Care 
Unit (ICU) Stay 
  
  
  
  
  
  
  
  
  
  
X 
Rehabilitation Stay at UPMC 
Institute for Rehabilitation and 
Research  
  
  
  
  
  
  
  
  
  
  
X 

 
22
Follow-up Clinical Visits with 
Neurosurgeon (1 & 4 weeks 
post-explant) and rehabilitation 
psychologist 
  
  
  
  
  
  
  
  
  
  
X 
Follow-up MEG Testing (2 
weeks, 6 weeks, and 3 months 
post-explant) 
  
  
  
  
  
  
  
  
  
  
X 
Adverse Event Assessment  
X 
X 
X  
X  
X  
X  
X  
X  
X  
X  
X  
* BMI training may begin immediately after discharge or later as determined by the participant and study team; A wound check will be performed 
by a study team member weekly after discharge even if BMI training has not begun; BMI training will be conducted at least once per week for the 
duration of implantation either at the University of Pittsburgh, the University of Pittsburgh Medical Center (UPMC), or in the participant’s home; 
Neural and behavioral data will be recorded during the BMI training/testing sessions in order to address the study specific aims. 
 
2.5 Study outcome evaluations 
2.5.1 Study endpoints 
The NeuroPort Arrays will be removed 1 year (+/- 30 days) after implantation.  A 
participant will be considered a success for safety if the device is not explanted for 
safety reasons during the 12-month post-implant evaluation.  If the subject 
experiences treatment resistant (serious) adverse events, he or she will be 
withdrawn and the arrays will be explanted early (See Section E 2.4.4).  The study 
may also end early if the subject is non-compliant (See Section E 2.4.4).  
We believe it is possible that a participant will not want the array removed. If the 
participant wants the NeuroPort Arrays to stay in, the study PI and neurosurgeon 
will assess whether this is acceptable.  This decision will be based on whether or 
not the participant is at increased risk by leaving the arrays in and whether the 
device is still measuring neural activity that is sufficient for brain control. We will 
consult our DSMB if conflicts arise.  One participant in the BrainGate trial has had 
a NeuroPort Array implanted for more than 1000 days without adverse event [9].  If 
the NeuroPort Arrays remain implanted for more than 1 year, we will continue to 
perform clinical follow-up as described in the current protocol.  We may also 
continue brain-machine interface testing although the frequency of the training 
sessions may be reduced.  We will remove the NeuroPort Arrays at anytime as 
directed by the participant, or as dictated by their clinical condition. 
If the participant wishes to leave the NeuroPort Array implanted, but the study PI 
and neurosurgeon do not feel that it is in their best interest, the participant will be 
counseled that they should have the NeuroPort Array removed and that not doing so 
could result in clinically significant adverse events.  They will also be informed that 
brain-machine interface training will not continue.  The consent form includes a 
statement that participants will be financially liable for any medical care resulting 
from complications of not having the device removed upon instruction of the study 
PI.  We will however allow participants to have the device removed at anytime and 
the explantation costs would be covered by this study. 
2.5.2 Sample size determination 
A maximum of 10 participants will be enrolled in order to implant a maximum of 5 

 
23
subjects.  Because it is possible that a subject may enroll and then be determined to 
be ineligible for anesthesia and/or surgery, the maximum number of subjects 
enrolled may exceed the number implanted.   
New information will be learned with each participant, as this is a feasibility study.  
Single-subject design statistical analyses will be used.  Our main goal is to 
demonstrate the safety and efficacy of NeuroPort Arrays for long-term recording of 
neural activity in order to control a high-dimensional BMI. 
2.5.3 Outcome data and data analysis 
Specific Aim 1a will be fulfilled through monthly clinical examinations as well as 
observations made by the research staff, participant, or their caregiver throughout 
the trial.  Research staff will document volunteered and observed adverse events at 
least weekly during the BMI training sessions.  Adverse events will be documented 
and reported to University of Pittsburgh IRB and to the FDA in accordance with the 
respective reporting requirements and in the annual report.  This documentation will 
serve as documentation of the safety of device in this small sample. 
Specific Aim 1b is to characterize signal quality (firing rate, number of units 
recorded) over the duration of implantation.  Data to support this aim will be 
collected at least weekly during the BMI training sessions.  Our primary method of 
analysis will be to plot the trends in signal quality measures over time.  The trend 
will be quantified using regression techniques. 
Specific Aim 2 is to demonstrate that individuals with tetraplegia can learn to 
successfully control of a variety of external devices and computer-driven tasks 
using signals recorded with the NeuroPort Array.  In additional to video 
documentation of brain-controlled device operation, we will quantify the number of 
degrees of freedom achieved by each participant at regular intervals for the duration 
of implantation.  Multiple baselines will be defined as the level of computer assist 
will decrease with training.  We will use regression to quantify changes in 
performance at a given assist level.  Similarly, trends in success rate and computer 
assist level for a given task will be quantified over the duration of the trial using 
regression.  
Specific Aim 3: Source localization (combining the MEG and structural MRI data) 
will be used to identify the anatomical foci of cortical activation controlling 
imagined and/or attempted movement. The coordinates (x,y,z) of the center of 
activation can be computed with fMRI or MEG relative to the head coordinate 
system defined using bony landmarks. The location and area of cortical activation 
measured by fMRI and MEG during imagined and/or attempted movement will be 
compared for each subject. A paired t-test will be used to compare location and area 
of cortical activation measured by the two imaging techniques using data from all 
participants, although the power of this test may be limited by sample size. 
Qualitative comparisons will be informative and we expect agreement between the 
two imaging techniques in terms of localizing the area for array implantation. MEG 

 
24
potentially offers additional information due to higher temporal resolution.  
Specific Aim 3a: Cortical modulation will be calculated as the power of the 4-40 Hz 
frequency band of MEG data that is recorded during imagined and/or attempted 
movement. Specific Aim 3a will be evaluated by applying repeated measures 
ANOVA to test for differences in modulation (magnitude and total area) during 
imagined and/or attempted movement during the pre-surgical procedures and the 
follow-up sessions. 
The study will be considered a success if the device is not explanted for safety 
reasons during the 12-month post-implant evaluation.  Further participants should 
demonstrate successful control of a high degree of freedom assistive technology in 
order to safely perform a task that replicates normal activities of daily living, such 
as grasping a cup with a robotic manipulator.  This study is not being proposed to 
support marketing applications (510(k) or PMA) for the NeuroPort Arrays.  Instead, 
the goal is to demonstrate that three-dimensional microelectrode arrays provide a 
safe way to record sufficient neural information for controlling complex assistive 
devices that will increase the independence of individuals with disabilities. 
2.5.4 Data and Safety Monitoring Committee 
An independent Data and Safety Monitoring Board (DSMB) will be created to 
review this study.  At periodic intervals (to be determined by the subcommittee) 
during the course of the study, the DSMB responsibilities are to: 
1. Review the research protocol, informed consent documents and plans for data 
and safety monitoring; 
2. Evaluate the progress of the study, including periodic assessments of data 
quality and timeliness, participant recruitment, accrual and retention, participant 
risk versus benefit, and other factors that can affect study outcome; 
3. Consider factors external to the study when relevant information becomes 
available, such as scientific or therapeutic developments that may have an 
impact on the safety of the participants or the ethics of the study; 
4. Review clinical center performance, make recommendations and assist in the 
resolution of problems reported by the PI; 
5. Protect the safety of the study participants; 
6. Report on the safety and progress of the study; 
7. Make recommendations to the PI, IRB, and if required, to the FDA concerning 
continuation, termination or other modifications of the study based on the 
observed beneficial or adverse effects of the treatment under study; 
8. Monitor the confidentiality of the study data and the results of monitoring; 

 
25
9. Assist the PI by commenting on any problems with study conduct, enrollment, 
sample size and/or data collection. 
The DSMB will include experts in neurosurgery or neurology, physical medicine 
and rehabilitation, occupational therapy, bioengineering, and biostatistics.  
Members will consist of persons independent of the investigators who have no 
financial, scientific, or other conflict of interest with the study.  Written 
documentation attesting to absence of conflict of interest will be required. 
The University of Pittsburgh, Office of Clinical Research - Health Sciences will 
provide the logistical management and support of the DSMB.  The Chairperson will 
be the contact person for serious adverse event reporting.  Procedures for this will 
be discussed at the first meeting. 
The first meeting will take place after all regulatory approvals are received to 
establish guidelines to monitor the study.  The follow-up meeting frequency of the 
DSMB will be determined during the first meeting, but it is anticipated that the 
meetings will occur at a minimum of every 6 months.  An emergency meeting of 
the DSMB will be called at any time by the Chairperson should questions of subject 
safety arise.  
 
Both the DSMB chairperson and the medical monitor will be physicians capable of 
overseeing the progress of research protocols, especially issues of individual 
subject/patient management and safety.  The medical monitor shall be independent 
of the investigative team and shall possess sufficient educational and professional 
experience to serve as the subject/patient advocate.  The medical monitor and 
DSMB may be assigned to assess one or more of the following phases of a research 
project: subject recruitment, subject enrollment, data collection, or data storage and 
analysis.  The medical monitor may be assigned to discuss research progress with 
the principal investigator, interview subjects, consult on individual cases, or 
evaluate adverse event reports.  Medical monitors shall promptly report 
discrepancies or problems to the IRB.  They will make recommendations to the IRB 
and PI about whether to stop a research study in progress, remove individual 
subjects from a study, or take steps to protect the safety and well-being of research 
subjects. 
Peter C. Gerszten, M.D., who is independent of the study team and has no conflicts 
of interest, will serve as the DSMB chairperson.  His contact information is as 
follows: 
Peter C. Gerszten, M.D., F.A.C.S, F.A.A.P. 
Peter E. Sheptak Professor of Neurological Surgery, University of Pittsburgh 
Director, Percutaneous Spine Service 
http://www.neurosurgery.pitt.edu/person/peter-gersztenNeurological Surgery 
UPMC Presbyterian, Suite B-400 
200 Lothrop Street, Pittsburgh, PA 15213 

 
26
gersztenpc@upmc.edu 
(412) 647-1700 (office) 
(412) 647-0989 (fax) 
(412) 647-3685 (lab) 
 
