Reanimation in Tetraplegia: Restoring Cortical Control of Functional Movement in Humans With Quadriplegia
Phase: NA
Conditions: Spinal Cord Injury (Quadraplegia)
Sponsor: Marcia Bockbrader

 
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Official Title : Reanimation in Tetraplegia - Restoring cortical control of 
functional movement in humans with quadriplegia  
NCT Number : 01997125 
Document date : 7/16/2019 
 

 
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 FDA INVESTIGATIONAL DEVICE EXEMPTION 
(IDE) APPLICATION 
 
 
 
 Reanimation in Tetraplegia 
 
ORIGINAL SUBMISSION 
 
 
 
 
 
Sponsor: 
 
Marcia Bockbrader, MD, PhD 
 
 
Submitted to: 
Food and Drug Administration 
Division of General and Restorative Devices 
IDE Document Mail Center 
HFZ-401 
9200 Corporate Boulevard 
Rockville, MD  20850 
 
Submitted on:  September 02, 2014 
 
 
 
 
Signed by: ______________________________ 
 
 

 
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TABLE OF CONTENTS 
 
PART I - Report of Prior Investigations 
1. General Introduction and Specific Prior Investigations…….…………… 
2. Potential Adverse Events……………………………………………....... 
 
PART II – Investigational Plan 
1. Investigational Purpose……………………………………………….. 
2. Protocol Overview and Design………………………………................ 
3. Protocol Specifics……………………………………………………… 
3.1 Participation Criteria ……………………............................................... 
3.1.1 Inclusion and Exclusion Criteria……………………………………... 
3.1.2 Informed Consent…………………………………………………….. 
3.2 Study Phases.......................................................................................…. 
3.2.1 Phase I………………………………………………………………... 
3.2.2 Phase II……………………………………………………………….. 
3.2.3 Phase III……………………………………………………………… 
3.2.4 Phase IV……………………………………………………………… 
3.2.5 Study Specific Procedures 
3.3 Outcomes and Data Analysis................................................................... 
4. Risk Analysis............................................................................................. 
4.1 Risks……………………………………………………………………. 
4.1.1 Safety Endpoints……………………………………………………... 
4.1.2 Serious Adverse Events……………………........................................ 
4.1.3 Unanticipated Adverse Device Effects…………………..................... 
4.1.4 Documentation of Adverse Events…………………………………... 
4.1.5 Reporting of Serious Adverse Events…………………....................... 
4.2 Procedures for Minimizing Risks…........................................................ 
4.3 Potential Benefits..................................................................................... 
4.4 Study Justification………………………………………………............ 
4.5 Device Description……………............................................................... 

 
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4.5.1 Clinical Safety and Hazard Analysis………………………………… 
4.5.2 Interaction between Devices……………………………………….. 
4.5.3 Stimulation Parameters………………………………………………. 
4.5.4 Battelle Quality System……………………………………………… 
4.5.5 Battelle Software Development……………………………………… 
5. Monitoring Plan......................................................................................... 
5.1 Plan Description.......................................................................................  
 
PART III – Other Study Information 
1. Manufacturing Information........................................................................ 
2. Investigator Agreements............................................................................ 
3. List of Investigators................................................................................... 
4. Certification of Investigator Agreement...................................................  
5. IRB Information........................................................................................ 
6. Devices Sales Information........................................................................ 
7. Device Labeling......................................................................................... 
8. Device Location………………................................................................. 
9. Informed Consent Materials...................................................................... 
10. Contact and Correspondence Address………………………………… 
 
REFERENCES 
 
APPENDICES 
1. Right of Reference Letter  
2. Case Report Forms 
3. Sample Consent Forms 
 
 
 
 
 
 

 
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PART I – REPORT OF PRIOR INVESTIGATIONS 
 
1. General Introduction 
Overview of disorder studied, and current treatments 
Spinal cord injury (SCI) is an insult to the spinal cord resulting in a change, either temporary or 
permanent, in its normal motor, sensory, and/or autonomic function. It is estimated that the 
annual incidence of spinal cord injury (SCI), not including those who die at the scene of the 
accident, is approximately 40 cases per million population in the U. S. or approximately 12,000 
new cases each year.  
SCI primarily affects young adults. As the average age of the population in the United States 
rises, the average age of the spinal cord injury increased from 28.7 years in the 1970’s to 41 
years as of 2005. In addition, advances in the chronic care of people with spinal cord injury have 
significantly increased their life expectancy. As a result, the number of people in the United 
States who are alive in 2012 who have SCI has increased to a 270,000 persons, with a range of 
236,000 to 327,000 persons.  
Persons with tetraplegia have sustained injuries to one of the eight cervical segments of the 
spinal cord; those with paraplegia have lesions in the thoracic, lumbar, or sacral regions of the 
spinal cord. Since 2005, the most frequent neurologic category at discharge of persons reported 
to the database is incomplete tetraplegia (40.8%), followed by complete paraplegia (21.6%), 
incomplete paraplegia (21.4%) and complete tetraplegia (15.8%). Less than 1% of persons 
experienced complete neurologic recovery by hospital discharge (National Spinal Cord Injury 
Database, 2012).   
 
Previous Work 
In a study published in Nature by Hochberg, et al tetraplegic participants were implanted with a 
96-channel microelectrode array in the cortex. Movement intentions from neural activity were 
decoded from the microelectrodes and used by tetraplegic participants to successfully operate a 
robotic arm by their thoughts.   The microelectrode array is a multichannel, high-density, device 
that allows neural recordings from large populations of neurons. Over the past two decades, this 
patented microelectrode array technology has undergone numerous refinements and repeated 
validations in a variety of species (humans, monkeys, birds, rodents, felines, fish) and 

 
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preparations (in vitro and in vivo). This effort delivered a proven and well-documented method 
to obtain stable and long-term neural recordings of action potentials (spikes) and field potentials 
in brain and peripheral-nerve tissue. Because the array can be wired to various connector types, 
researchers can choose a connector that is optimal for chronic (long-term) or acute (short-term) 
recordings from small to large participants as well as from slice and cell culture preparations 
(Blackrock Microsystems). 
 
Battelle, (a private nonprofit applied science and technology development company 
headquartered in Columbus, Ohio) was directly involved with the Hochberg study referenced, 
and specifically developed the decoding algorithms used in four of the participants (Bouton 
2009), and has now developed a technology called “Neural Bridge” to link neural decoding to 
neurostimulation (Bouton 2011, Bouton et al, 2016, Sharma et al, 2016).  Specifically, Battelle 
has developed a technology that decodes brain activity for imagined movements and then 
transforms the data into neuromuscular stimulation patterns to evoke the limb movement that 
was imagined.  This technology in effect creates a ‘neural bridge/bypass’ or ‘virtual spinal cord’ 
to bypass injured or degenerated pathways.  This technology can target specific muscles in the 
forearm, for example, to allow wrist and hand/finger movements based on the decoded brain 
activity in the participant’s motor cortex. The objective of the study proposed in this submission 
is to allow reanimation of a paralyzed limb under complete voluntary control of the participant.  
This will be a significant step towards the artificial spinal cord / nervous system with potential 
applications beyond spinal cord injury, including stroke and motor neuron disease. See Figure 1 
for an overall system diagram and neuromuscular sleeve and glove components of the system. 
The Neuroport device is a (510(k) K070272, K090957) cleared device manufactured by 
Blackrock Microsystems (Salt Lake, Utah