The position of Medical Monitor will be held by: 
Ronald M. Glick, M.D. 
Medical Director, Department of Psychiatry 
Center for Integrative Medicine 
UPMC Shadyside 
Shadyside Place, Suite 310 
580 South Aiken Ave. 
Pittsburgh, PA 15232 
glickrm@upmc.edu 
(412) 623-3023 (office) 
(412) 623-6414 (fax) 
Additional Data and Safety Monitoring by the Study Team: 
The core members of this research team will meet at least monthly to discuss study 
recruitment, study goals and progress, adverse events, participant complaints, 
modifications, and confidentiality of ongoing studies. The investigators and study 
team will ensure that proper procedures are in place to ensure data integrity and 
participant safety. Data will be reviewed and any possible study design changes 
resulting from our experience or external studies/publications will be discussed. Our 
priority is to maintain participant safety and confidentiality while collecting data 
that accurately demonstrates the efficacy of using the NeuroPort Arrays as a direct 
brain interface. We will comply with the IRB's policy for the reporting of serious 
and unexpected adverse events as described in Chapter 3.0 of the University of 
Pittsburgh’s IRB Reference Manual. Similarly, we will report adverse device events 
to the FDA in accordance with the agency’s expedited reporting requirements.  The 
outcomes of these meetings will be summarized and included in the annual IRB 
continuing review. Minutes for these meetings will be kept on file. 
3.0 Clinical Protocol For Extension Study 
3.1 Title of clinical protocol 
Long-Term Microelectrode Brain-Machine Interface (Extension Study) 
3.1.1 Protocol number 
University of Pittsburgh, PRO12090216 
3.1.2 Version number and date  
Version 6, January 14, 2013 (Expiration Date: 10/7/2014) 

 
27
3.2 Study design 
3.2.1 General study design 
This study is an extension to a prospective, non-randomized, open-label feasibility 
study that will be conducted at the University of Pittsburgh.   
3.2.2 Study design schematic 
Figure 2 illustrates the proposed study design for the core study.  For the extension 
study, the Experimental Procedures section (BMI testing, wound checks, clinical 
exams, etc.) would be expanded from 1 year in duration to up to 5 years. The 
explant surgery and follow-up visits would continue as described in Figure 2 after 
the extended implanation period.   
3.3 Subject selection 
3.3.1 General characteristics of the proposed subject populations(s) 
Participants who participated in the core study (IDE G100298, University of 
Pittsburgh PRO10080021) may be eligible for the extension study if they have had 
positive clinical and research outcomes after 6 months of implantation and meet the 
elgibility criteria described in Sections 3.3.3 and 3.3.4. 
3.3.2 Anticipated number of research subjects 
Up to 5. 
3.3.3 Inclusion criteria 
1) Participant in PRO10080021 study (IDE G100298) who is at least 6 months post-
implant 
2) Have no unresolved significant adverse events during participation in 
PRO10080021 
3) Have demonstrated at least 4-dimensional control of a virtual or real robotic arm 
during participation in PRO10080021 
4) Have a stable psychosocial support and caregivers who are able to perform the 
necessary daily care of the participant’s skin and pedestal site; This requires that 
the subject identify a caregiver and a back up who have been in place for greater 
than 6 months and are able to provide needed physical and psychosocial 
support. This will be assessed by the study PI and neurosurgeon. 
5) Age 18-70 years old at the time of consent and planned explant 
6) Have a life expectancy greater than 12 months as assessed by the study principal 
investigator and neurosurgeon sub-investigator 
7) Live within 1 hour of the University of Pittsburgh, or be willing to travel there, 
once per week for BMI testing 
8) Interested in having the NeuroPort arrays remain in place for 6 months to 4 years 
beyond the 1 year implantation that is part of PRO10080021.  Participants can 

 
28
decide to extend the implantation for any duration between 6 months and 4 
years.  This can be decided at any point during the study. 
9) Participation is not expected to have an adverse effect on mental well-being as 
judged by the rehabilitation psychologist 
10) Documentation of informed consent is obtained from the participant or their 
legal representative 
3.3.4 Exclusion criteria 
1) Women of childbearing age who are pregnant, lactating, or plan to become 
pregnant during the next 60 months 
2) Development of any medical condition that would put the participant at increased 
clinical risk during extended implantation 
 
3.4 Study procedures 
3.4.1 Screening procedures 
Participants must already been enrolled in PRO10080021 to be eligible.  They will 
meet with one of the physicians on the study (PI or neurosurgeon) to discuss the 
study procedures and risks of the proposed study.  Informed consent will be 
obtained by the study PI after these discussions to ensure that the participant has 
time to review the consent form.  As in the core study, a family member or 
caregiver will also sign the consent form acknowledging that they will support the 
participant as described in the protocol.  It is the responsibility of the principal 
investigator (PI) that each subject being considered for participation in the study be 
given a full explanation of the protocol.  Informed consent is mandatory after 
adequate explanation of the objectives, methods, anticipated benefits, and potential 
risks of the study before any study specific procedures are performed.  The 
informed consent form must include the required eight basic elements.  Informed 
consent will, consistent with site institutional policies and FDA regulations 
(21CFR, Part 50), be obtained in the following manner. 
Participants will already have the NeuroPort Arrays implanted for at least 6 months 
before being approached about the extension study so they will be very familiar 
with the study procedures and risks.  The study PI will inform the participant and 
their family or caregiver about the study procedures and risks for the extension 
study.  During a separate meeting, after the subject has had time to review the 
consent, an investigator will meet with them to review any additional questions. 
Because the device will be utilized in the subject’s chronic care environment, which 
may be the subject’s home, an understanding of the requirements of participation is 
important to the subject as well as a committed family member and/or caregiver.  If 
the subject is interested in participating, the consent will be completed by the 
subject, a family member or primary caregiver, and the study PI.  After completion 
of the consent, participation in the study is initiated.  As part of screening, the 
subject will complete a evaluation by the rehabilitation psychologist to document 
that participation in an extended duration study is not expected to have any adverse 

 
29
effect on the participant's well being and that they understand the limited duration 
of the extension study (up to 5 years post-implant) and the risk that their 
performance in BMI related activity may degrade over time.  All of these 
interactions between the subject and study personnel will serve to further educate 
the subject.  The subject may withdraw at any time. 
After consent, eligibility criteria will be verified by self-report, using data from 
PRO10080021, checking the participant's medical records as necessary, or via 
interview as described below. 
 
(1) Psychology interview: The rehabilitation psychologist will provide independent 
determination of eligibility on the basis that the participant understands the study 
procedures and limited duration.  The psychologist will give a recommendation of 
"eligible" if they believe that participation in the extension study will have no 
adverse effect on the participant's mental well-being. 
3.4.2 Experimental procedures 
This study is an optional extension to PRO10080021. Consent and screening for 
this study may occur as early as 6 months after implant and up to 13 months after 
implant (the maximum duration allowed in the original protocol).  BMI testing will 
occur as described in the original protocol with similar ongoing clinical monitoring 
and follow-up as described below: 
Brain-Machine Interface (BMI) Training/Testing: 
Neural recording will be conducted for the duration of implantation.  The recorded 
neural data will be used to operate a BMI system that allows the participant to 
control a computer cursor, virtual object, or assistive device.  While the NeuroPort 
Arrays are implanted, we will conduct BMI training for up to 8 hours per day for up 
to 5 days per week.  At least 1 session per week will be attempted while the array is 
implanted. BMI testing may occur at the University of Pittsburgh, UPMC, or in the 
participant’s home. Rest, meals, and other breaks will be scheduled as needed.  We 
may not conduct training sessions every day.  This will be determined by the 
research staff and the subject.  Also, we may not conduct testing sessions for up to 8 
weeks per year.  Since participants will have already completed 1 year of testing, 
we hope to minimize the burden on participants while still collecting valuable data 
related to signal quality and BMI control.  The subject will go no longer than 3 
weeks between testing sessions.  This will assure that the study team can continue 
to monitor the wound site and well being of the participant. 
At the beginning of each BMI testing session, an investigator will connect the 
Patient Cable to the Patient Pedestal.  We may also record neural activity using 
EEG electrodes which are placed on the scalp in order to measure larger networks 
of brain activation.  There are two types of behavioral tasks that the subject will 
participate in as part of the BMI training/testing: 1. Open-loop and 2. Closed Loop.  
These tasks are the same as described in Section 2.4.2.   

 
30
Neural and behavioral data will be recorded during each BMI session in order to 
address the Specific Aims.  As described in Section 2.4.2, we will track neural data, 
including the number of single units and the average firing rate over the duration of 
the implant.  Behavioral data may include kinematics of a cursor, virtual object, 
robotic arm, etc.  We will also compute the success rate achieved by the participant 
for a given task over a number of sessions.  Impedance measurements will be 
collected during BMI testing sessions throughout the study.  We will also document 
volunteered or observed adverse events at least weekly as part of the BMI training 
sessions as a measure of device safety.  Subject may be asked at test sessions about 
level of fatigue, quality of sleep at home or other factors that may affect quality of 
testing performance. 
At the end of each session, an investigator will remove the Patient Cable and clean 
the device.  At a minimum, the Patient Pedestal should be cleaned every 7 days by a 
family member, caregiver, medical professional, or study team member.  We will 
provide detailed cleaning instructions to the participant and anyone who may assist 
with the cleaning.  We will monitor the subject’s temperature on days that BMI 
testing occurs as this can be an early indicator of infection.  In addition, we will 
instruct the subject to monitor and record their own temperature daily as well.  A 
family member or caregiver will be asked to inspect the Patient Pedestal sites on a 
daily basis to identify any changes that may indicate an infection such as erythema, 
drainage, ecchymosis, pain, or unusual redness along the lead tunnel or pedestal. 
The study neurosurgeon and PI will train the research team and family member or 
caregiver in how to monitor wound healing.  
Sleep Diary: 
We may ask the participant to maintain a sleep diary which measures the amount 
and quality of sleep each night. 
In-Home Sleep Evaluation: 
An in-home sleep evaluation may be performed to evaluate how sleep, or lack of 
sleep, impacts a participant’s performance with the neuroprosthetic device.  We 
may measure the participant’s brain activity during sleep (in their home) using EEG 
and/or intracortical recordings from the NeuroPort electrodes.  This testing may be 
completed by a study team member in the subject’s home, or in the case of EEG 
monitoring, it could be conducted by the subject and a caregiver once the electrodes 
are setup by a study team member.  In addition to brain activity, we may record 
additional physiological information including electrocardiogram (EKG) activity, 
temperature (using a small sensor near the nose), and respiration (using elastic belts 
around the chest and abdomen).  We will plan to set up the equipment early enough 
so as not to interfere with their normal sleep routine.  The equipment will be 
removed after their normal wake-up time.  We may ask the subject to perform 
simple BMI tasks before and after periods of normal sleep.  Our goal is to 
determine how normal sleep (including normally occurring variations in sleep 
quantity and quality) affects neural activity and BMI performance. 

 
31
Ongoing Clinical Evaluations: 
A clinical investigator will perform a monthly clinical evaluation to monitor the 
participant’s neurological and musculoskeletal status. Wound checks will also be 
performed at this visit.  If any changes in neurological status or musculoskeletal 
functioning are noted, appropriate medical care will be provided.  These clinical 
visits will likely be combined with research visits to the University of Pittsburgh or 
UPMC. 
Ongoing Psychological Evaluations: 
The subject will have opportunities to talk to a psychologist throughout the study, 
either over the phone or in person.  These discussions will be scheduled regularly 
(approximately every 3 months) to discuss any concerns the subject may have.  The 
psychologist may refer the subject for additional meetings as necessary.  In 
addition, physician-investigators, including the study PI and neurosurgeon, will be 
interacting with the subject on a regular basis and can refer the subject to a 
psychologist at their discretion.  If the subject has severe problems or concerns, he 
or she may be withdrawn from the study.  
Imaging: 
The study neurosurgeon may order a head x-ray or CT if there is a change in the 
patient’s neurological examination or the patient experiences severe headaches, 
nausea, and/or abnormal behavior.  These procedures will enable our neurosurgeon 
and their clinical team to identify infection, bleeding, edema, or neurological 
dysfunctions as early as possible and treat them properly.  These imaging 
procedures will take place in UPMC facilities. 
Removal of the electrodes: 
Subjects will undergo a second surgery at UPMC Presbyterian Hospital 
approximately 5 years after implantation of the NeuroPort Arrays.  It is possible 
that the NeuroPort Arrays may be explanted earlier due to technical problems, 
clinical complications, investigator-initiated withdrawal, or subject-initiated 
withdrawal.  The participant will go through standard preoperative screening 
procedures which may include a blood draw.  Explantation procedures are the same 
as described in Section 2.4.2.   
Post-operative care: 
Post-operative care will depend on the participant's condition.  The participant will 
remain in the post anesthesia care unit (PACU) for approximately 3 hours after 
surgery.  They will be transferred to the neurosurgical intensive care unit (ICU) for 
approximately 24 hours before transitioning to the neurosurgical medical surgery 
recovery unit where they will stay for 1-2 days.  The PACU, ICU, and medical 
surgery recovery unit are all located at UPMC Presbyterian Hospital.  Post-
operative imaging may be requested by the study neurosurgeon depending on the 

 
32
participant's condition.  The participants will then stay at the UPMC Rehabilitation 
Institute for up to 3 days for post-operative rehabilitation.  The rehabilitation stay 
serves primarily to ensure that the participant is ready to resume normal daily 
activities while medical staff can monitor wound healing.  The study neurosurgeon, 
PI and rehabilitation team will determine when the participant will be discharged 
and sent home. 
3.4.3 Follow-up procedures 
Post-surgical MEG testing: 
We will ask the subject to come back for up to 3 MEG sessions within 6 months 
after completion of the BMI training. The follow-up MEG sessions are optional 
visits for the subjects.  If the subject is interested in participating, we will plan to 
schedule the visits at 2 weeks, 6 weeks, and 3 months after the explantation surgery. 
The same tasks that were completed during the pre-surgical MEG session will be 
repeated. In addition to measuring changes in single unit activity over the duration 
of the study, the MEG studies will allow us to determine if plasticity was induced 
due to BMI training in terms of volitional modulation of motor cortex activity.  
These visits are expected to last up to 2 hours each. 
Clinical follow-up: 
Follow-up visits will be scheduled in order to ensure that the bone flap and Patient 
Pedestal sites are healing properly.  These visits will be scheduled at the discretion 
of the study neurosurgeon and the subject.  We expect that each subject will have 
two follow-up visits with the study neurosurgeon and their clinical team at 1 and 4 
weeks (+/- 3 days) after explantation.  Depending on the healing process of the 
implantation site and percutaneous port, additional imaging studies (x-ray, CT scan, 
or MRI) may be performed although this is unlikely. 
Post-explant counseling: 
Subjects will be scheduled for an appointment with a licensed rehabilitation 
psychologist to assure that they have an opportunity to discuss any concerns they 
may have post explantation. 
3.4.4 Study compliance and withdrawal: 
The subject will be under medical supervision for the duration of this study.  Their 
health will be the top priority and participation will be discontinued if surgical 
intervention is required.  The study neurosurgeon and PI will be primarily 
responsible for evaluating the subject’s condition.  Complications that could result 
in removal from the study (and having the NeuroPort Array removed) include: 
-  Treatment resistant (serious) infection at the implantation site or Patient pedestal 
-  Array technical malfunction resulting in an inability to collect data that is useful 

 
33
for brain-control tasks  
-  Serious medical complications that compromise the subject’s safety or health 
-  Psychological distress associated with decrements in performance or continued 
implantation.  
If the participant is non-compliant (e.g., unwilling to participate in BMI training 
sessions) they may be withdrawn from the study.  The NeuroPort Arrays will be 
explanted and they will be strongly encouraged to attend the follow-up monitoring 
visit with the study neurosurgeon. 
3.4.5 Schedule of activities (Study Table): 
The schedule of activities remains the same as in Table 1, Section 2.4.5, except that 
the implantation duration and all affiliated procedures (BMI testing, psychological 
evaluations, clinical exams, etc.) may be extended for up to 5 years post-implant.   
3.5 Study outcome evaluations 
3.5.1 Study endpoints 
The NeuroPort Arrays will be removed up to 5 years after implantation.  A 
participant will be considered a success for safety if the device is not explanted for 
safety reasons during the 5 year post-implant evaluation.  If the subject experiences 
treatment resistant (serious) adverse events, he or she will be withdrawn and the 
arrays will be explanted early (See Section E 3.4.4).  The study may also end early 
if the subject is non-compliant (See Section E 3.4.4).  
If the participant wishes to leave the NeuroPort Array implanted after 5 years, the 
participant will be counseled that they should have the NeuroPort Array removed 
and that not doing so could result in clinically significant adverse events.  They will 
also be informed that brain-machine interface training will not continue.  The 
consent form includes a statement that participants will be financially liable for any 
medical care resulting from complications of not having the device removed upon 
instruction of the study PI.  We will however allow participants to have the device 
removed at anytime and the explantation costs would be covered by this study. 
3.5.2 Sample size determination 
This is the first study to evaluate a long-term implantation of microelectrode arrays 
in individuals with spinal cord injury (or other impairment resulting in upper limb 
paralysis).  Because this is a feasibility study, we feel that it is appropriate to begin 
with a small sample size in this initial investigation.  We are recruiting up to 5 
participants for PRO10080021 and only these people would be eligible for the 
current study. 
3.5.3 Outcome data and data analysis 

 
34
Specific Aim 1a will be fulfilled through monthly clinical examinations as well as 
observations made by the research staff, participant, or their caregiver throughout 
the trial.  Research staff will document volunteered and observed adverse events at 
least weekly during the BMI training sessions.  Adverse events will be documented 
and reported to University of Pittsburgh IRB and to the FDA in accordance with the 
respective reporting requirements and in the annual report.  This documentation will 
serve as documentation of the safety of device in this small sample. 
Specific Aim 1b is to characterize signal quality (firing rate, number of units 
recorded) over the duration of implantation.  Data to support this aim will be 
collected at least weekly during the BMI training sessions.  Our primary method of 
analysis will be to plot the trends in signal quality measures over time.  The trend 
will be quantified using regression techniques. 
Specific Aim 2 is to demonstrate that individuals with tetraplegia can learn to 
successfully control of a variety of external devices and computer-driven tasks 
using signals recorded with the NeuroPort Array.  In additional to video 
documentation of brain-controlled device operation, we will quantify the number of 
degrees of freedom achieved by each participant at regular intervals for the duration 
of implantation.  Multiple baselines will be defined as the level of computer assist 
will decrease with training.  We will use regression to quantify changes in 
performance at a given assist level.  Similarly, trends in success rate and computer 
assist level for a given task will be quantified over the duration of the trial using 
regression.  
Specific Aim 3: Source localization (combining the MEG and structural MRI data) 
will be used to identify the anatomical foci of cortical activation controlling 
imagined and/or attempted movement.  The coordinates (x,y,z) of the center of 
activation can be computed with fMRI or MEG relative to the head coordinate 
system defined using bony landmarks.  The location and area of cortical activation 
measured by fMRI and MEG during imagined and/or attempted movement will be 
compared for each subject.  A paired t-test will be used to compare location and 
area of cortical activation measured by the two imaging techniques using data from 
all participants, although the power of this test may be limited by sample size. 
Qualitative comparisons will be informative and we expect agreement between the 
two imaging techniques in terms of localizing the area for array implantation.  MEG 
potentially offers additional information due to higher temporal resolution.  
Specific Aim 3a: Cortical modulation will be calculated as the power of the 4-40 Hz 
frequency band of MEG data that is recorded during imagined and/or attempted 
movement.  Specific Aim 3a will be evaluated by applying repeated measures 
ANOVA to test for differences in modulation (magnitude and total area) during 
imagined and/or attempted movement during the pre-surgical procedures and the 
follow-up sessions. 

 
35
Specific Aim 4: Sleep quality measures will be correlated to BMI performance on 
the following day while controlling for differences in task difficulty.  Linear 
regression will be used to determine the most predictive sleep quality metrics. 
 
The study will be considered a success if the device is not explanted for safety 
reasons during the 12-month to 5 year post-implant evaluation.  This study is not 
being proposed to support marketing applications (510(k) or PMA) for the 
NeuroPort Arrays.  Instead, the goal is to demonstrate that three-dimensional 
microelectrode arrays provide a safe way to record sufficient neural information for 
controlling complex assistive devices that will increase the independence of 
individuals with disabilities. 
3.5.4 Data and Safety Monitoring Committee 
The independent Data and Safety Monitoring Board (DSMB) that oversees the core 
study, will also oversee the extension study following the procedures described in 
section 2.5.4.  Similarly, the core members of the research team will meet at least 
monthly to provide additional internal study monitoring as for the core study.  We 
will comply with the IRB's policy for the reporting of serious and unexpected 
adverse events as described in Chapter 3.0 of the University of Pittsburgh’s IRB 
Reference Manual. Similarly, we will report adverse device events to the FDA in 
accordance with the agency’s expedited reporting requirements.   
4.0 Risk Analysis 
For each risk, we have noted whether it is applicable to the core study, extension study, or 
both. 
 
4.1 Anticipated risks 
This study involves potentially serious risks.  The risks of all experimental procedures are 
described below along with the steps that will be taken to minimize those risks.   
Risks Common to all Study-Related Activities (Core Study and Extension Study) 
There is a risk of breach of confidentiality since personal information will be obtained. 
Some of the research activities may require the participant to transfer out of their 
wheelchair such as the MRI, CT, MEG, and x-ray.  There is a risk of falling during the 
transfer. 
There is also a risk of pressure sores with any prolonged sedentary activity for individuals 
with compromised nervous systems, such as those with SCI.  This risk is not unique to 
participating in this study, and it is a common risk for prolonged sitting (e.g. in 
wheelchairs).  This includes imaging sessions (MRI, CT, MEG, and x-ray) as well as 
BMI training/testing.   
Some of the research procedures involve radiation exposure including the pre-operative 

 
36
chest x-ray, and post-operative head CT and x-ray.  The exposure for each procedure is 
specified below, but the expected total radiation exposure to the head is expected to be 
2.6-5.6 rems.  More imaging studies may be necessitated by the participant’s medical 
condition.  For reference, an annual radiation exposure of 20 rems is permitted to the 
most sensitive organs of radiation workers by federal regulations.  There is no minimal 
level of radiation exposure that is recognized as being totally free of the risk of causing 
genetic mutations (abnormal cells) or cancer.  
Steps taken to minimize these risks: 
Identifiable data will be filed in locked areas immediately after collection.  Study ID 
numbers will be used instead of the participant’s name when recording study-related 
data.  The information collected in this study, such as neural recordings, will 
generally consist of numbers with little or no meaning to the casual observer. 
Electronic data is stored on password-protected network drives.  Staff has been 
trained regarding the critical nature of participants’ privacy, and about the procedures 
for respecting their privacy and maintaining confidentiality. 
The research staff will be trained to assist participants with transfers as well as to 
perform dependent transfers. If the participant can transfer independently, they will 
be spotted. Assistive devices (e.g. sliding board or hoyer lift) will be available as 
necessary. 
We will exclude individuals with a recent history of pressure sores from this study. 
The risk of developing a pressure sore is infrequent and can be significantly reduced 
by frequent change of sitting position, pressure relief movement, and usage of 
cushion.  The duration of the imaging sessions that require the participants to remain 
still will be minimized.  We will encourage participants to follow their normal 
pressure relief routines during experimental sessions. 
The imaging studies are required to ensure the participant’s safety both pre-
operatively and post-operatively.  The risk associated with the amount of radiation 
exposure that the subject will receive from this additional x-ray exam is considered to 
be low and comparable to everyday risks. 
Risks of the Screening Interview Neuropsychological Examination, and Post-Operative 
Visit with Rehabilitation Psychologist (Core Study) 
There is a risk of breach of confidentiality as personal information will be recorded.  
Steps taken to minimize this risk: 
A screening script will be used to determine whether the subject meets the 
inclusion/exclusion criteria.  This information will be recorded using a coded subject 
ID. If it is determined that the subject is not eligible or does not wish to participate, 
this information will be destroyed.  
Information from the neuropsychological examination will be recorded using a coded 

 
37
subject ID.  If it is determined that the subject is not eligible or does not wish to 
participate, this information will be destroyed.  
Risks of fMRI (Core Study) 
MRI is widely used in clinical practice, and the risks of MRI are believed to be very low. 
There is no ionizing radiation exposure involved and the studies are non-invasive. The 
magnet will make intermittent, loud, knocking noises that could cause ear discomfort in 
some people.  Also, the rapidly switched magnetic fields used during imaging may cause 
nerve stimulation (e.g., an uncontrolled twitch or tickle near the waist).  It is possible that 
the subject may experience feelings of anxiety or claustrophobia during the MRI scans. 
There is also a risk of the MRI scanner attracting metal objects.  
Steps taken to minimize these risks: 
Steps will be taken to minimize potential discomforts due to noise in the fMRI, such 
as wearing earplugs and informing the subject about the procedures.  Two-way 
communication will be maintained at all times in case the subject experiences feelings 
of anxiety or claustrophobia. 
The fMRI scanner may attract metal objects.  Metallic implants, pacemakers, and 
other metallic substances are considered contraindications for MRI and therefore 
would exclude someone from participating in this study.  It is possible to use a MRI-
compatible ventilator for someone who is normally ventilator-dependent.  Therefore 
this would not exclude someone from participating in this study.  The Magnetic 
Resonance Research Center will also perform their standard screening procedures 
prior to the scan to ensure the subject’s safety. 
Risks of Blood Draw for Pre-Operative Screening (Core Study and Extension Study) 
The insertion of the needle to draw blood may cause temporary discomfort, bruising from 
where the needle enters the vein, or soreness.  These risks related to the blood draw are 
anticipated to be common, or expected to occur in 10% or greater of the participants (10 
or more out of 100 people). 
There is a slight risk of infection.  Fainting may occur, but this risk is expected to be rare, 
or occur in less than 1% of people, or less than 1 out of 100 people. 
Steps taken to minimize these risks: 
Pre-operative screening will be performed at the Anesthesia Pre-Op clinic which 
routinely performs this evaluation for neurosurgical candidates.  This screening is 
necessary to ensure that the participants are not at increased risk for complications 
during surgical procedures. 
Risks of Chest X-ray for Pre-Operative Screening (Core Study and Extension Study) 
The maximum amount of radiation exposure that participants will receive from the x-ray 

 
38
exam is approximately 0.3 rem (a unit of radiation exposure) to the area of the body 
evaluated with minimal exposure of other areas of your body.  For comparison, this is a 
small fraction (1-2%) of the annual radiation exposure (20 rems) permitted to the most 
sensitive organs of radiation workers by federal regulations.  There is no minimal level of 
radiation exposure that is recognized as being totally free of the risk of causing genetic 
mutations (abnormal cells) or cancer.  However, the risk associated with the amount of 
radiation exposure that the subject will receive from this additional x-ray exam is 
considered to be low and comparable to everyday risks. 
Steps taken to minimize these risks: 
Pre-operative screening will be performed at the Anesthesia Pre-Op clinic which 
routinely performs this evaluation for neurosurgical candidates.  This helps assure 
minimal radiation exposure and good technique for acquiring the film.  This 
screening is necessary to ensure that the participants are not at increased risk for 
complications during surgical procedures. 
Risks of EKG for pre-operative screening (Core Study and Extension Study) 
There is a risk of skin irritation after removal of the electrodes used for EKG monitoring. 
Steps taken to minimize these risks: 
Pre-operative screening will be performed at the Anesthesia Pre-Op clinic by 
personnel who are trained to perform EKG screening.  Cleaning the skin after 
removal of the electrodes will reduce the risk of skin irritation.   
Risks of Structural MRI with IV Contrast (Core Study) 
MRI is widely used in clinical practice, and the risks of MRI are believed to be very low. 
There is no ionizing radiation exposure involved and the studies are non-invasive.  The 
magnet will make intermittent, loud, knocking noises that could cause ear discomfort in 
some people.  Also, the rapidly switched magnetic fields used during imaging may cause 
nerve stimulation (e.g., an uncontrolled twitch or tickle near the waist).  It is possible that 
the subject may experience feelings of anxiety or claustrophobia during the MRI scans. 
There is also a risk of the MRI scanner attracting metal objects.  The contrast agent is 
FDA-approved and used routinely for MRI exams.  It contains a material called 
gadolinium.  The injection of contrast may cause discomfort, tingling or warmth in the 
lips, metallic taste in the mouth, tingling in the arm, nausea, or headache.  These 
symptoms occur in less than 1% (less than 1 in 100) of people and go away quickly.   
There is a small risk of an allergic reaction to gadolinium; however, a severe allergic 
reaction occurs in less than one in 300,000 people.  Insertion of the needle (small plastic 
tube) to inject the gadolinium may cause minor pain, bruising and/or infection at the 
injection site.  People with severe kidney failure who receive gadolinium are at risk of 
developing Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy 
(NSF/NFD).  This disease causes fibrosis, which is the formation of too much connective 
tissue in the skin and internal organs throughout the body.  People develop skin 
thickening that may prevent bending and extending joints, resulting in decreased 

 
39
movement of the joints.  The skin changes can cause feelings of burning, itching and pain 
that can be severe.  In addition, people may experience fibrosis that spreads to other parts 
of the body such as the diaphragm, muscles in the thigh and lower abdomen, and the 
lining of blood vessels in the lung.  NSF/NFD is a serious progressive disease and can 
result in death.  If the subject has severe kidney failure and receives gadolinium, the risk 
of developing NSF/NFD is 1-5 % (up to 1 to 5 per 100 people).  We may require a blood 
sample (about 1 tablespoon) to check kidney function before gadolinium contrast is 
injected.  
Steps taken to minimize these risks: 
Steps will be taken to minimize potential discomforts due to noise, such as wearing 
earplugs and informing the subject about the procedures.  Two-way communication 
will be maintained at all times in case the subject experiences feelings of anxiety or 
claustrophobia. 
The MRI scanner may attract metal objects.  Metallic implants, pacemakers, and 
other metallic substances are considered contraindications for MRI and therefore 
would exclude someone from participating in this study.  It is possible to use a MRI-
compatible ventilator for someone who is normally ventilator-dependent.  Therefore 
this would not exclude someone from participating in this study.  The Magnetic 
Resonance Research Center will also perform their standard screening procedures 
prior to the scan to ensure the subject’s safety. 
Participants will be asked to notify a doctor, nurse or technologist if they are allergic 
to gadolinium, if they have any kidney problems, or if they experience any of these or 
other side effects.  Individuals with renal failure or dysfunction will be excluded from 
study participation.  A physician will be available during the procedure to administer 
any necessary care if side effects do occur, and to determine when or if the injection 
of the gadolinium should be stopped. 
 
Risks of MEG Testing (Core Study and Extension Study) 
MEG testing has minimal risks.  The MEG system records brain activity non-invasively. 
It does not require implantation of electrodes in the brain or the application of electrodes 
to the scalp. MEG recording will be conducted with an FDA-approved MEG system 
(Neuromag®) located in the MEG Center at University of Pittsburgh Medical Center 
(UPMC).  This facility is also used routinely for clinical diagnostics, and the MEG 
system is well-maintained to be used safely on humans.  During experiments, participants 
will sit in a chair that is part of the MEG system with a comfortable posture.  Participants 
will be asked to keep still during MEG recording and they may become fatigued during 
the session since long periods of concentration may be required.  It is also possible that 
the subject may experience feelings of anxiety or claustrophobia during MEG testing.  
Steps taken to minimize these risks: 

 
40
We will have a seat belt available to help with postural support and will have the 
option to conduct the MEG while the participant is in a supine position if necessary. 
Rest breaks will be incorporated throughout the testing session to minimize the risk of 
fatigue.  We will encourage participants to perform frequent pressure relief 
movements and will provide a MEG-compatible cushion to reduce the risk of 
pressure sores.  Two-way communication will be maintained at all times in case the 
subject experiences feelings of anxiety or claustrophobia. 
Risks of Surgical Procedures (Core Study Implantation and Explantation and Extension 
Study Explantation Only) 
In general, the surgical risks associated with implanting the NeuroPort Arrays are 
anticipated to be typical for any surgery for implanting a device in the brain.  The risks 
should be similar to those for implanting a Deep Brain Stimulator (DBS).  However, 
unlike a DBS implant, the NeuroPort Arrays are not implanted deep into the brain, but 
rather on the surface of the cortex.  The risks associated with surgery include adverse 
reactions to surgical procedure, bleeding during surgery, infection post-surgery and 
potential tissue damage to the primary motor cortex during implantation of the NeuroPort 
Arrays.  The risks associated with explantation surgery of the NeuroPort Array are 
similar to those during implantation surgery.  Animal study data show that post-
explantation, the primary motor cortex heals with no external signs of irreversible 
adverse effects.  There is also a risk of developing a pressure sore during surgery for 
individuals with SCI.  
There is a risk of bone resorption after the two surgeries where the bone flap is removed 
and replaced.  The bone flap may breakdown and not heal properly however this risk is 
rare (<1%).  If this occurs, the study neurosurgeon may perform an additional surgical 
procedure to replace the bone flap with an artificial material. 
The subject will be under general anesthesia for the duration of the surgery. Minor risks 
of general anesthesia include nausea and vomiting (25%), sore throat (10-50%), post-
operative pain (10-30%), headache (20%), drowsiness (50%), dizziness (20%), damage to 
the teeth or oral tissue (<1%), and peripheral nerve injuries (<0.3%).  These risks are 
common but are typically temporary.  Serious risks of general anesthesia, which are very 
rare (40), include: vision loss or blurriness (0.0008%), hearing loss (0.01%), anaphylaxis 
(allergic reaction, 0.01%), post-operative cognitive dysfunction (difficulty with 
concentration and memory, 1% for individuals over the age of 60), respiratory 
complications (0.03%), cerebrovascular accident (stroke, 1%), and cardiac arrest 
(<0.01%). 
Autonomic hyperreflexia occurs during the life of up to 85% of patients with a complete 
spinal cord injury above T5.  This occurs due to excessive sympathetic response to stimuli 
below the level of injury, absent the brain’s normal damping effect [50].  As a result, 
exaggerated hypertensive responses can be expected due to surgical stimuli that can be 
properly blocked by deep anesthesia, or vasoactive agents.  In a large case series (n=271 
individuals with SCI at T5 or higher), 16% of patients experienced mild or severe 
autonomic hyperreflexia in the presence of anesthesia [51].  However, all but ten of these 

 
41
cases involved urological procedures.  Since the current study involves a neurosurgical 
procedure, the stimuli will be above the level of the lesion and therefore the risk of 
hyperreflexia is reduced.  Also, in response to hypertensive episodes, significant 
bradycardia can occur due to unopposed parasympathetic cardiac tone that can be treated 
with vasoactive agents.   
 
Patients with chronic SCI also have a risk of deficient body temperature regulation due to 
loss of supraspinal regulation requiring meticulous management of hypothermia.  An 
additional anesthesia-related risk in chronic SCI patients is an increased incidence of 
atelectasis postoperatively due to respiratory muscle compromise requiring extended 
controlled or assisted ventilation and chest physiotherapy, as well as postural drainage.  
Based on the literature and our experience, we believe the risks of anesthesia that are 
specific to SCI to be infrequent (1-10%). 
 
After a neurosurgical procedure, common minor risks include mild to moderate 
headache, eyelid swelling, bruising around the eye, minor swelling of the incision, and 
minor CSF leaks that are easily stopped [52]. These risks are common to implantation 
and explantation of the device.  
Steps taken to minimize these risks: 
Participants will undergo pre-operative labs and screening at the Pre-Op Anesthesia 
Clinic to ensure that they are not deemed to have an increased surgical risk beyond 
the increased risk that is associated with spinal cord injury or other neurological 
disease/condition. 
The director of Neuroanesthesiology at UPMC will oversee anesthesia care for 
participants in this study to ensure that participants are monitored adequately to allow 
for rapid intervention.  As an additional layer of protection for responding to 
autonomic hyperreflexia, an A-line (intra-arterial catheter) will be inserted to allow 
for rapid intervention if necessary.  In order to minimize autonomic hyperreflexia-
related risk, participants with cardiovascular disease and coagulopathies (identified by 
pre-operative screening) will be excluded from this study.   
We will follow the standard clinical procedures to minimize the risks associated with 
surgical implantation or removal of electrodes.  For example, antibiotic prophylaxis 
administration is usually initiated for the patient approximately two hours before the 
surgery and will be maintained as directed by the study neurosurgeon and their 
clinical team.  We have excluded pregnant females and those with renal failure as 
they may be at an increased risk for complications resulting from administration of 
the antibiotics.  Complications or side effects usually result from prolonged dosing, 
rather than the single dosing that will be administered in this study.  Antibiotic 
ointment and sterile dressings will be applied to the implantation site to minimize the 
risk of infection.  Standard sterile surgical techniques will be followed for this study. 
This includes sterilization of the NeuroPort Arrays before the surgery and proper 
handling of NeuroPort Arrays during the surgery.  The Patient Pedestals will be 
covered with antibiotic ointment and sterile dressings.  These procedures will greatly 

 
42
minimize the risk of infection.  The NeuroPort Arrays will be placed away from 
blood vessels to minimize the risk of bleeding/bruising.  Sufficient padding will be 
used to reduce the risk of pressure sores during surgery and individuals with a recent 
history of pressure sores will be excluded from participation. 
Risks of Chronic Recording with NeuroPort Arrays (Core Study and Extension Study) 
The primary risks of chronic recording center around the long-term presence of the 
NeuroPort Arrays and Patient Pedestals.  The risks associated with the chronic 
implantation of the NeuroPort Arrays are expected to be similar to those observed with 
the implantation of other chronic devices such as deep brain stimulators and cochlear 
implants.  Some of these include, but are not limited to thrombosis, embolism, body 
rejection phenomena, neurological complications, and infection (meningitis and 
cellulites) (see full list below).  The most common complication for these types of 
devices is infection. Infection rates for other implanted devices requiring a craniotomy 
range from 4 to 12% [20-22].  The outcome of infection may be serious and may lead to 
brain edema or other sequelae. If the infection cannot be treated with antibiotics, the 
NeuroPort Arrays may need to be explanted.  Some of these procedures included in the 
infection risk estimate are more invasive than that proposed in the current study.  Because 
we will perform a smaller craniotomy with a wound closure away from the implantation 
site, and due to the lack of clinical adverse events observed in the BrainGate trial, we 
believe that the risk of infection for a single NeuroPort Array is at the low end of this 
range (approximately 5-6%).  Based on our team’s experience with other neurosurgical 
procedures, we estimate the elevated risk of infection due to the presence of two 
percutaneous Patient Pedestals to be less than 50% of the current risk.  Therefore the 
expected risk of infection for the proposed study is approximated to be less than 9%.  
Most of the risk for infection is due to environmental factors in the operating room and 
therefore having two percutaneous sites only introduces an incremental increase in the 
risk of infection. 
 
There is also the potential for seizure and other neurological sequelae due to the presence 
of a chronic implant in the brain.  It is possible that a subject that has limited ability to 
move finger(s) may lose that ability due to implant of the NeuroPort Array.  It is unlikely 
that local tissue damage resulting from the inflammatory response will lead to functional 
deficits.  No such deficits have been reported in any of the previous animal or human 
studies.  As a point of reference multiple subpial transections, in which a series of 
shallow cuts are made into the cortex, are performed for treatment of intractable epilepsy 
where the seizure foci are located in areas of the brain that cannot be removed safely, 
such as the motor cortex.  Major complications with this type of procedure are rare and 
neurological deficits appear to be only temporary [25, 26].  While unexpected, if any 
serious adverse events occur and they are resistant to treatment, the PI will recommend to 
the subject that the NeuroPort Array be explanted. Subjects will be followed for at least 
three weeks post-explant, and longer, if clinically necessary. 
 
Based on published literature, and our plan for continued wound care and clinical 
monitoring, we do not believe that extending the implantation duration increases the risks 
of chronic implantation.   

 
43
 
Table 2 summarizes possible risks, along with a brief definition, that may occur due to 
implantation and chronic recording with NeuroPort Arrays.  Due to the limited number of 
human studies with the NeuroPort Arrays, it is difficult to provide quantitative estimates 
for each possible risk.  However, based on published reports and discussions with 
BrainGate investigators, we expect the risk of serious or chronic adverse events to be 
very low.  Based on our experience with other common neurosurgical procedures (such 
as deep brain stimulation and electrocorticography monitoring), we have provided our 
best estimate of the expected rate of occurrence for each clinical event. 
 
Table 2. Possible risks of chronic implantation of the NeuroPort Array 
 
Risk 
Definition 
Rate of 
Occurrence 
Rare: <1% 
Infrequent: 1-10% 
Common: >10% 
Additional paralysis 
Permanent or temporary loss or impairment of 
the subject’s ability to move a body part 
Rare 
Adverse reaction to 
anesthesia 
Reaction to any anesthetic agent given 
Rare 
Allergic reaction 
Hypersensitivity reaction to a particular 
allergen  
Infrequent 
Ataxia of neck and 
facial muscles 
Loss of the ability to coordinate muscular 
movement of the neck and facial muscles 
Rare 
Attention deficit 
A deficiency or impairment in ability of the 
subject to concentrate 
Rare 
Autonomic 
dysreflexia 
Paroxysmal rises in blood pressure  
Rare 
Bald spot 
Lacking hair  
Common 
Blood clot 
Blood clot (near surgical site) 
Infrequent 
Cognitive deficit 
A permanent or temporary deficiency or 
impairment in mental functioning 
Rare 
Cramping 
A sudden, involuntary, spasmodic muscular 
contraction causing severe pain, often 
occurring in the leg or shoulder as the result of 
strain or chill 
Rare 
Death 
Subject death 
Rare 
Diplopia 
A disorder of vision in which a single object 
appears double 
Rare 
Disequilibrium 
Loss or lack of stability or equilibrium 
Infrequent 
Dizziness/vertigo 
Having a whirling sensation and a tendency to 
fall 
Infrequent 
Dysarthria 
A disturbance of speech due to emotional 
stress, to brain injury, or to paralysis, in 
coordination or spasticity of the muscles 
Rare 
Dysphagia 
Difficulty in swallowing 
Infrequent 

 
44
Encephalitis 
Inflammation of the brain 
Rare 
Epidural hematoma 
A localized swelling filled with blood resulting 
from a break in a blood vessel located on or 
over the dura mater 
Rare 
Erosion around lead 
or pedestal 
An eating or gnawing away of the tissue 
around the pedestal 
Infrequent 
Erythema along lead 
tunnel or pedestal 
Redness of the skin caused by dilatation and 
congestion of the capillaries 
Common 
Exacerbation of 
underlying motor 
deficit 
Temporary aggravation of the preexisting basic 
or fundamental motor deficit 
Infrequent 
Facial paresis 
Paralysis of the face  
Rare 
Fatigue 
Temporary physical or mental weariness 
resulting from exertion 
Common 
Fever 
Abnormally high body temperature 
Infrequent 
Hemorrhage 
Excessive discharge of blood from the blood 
vessels; profuse bleeding 
Rare 
Headache 
A pain in the head 
Common 
Histotoxic reaction 
The chronically implanted components have a 
poisonous effect on the tissues 
Rare 
Hoarseness 
Having or characterized by a husky, grating 
voice 
Infrequent 
Hypersensitivity to 
Chlorhexidine 
Highly or excessively sensitive to 
chlorhexidine 
Infrequent 
Immune rejection 
The failure of the body to accept implanted 
material as a result of immunological 
incompatibility; immunological resistance to 
foreign material 
Rare 
Incision site pain 
Temporary pain along the cut made during 
surgery  
Common 
Infection 
Invasion by and multiplication of pathogenic 
microorganisms in a bodily part or tissue, 
which may produce subsequent tissue injury 
and progress to overt disease through a variety 
of cellular or toxic mechanisms. One type of 
infection is cellulitis or insertion site skin 
infection 
Infrequent 
Inflammatory 
process 
A protective tissue response to injury or 
destruction of tissues 
Infrequent 
Intraparenchymal 
hemorrhage 
Excessive discharge of blood from the blood 
vessels; profuse bleeding occurring within the 
parenchyma 
Rare 
Lead migration 
A spontaneous change in the place of the lead  
Rare 
Loss of residual 
movements 
Loss of any movements that the subject had 
prior to the surgery 
Rare 
Meningitis 
Inflammation of the meninges of the brain and 
the spinal cord, most often caused by a 
bacterial or viral infection and characterized by 
Rare 

 
45
fever, vomiting, intense headache, and stiff 
neck  
Nausea 
Nausea  
Common 
Neck dystonia 
Abnormal tonicity of muscle, characterized by 
prolonged, repetitive muscle contractions that 
may cause twisting or jerking movements of 
the neck 
Rare 
Neck pain 
An unpleasant sensation occurring in varying 
degrees of severity as a consequence of injury 
or disease in the neck 
Rare 
Neck paresis 
Paralysis of the neck 
Rare 
Neurological deficits A permanent or temporary deficiency or 
impairment in neurological functioning 
Infrequent 
Non healing wound 
A wound that because of infection or disease 
will not close with granulation tissue 
Rare 
Numbness 
Deprived of the power to feel normally  
Rare 
Pedestal site 
drainage 
Fluid leaving the pedestal site  
Rare 
Pedestal site 
ecchymosis 
The passage of blood from ruptured blood 
vessels into subcutaneous tissue, marked by a 
purple discoloration of the skin 
Common 
Pedestal site pain 
An unpleasant sensation occurring in varying 
degrees of severity as a consequence of injury 
or disease 
Infrequent 
Percutaneous site 
infection 
Invasion by and multiplication of pathogenic 
microorganisms in the area of the pedestal 
Infrequent 
Perioperative 
bleeding 
Bleeding during surgery 
Rare 
Post-operative 
bleeding 
Bleeding after surgery 
Rare 
Psychiatric episode 
Mental and emotional disorder of brief 
duration  
Infrequent 
Scalp necrosis 
Scalp tissue that dies  
Rare 
Scalp numbness 
Deprived of the power to feel the scalp  
Common 
Scarring 
Scar at site of implant/explant 
Common 
Seizure 
A sudden attack, spasm, or convulsion, as in 
epilepsy or another disorder 
Infrequent 
Sensor migration 
Sensor moves outside the primary motor cortex  Rare 
Skin inflammation 
A localized protective reaction of skin to 
irritation, injury, or infection, characterized by 
pain, redness and swelling 
Common 
Skin irritation 
A condition of inflammation, soreness, or 
irritability of the skin 
Common 
Spasticity 
A state of increased tone of a muscle 
Rare 
Speech deficits 
A deficiency or impairment in mental or 
physical function of speech 
Rare 
Stroke 
Sudden loss of brain function caused by a 
blockage or rupture of a blood vessel to the 
Rare 

 
46
brain, characterized by loss of muscular 
control, diminution or loss of sensation or 
consciousness, dizziness, slurred speech, or 
other symptoms that vary with the extent and 
severity of the damage to the brain 
Subarachnoid 
hemorrhage 
Excessive discharge of blood from the blood 
vessels; profuse bleeding occurring beneath the 
arachnoid membrane 
Rare 
Subdural hematoma 
A localized swelling filled with blood resulting 
from a break in a blood vessel located or 
occurring beneath the dura mater 
Rare 
Tissue granulation 
Small, fleshy, beadlike protuberances, 
consisting of outgrowths of new capillaries, on 
the surface of a wound that is healing 
Common 
Wound healing 
difficulties 
Occurs when wound does not heal as expected 
or within expected time frame 
Infrequent 
Vocal cord paresis 
Paralysis of the vocal cord 
Rare 
 
Steps taken to minimize these risks: 
 
Several steps have been taken to mitigate potential risks associated with the 
NeuroPort Arrays. By design, the NeuroPort Arrays have a small profile to minimize 
impact to the cortex tissue and thereby reduce bleeding following insertion. This 
means that a relatively small craniotomy can be made in comparison to other 
procedures such as invasive epilepsy monitoring. 
 
To minimize tissue damage at the site of implantation, a pneumatic Array Inserter 
tool which standardizes the implantation of the NeuroPort Array, will be provided. 
The tool inserts the Sensor at a specific rate and is designed to cause minimal tissue 
damage. Animal studies of the NeuroPort Array have shown little or no tissue damage 
at the implantation site. Due to the subject’s preexisting condition this area of the 
brain has been essentially disconnected from communicating with other parts of the 
body. So, the visible effects directly related to potential injury to the primary motor 
cortex tissue are expected to be insignificant and are not anticipated to compromise 
the subject’s medical or neurological baseline status. 
 
The device materials in contact with the body are known biocompatible materials. 
Animal study results of the NeuroPort Array reveal an absence of, or a limited 
observed, systemic toxic effects or adverse neurological effects. 
 
Because the pedestal protrudes through the skin, there is a risk of infection even after 
surgical healing and recovery. The risks of the long-term presence of the Patient 
Pedestal are minimized by an infectious disease screen, frequent checks performed by 
a caregiver, and a specific wound/skin care procedure designed to reduce the chance 
of infection. The protocol describes steps taken before and during surgery to create a 
sterile environment and to exclude individuals who may be at high risk for infection.  
Participants will also undergo immediate post-operative care in the neurosurgical 

 
47
ICU, neurosurgical medical surgery recovery unit, and the UPMC Rehabilitation 
Institute.  During ongoing device use, a family member or caregiver will be instructed 
to inspect the Patient Pedestal site daily.  The Patient Pedestal will be cleaned at least 
every 7 days.  Also, we will monitor the subject’s temperature each day when BMI 
training occurs since this is a reliable indicator of infection.  The subject will also be 
instructed to monitor and record their temperature daily.  This will allow us to 
provide appropriate clinical care in a timely manner. 
 
Risk of Fibrosis due to Chronic Implantation (Core Study and Extension Study) 
 
There is a risk that it may not be possible to remove one or both of the arrays due to 
fibrosis (excessive tissue growth).  We believe that it is very unlikely (<1%) that this will 
occur.  If the risk of damage to the cortex outweighs the priority to remove the Arrays, 
our surgeon sub-investigator would cut the lead wire and remove the pedestal(s) leaving 
the 4 x 4 mm array(s) implanted.  The risk of migration would be minimal since the array 
would be encased in the fibrous tissue.  It is possible that the participant may not be able 
to have an MRI if the array(s) remains implanted since MR safety guidelines differ 
between institutions.  The procedure for evaluation would be similar to other devices that 
remain implanted near the brain such as titanium plates, metal (aneurysm) clips, and 
silastic catheters.   We do not expect that additional follow-up, beyond the 2 planned 
visits (1 and 4 weeks post explant) with the neurosurgical team, will be required. We do 
not believe that extending the implantation duration for up to 5 years increases the risk of 
fibrosis that would make it more difficult to remove the array. 
 
Steps taken to minimize these risks: 
 
The neurosurgeon sub-investigator will evaluate the extent of fibrosis prior to 
removing the arrays and determine whether they can be removed safely.  The 
neurosurgeon sub-investigator is board-certified and experienced in removal of 
implanted devices.  Based on our experience with non-human primate research at the 
University of Pittsburgh and the published results of the human BrainGate trials, we 
believe that the risk of having to leave the arrays implanted is very low (<1%). 
 
Risks of Post-Operative Head CT (Computed Tomography) (Core Study) 
The amount of radiation exposure that participants will receive from the head CT is 
approximately 2-5 rems (a unit of radiation exposure) to the area of the body evaluated 
with minimal exposure of other areas of your body.  For comparison, this is a small 
fraction (<25%) of the annual radiation exposure (20 rems) permitted to the most 
sensitive organs of radiation workers by federal regulations.  There is no minimal level of 
radiation exposure that is recognized as being totally free of the risk of causing genetic 
mutations (abnormal cells) or cancer.  However, the risk associated with the amount of 
radiation exposure that the subject will receive from this study is considered to be low.  A 
head CT will only be conducted as part of the extension study if ordered by the 
neurosurgeon to investigate a change in the participant’s neurological status. 
Steps taken to minimize these risks: 

 
48
It is standard clinical procedure to perform a head CT after a neurosurgical procedure 
in which electrodes are implanted.  This allows for documentation of electrode 
location and can identify possible adverse reactions (such as bleeding or swelling) 
following surgery.  The risk associated with the amount of radiation exposure that the 
subject will receive from this exam is considered to be low and comparable to 
everyday risks. 
 
Risks of Post-Operative Head X-ray (Core Study) 
 
The maximum amount of radiation exposure that participants will receive from the x-ray 
exam is approximately 0.3 rem (a unit of radiation exposure) to the area of the body 
evaluated with minimal exposure of other areas of your body.  For comparison, this is a 
small fraction (1-2%) of the annual radiation exposure (20 rems) permitted to the most 
sensitive organs of radiation workers by federal regulations.  There is no minimal level of 
radiation exposure that is recognized as being totally free of the risk of causing genetic 
mutations (abnormal cells) or cancer.  However, the risk associated with the amount of 
radiation exposure that the subject will receive from this additional x-ray exam is 
considered to be low and comparable to everyday risks.  A head x-ray will only be 
conducted as part of the extension study if ordered by the neurosurgeon to investigate a 
change in the participant’s neurological status. 
 
Steps taken to minimize these risks: 
 
It is standard clinical procedure to perform a head x-ray after a neurosurgical 
procedure in which electrodes are implanted.  This allows for documentation of 
electrode location.  The risk associated with the amount of radiation exposure that the 
subject will receive from this exam is considered to be low and comparable to 
everyday risks. 
 
 
Risks of BMI Training/Testing (Core Study and Extension Sudy) 
 
During training, subjects will be asked to perform simple tasks that carry no risk above 
what is experienced during a typical daily routine.  Subjects will perform simple 
movements or learn to control computer cursors or virtual objects.  The research 
personnel will ensure that the behavioral tasks and their difficulty levels are set properly 
for each subject.  We may ask them to attempt to control a prosthetic limb or robotic arm.  
Risks from interaction with the prosthetic or robotic arm or from dropping objects being 
transported by the arm include potential bruises or abrasions or minor damage to the 
participant’s wheelchair.  The risk of these is infrequent (1-10%) and precautions will be 
taken to minimize this risk.  We may ask them to attempt to control a robotic arm 
exoskeleton (Figure 5).  Risks from interaction with the exoskeleton arm would include 
possible injury to subject’s arm if it moves past a comfortable joint position or if it 
collides with wheelchair or other parts of subject’s body. 

 
49
 
We may attach additional skin electrodes to record EMG or provide a ground for our 
BMI system.  These electrodes are commonly used for this type of recording, but they 
may cause minor skin irritation.  Also, we may stimulate peripheral nerves as part of our 
somatosensory testing which may cause discomfort or spasticity in some subjects.  This 
testing can be stopped at any time.  
 
In addition to physical risk, there is a psychological risk to participation in BMI training 
sessions.  Individuals may experience frustration during the training, particularly early in 
the study.  During the extension study, participants may experience frustration as signal 
quality starts to decline.  Participants may have feelings of negativity or other emotional 
concerns during the study. 
 
Steps taken to minimize these risks: 
During training, subjects will be asked to perform simple tasks that carry no risk 
above what is experienced during a typical daily routine.  The research personnel will 
ensure that the behavioral tasks and their difficulty levels are set properly for each 
subject.  Testing can be stopped at any time and we will work with the subject to 
determine session start time and duration.  Investigators will be present during all 
testing sessions to ensure safe operation of any external devices that are used.  Safe 
operation will be ensured in a variety of ways including manual override control by 
the operator, slow operation speed of the device, and defined workspaces that prohibit 
contact between the participant and the technology.   
 
In order to avoid risks from close proximity with the prosthetic or robotic arm or 
robotic arm exoskeleton, the following precautions are in place: (1) ensuring the 
subject has demonstrated adequate brain control of the robotic arm when positioned at 
a safe distance away from the participant (judged by the sponsor/investigator, likely 
>75% success on simple reaching tasks), (2) ability to program the robotic arm or 
exoskeleton with appropriate workspace and/or range-of-motion limits and 
definitions, and (3) constant monitoring of interaction with the robotic arm or 
exoskeleton by the study team who have the ability to stop the robotic arm via 
computer control or manual power shut-off. 
 

 
50
 
 
Figure 5: Robotic Arms: Modular Prosthetic Limb (LEFT) and ArmeoPower exoskeleton (RIGHT) 
 
Since BMI testing requires frequent sessions and significant effort on the part of the 
participant, older participants may become easily fatigued and therefore we have 
limited our age group to 18-70 years.  Additionally, frequent training is necessary to 
induce neuroplasticity and we believe it may be more difficult to induce 
neuroplasticity in older individuals. 
 
Individuals may experience frustration during BMI training sessions, particularly 
early in the study.  For the extension study, participants will be informed that it is 
likely that signal quality will degrade over time.  This may make it more difficult to 
complete the tasks so the difficulty and complexity may need to be reduced. 
Participants can be scheduled for appointments to speak with a psychologist 
throughout the study (approximately 1, 3, 6 and 9 months after implantation and 
again prior to explantation) to discuss any concerns they have during the study.  The 
visits will occur every 3 months during the extension study as well.  In addition, 
physician-investigators may refer the subjects to additional psychological 
appointments at their discretion. 
 
Risks of EEG/EKG Recording (Extension Sudy) 
Minor skin irritation may develop from the placement and removal of EKG and EEG 
electrodes. 
Steps taken to minimize these risks: 
Cleaning the skin after removal of the electrodes will reduce the risk of skin irritation.  
If skin irritation does occur, an over-the-counter ointment can remedy this. 
 
Risks of In-Home Sleep Evaluation (Extension Sudy) 
Participant may experience fatigue following sleep evaluation, if amount of sleep was 
insufficient or below normal amount. 

 
51
Steps taken to minimize these risks: 
Participant and caregiver will be asked to ensure that participant does not perform any 
activities that would invite risk of injury until the fatigue has subsided..   
 
 
Risks of Pregnancy (Core Study and Extension Study) 
 
Women who are, or plan to become, pregnant are excluded from the study due to 
potential risks to the unborn fetus or themselves.  These risks include radiation exposure 
during x-ray or CT imaging which may lead to birth defects, mental impairment, cancer, 
or miscarriage.  There are no known risks associated with undergoing an MRI scan while 
pregnant and the risks of MRI to the fetus are felt to be very small, but are nevertheless 
also not known.  Any complications during surgery would put the fetus at risk for 
distress.  We do not believe that pregnancy would carry any additional risks while the 
array is implanted, however this has not been studied and therefore the risks are 
unknown. 
 
 
 
Steps taken to minimize these risks: 
 
Study investigators will discuss the risks of pregnancy during the course of the study 
and will advise women against becoming pregnant.  Women will be advised to notify 
the study team immediately if they learn they are pregnant. 
 
4.2 Adverse event recording/reporting 
4.2.1 Adverse event definitions 
Adverse effect. Any untoward medical occurrence in a clinical study of an 
investigational device; regardless of the causal relationship of the problem with the 
device or, if applicable, other study treatment or diagnostic product(s). 
Associated with the investigational device or, if applicable, other study treatment 
or diagnostic product(s).  There is a reasonable possibility that the adverse effect 
may have been caused by the investigational device or, if applicable, the other 
study treatment or diagnostic product(s). 
Disability. A substantial disruption of a person’s ability to conduct normal life 
functions. 
Life-threatening adverse effect.  Any adverse effect that places the subject, in the 
view of the investigator-sponsor, at immediate risk of death from the effect as it 
occurred (i.e., does not include an adverse effect that, had it actually occurred in a 
more severe form, might have caused death). 

 
52
Serious adverse effect. Any adverse effect that results in any of the following 
outcomes: death, a life-threatening adverse effect, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. 
 
Hospitalization shall include any initial admission (even if less than 24 
hours) to a healthcare facility as a result of a precipitating clinical adverse 
effect; to include transfer within the hospital to an intensive care unit.  
Hospitalization or prolongation of hospitalization in the absence of a 
precipitating, clinical adverse effect (e.g., for a preexisting condition not 
associated with a new adverse effect or with a worsening of the preexisting 
condition; admission for a protocol-specified procedure) is not, in itself, a 
serious adverse effect.   
Unexpected adverse effect.  Any adverse effect, the frequency, specificity or 
severity of which is not consistent with the risk information described in the 
clinical study protocol(s) or elsewhere in the current IDE application, as amended. 
Unanticipated adverse device effect.  Any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or IDE application (including a 
supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
4.2.2 Eliciting adverse effect information 
Study subjects will be routinely questioned about adverse effects at study visits. 
4.2.3 Recording and assessment of adverse effects 
All observed or volunteered adverse effects (serious or non-serious) and abnormal 
test findings regardless of suspected causal relationship to the investigational 
device or, if applicable, other study treatment or diagnostic product(s) will be 
recorded in the subjects’ case histories.  For all adverse effects, sufficient 
information will be pursued and/or obtained so as to permit 1) an adequate 
determination of the outcome of the effect (i.e., whether the effect should be 
classified as a serious adverse effect) and; 2) an assessment of the casual 
relationship between the adverse effect and the investigational device or, if 
applicable, the other study treatment or diagnostic product(s).    
Adverse effects or abnormal test findings felt to be associated with the 
investigational device or, if applicable, other study treatment or diagnostic 
product(s) will be followed until the effect (or its sequelae) or the abnormal test 
finding resolves or stabilizes at a level acceptable to the investigator-sponsor. 
4.2.3.1 Abnormal test findings  

 
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An abnormal test finding will be classified as an adverse effect if one or more 
of the following criteria are met: 
 The test finding is accompanied by clinical symptoms. 
 The test finding necessitates additional diagnostic evaluation(s) or 
medical/surgical intervention; including significant additional concomitant 
drug or other therapy.  (Note: simply repeating a test finding, in the 
absence of any of the other listed criteria, does not constitute an adverse 
effect.) 
 The test finding leads to discontinuation of subject participation in the 
clinical study. 
 The test finding is considered an adverse effect by the investigator-
sponsor. 
 
 
4.2.3.2 Causality and severity assessment  
The investigator-sponsor will promptly review documented adverse effects 
and abnormal test findings to determine 1) if the abnormal test finding should 
be classified as an adverse effect; 2) if there is a reasonable possibility that the 
adverse effect was caused by the investigational device or, if applicable, other 
study treatment or diagnostic product(s); and 3) if the adverse effect meets the 
criteria for a serious adverse effect. 
If the investigator-sponsor’s final determination of causality is “unknown and 
of questionable relationship to the investigational device or, if applicable, 
other study treatment or diagnostic product(s)”, the adverse effect will be 
classified as associated with the use of the investigational device or study 
treatment or diagnostic drug product(s) for reporting purposes.  If the 
investigator-sponsor’s final determination of causality is “unknown but not 
related to the investigational device or, if applicable, other study treatment or 
diagnostic product(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history. 
4.2.4 Reporting adverse effects to the FDA 
The investigator-sponsor will submit a completed FDA Form 3500Ato the FDA’s 
Center for Devices and Radiological Health for any observed or volunteered 
adverse effect that is determined to be an unanticipated adverse device effect.  A 
copy of this completed form will be provided to all participating sub-investigators.   
The completed FDA Form 3500A will be submitted to the FDA as soon as possible 
and, in no event, later than 10 working days after the investigator-sponsor first 
receives notice of the adverse effect. 

 
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If the results of the sponsor-investigator’s follow-up evaluation show that an 
adverse effect that was initially determined to not constitute an unanticipated 
adverse device effect does, in fact, meet the requirements for reporting; the 
investigator-sponsor will submit a completed FDA Form 3500A as soon as 
possible, but in no event later than 10 working days, after the determination was 
made. 
For each submitted FDA Form 3500A, the sponsor-investigator will identify all 
previously submitted reports that that addressed a similar adverse effect experience 
and will provide an analysis of the significance of newly reported adverse effect in 
light of the previous, similar report(s). 
Subsequent to the initial submission of a completed FDA Form 3500A, the 
investigator-sponsor will submit additional information concerning the reported 
adverse effect as requested by the FDA. 
 
4.2.5 Reporting of adverse effects to the responsible IRB 
In accordance with applicable policies of the University of Pittsburgh Institutional 
Review Board (IRB), the investigator-sponsor will report, to the IRB, any observed 
or volunteered adverse effect that is determined to meet all of the following criteria: 
1) associated with the investigational device or, if applicable, other study treatment 
or diagnostic product(s); 2) a serious adverse effect; and 3) an unexpected adverse 
effect.  Adverse event reports will be submitted to the IRB in accordance with the 
respective IRB procedures.  
Applicable adverse effects will be reported to the IRB as soon as possible and, in no 
event, later than 5 calendar days following the investigator-sponsor’s receipt of the 
respective information.  Adverse effects which are 1) associated with the 
investigational device or, if applicable, other study treatment or diagnostic 
product(s); 2) fatal or life-threatening; and 3) unexpected will be reported to the 
IRB within 24 hours of the investigator-sponsor’s receipt of the respective 
information.  
Follow-up information to reported adverse effects will be submitted to the IRB as 
soon as the relevant information is available.  If the results of the sponsor-
investigator’s follow-up investigation show that an adverse effect that was initially 
determined to not require reporting to the IRB does, in fact, meet the requirements 
for reporting; the investigator-sponsor will report the adverse effect to the IRB as 
soon as possible, but in no event later than 10 calendar days, after the determination 
was made. 
Adverse events will also be summarized in reports to the DSMB.  Any events 
related to wound infections, scalp or skull breakdown, or other local wound issues 
will be reported to the DSMB Chairperson within 24 hours.   

 
55
4.3 Withdrawal of subjects due to adverse effects 
The subject will be under medical supervision for the duration of this study. Their health 
will be the top priority and participation will be discontinued if an intervention is 
required. The study neurosurgeon and PI will be primarily responsible for evaluating the 
subject’s condition. Complications that could result in removal from the study (and 
having the NeuroPort Array removed) include: 
-  Treatment resistant (serious) infection at the implantation site or Patient pedestal 
-  Array technical malfunction resulting in an inability to collect data that is useful for 
brain-control tasks  
-  Serious medical complications that compromise the subject’s safety or health 
 
5.0 Monitoring Procedures 
Independent monitoring of the clinical study for clinical protocol and IDE application 
compliance will be conducted periodically (i.e., at a minimum of annually) by qualified staff 
of the University of Pittsburgh’s Education and Compliance Office – Human Subject 
Research (ECO-HSR).  The address of the ECO-HSR is listed below.  Monitoring procedures 
of the ECO-HSR are listed on its website at http://www.rcco.pitt.edu/educ/. 
Education and Compliance Office – Human Subject Research 
Research Conduct and Compliance Office 
University of Pittsburgh 
Hieber Building, Suite 205 
3500 Fifth Avenue 
Pittsburgh, PA 15213 
 
The investigator-sponsor and the University of Pittsburgh and University of Pittsburgh 
Medical Center will permit direct access of the study monitors and appropriate regulatory 
authorities to the study data and to the corresponding source data and documents to verify the 
accuracy of this data. Representatives from the Department of the Navy Human Research 
Protection Program may also provide study oversight and monitoring as part of their 
responsibility to protect human research subject volunteers. 
6.0 Labeling 
Refer to section K. of the IDE application. 
7.0 Consent Materials 
Refer to section L. of the IDE application. 
8.0 IRB Information 
Refer to section H. of the IDE application. 

 
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9.0 Other Institutions 
Refer to section I. of the IDE application. 
10.0 Additional Records and Reports 
10.1 Data handling and record-keeping 
Case Report Forms (CRFs) will be completed for each subject enrolled into the clinical 
study.  CRFs are included in Appendix I.  CRFs will be signed by the principal 
investigator or a qualified sub-investigator as indicated on each individual form.  The 
principal investigator will sign a Case Report Verification Form prior to the 
implantation surgery, every month following implantation, and following explantation 
to verify that they have reviewed all CRFs completed prior to the date of review.  The 
investigator-sponsor’s signature serves as attestation of the investigator-sponsor’s 
responsibility for ensuring that all clinical and laboratory data entered on the CRF are 
complete, accurate and authentic.  Any data that is missed will be noted with an 
explanation and investigator initials.  Protocol deviations will be reported to the IRB as 
required. 
Source Data are the clinical findings and observations, laboratory and test data, and 
other information contained in Source Documents.  Source Documents are the original 
records (and certified copies of original records); including, but not limited to, hospital 
medical records, physician or office charts, physician or nursing notes, subject diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, x-rays, etc.  When applicable, information recorded on the CRF shall 
match the Source Data recorded on the Source Documents.  Whenever possible, Source 
Data for clinical research procedures will be stored as a print out of the electronic 
medical record note.  CRFs will be used to document the key outcome variables for 
each procedure and will also indicate that all original data was stored and backed up as 
appropriate. 
Paper-based records will be kept in a secure location in locked file cabinets within 
UPMC/University facilities. All researchers involved with the conduct of this research 
have been appropriately trained in the proper practices of research conduct. Each 
subject will be assigned a unique subject identification code and the link to that code 
will be stored on a restricted research server (described below). Whenever feasible, 
identifiers will be removed from study-related information and replaced by the subject 
identification code. 
Photographing, videotaping, and/or voice-recording will be performed as part of this 
study and these data will be stored with study ID numbers in a locked office or on a 
password-protected research drive that can only be accessed by research staff only.  
Electronic storage of research study information will be on a restricted access, separate 
server used only by PMR research faculty and staff.  In order to maximize data security 
as well as our ability to analyze the data efficiently, we will utilize two research 
servers: (1) University of Pittsburgh Medical Center (UPMC) and (2) Rehabilitation 

 
57
and Neural Engineering Laboratory (RNEL) on the University of Pittsburgh network.  
All identifiable information (excluding photographs, videotapes, and voice recordings) 
will be stored on the UPMC server.  The UPMC server is managed by an information 
security group which is comprised of three main areas: threat and vulnerability 
management, identify management and account administration, and the technical team.  
Protection of information is maintained in a variety of ways including: firewall, 
individual password accounts, and identify management.   
Due to the large file size of the research data, we plan to store deidentified data locally 
on the RNEL laboratory server. This server is password protected and only research 
personnel affiliated with this project will be able to access study-related data.  All 
original data will be stored in a ‘read only’ folder and will also be backed up at a 
separate location either on DVD in a locked file cabinet or on a separate password-
protected backup server.  The case report forms related to electronic data collection will 
also document that the data was stored and backed-up appropriately.  All case report 
forms will be verified by the principal investigator. 
The neural data collected during BMI training is the primary data of interest for 
addressing the specific aims of this investigation.  Data will be stored electronically on 
the local testing computer during each BMI testing session.  At each session, a hard-
copy log sheet will be completed by a research staff member that includes the coded 
subject ID, filenames, and task descriptions.  Important parameters related to the 
participant (e.g. subject ID), task (e.g. target size and location, assist level, and task 
name) and session (e.g. date and time of data collection) are also saved within the 
structure.  While all original data will be stored as ‘read only’, this provides extra 
protection that the data can always identified and/or linked to the log sheet using 
information stored within the structure.  Deidentified neural data will be transferred 
from the local test computer to the research server and stored and backed up as 
described above. 
Our study team will conduct regular reviews of ongoing data analysis to ensure the 
accuracy and validity of these methods.  In no way will any of the original data be 
altered through these procedures.  All case report forms, log sheets, and data and safety 
monitoring minutes will be made available to FDA or IRB representatives as requested. 
All data will be kept for a minimum of 7 years after the study ends in compliance with 
the University of Pittsburgh guidelines. Collaborating investigators may have access to 
study data after they are de-identified. 
10.2 Record maintenance and retention 
The investigator-sponsor will maintain records in accordance with Good Clinical 
Practice guidelines to include: 
 FDA correspondence related to the IDE application and Investigational Plan; 
including copies of submitted FDA Form 3500As, supplemental IDE applications, 
current investigator lists, progress reports, notice of device recall or disposition, and 

 
58
failure to obtain informed consent reports; 
 IRB correspondence (including approval notifications) related to the clinical 
protocol; including copies of adverse event reports and annual or interim reports; 
 Current and past versions of the IRB-approved clinical protocol and corresponding 
IRB-approved consent form(s) and, if applicable, subject recruitment 
advertisements. 
 Signed Investigator’s Agreements and Certifications of Financial Interests of 
Clinical Investigators; 
 Curriculum vitae (investigator-sponsor and clinical protocol sub-investigators); 
 Certificates of required training (e.g., human subject protections, Good Clinical 
Practice, etc.) for investigator-sponsor and listed sub-investigators; 
 Instructions for on-site preparation and handling of the investigational device and/or 
study treatment or diagnostic product(s), and other study-related materials (i.e., if 
not addressed in the clinical protocol); 
 Signed informed consent forms; 
 Completed Case Report Forms; signed and dated by investigator-sponsor; 
 Source Documents or certified copies of Source Documents; 
 Monitoring visit reports; 
 Copies of investigator-sponsor correspondence to sub-investigators, including 
notifications of adverse effect information; 
 Subject screening and enrollment logs; 
 Subject identification code list; 
 Investigational device accountability records, including documentation of device 
disposal; and the 
 Final clinical study report. 
 
Identifiable data will be filed in locked areas immediately after collection. Study ID 
numbers will be used instead of the participant’s name when recording study-related data. 
The information collected in this study, such as neural recordings, will generally consist 
of numbers with little or no meaning to the casual observer. Electronic data is stored on 
password-protected network drives. Staff has been trained regarding the critical nature of 
participants’ privacy, and about the procedures for respecting their privacy and 
maintaining confidentiality.  Subject names and other directly identifiable information 
will not appear on any reports, publications or other disclosures of clinical study 
outcomes.   
 
The investigator-sponsor will retain the specified records and reports for up to 2 years 
after the marketing application is approved for the investigational device; or, if a 
marketing application is not submitted or approved for the investigational device, until at 
least 2 years after investigations under the IDE have been discontinued and the FDA so 
notified.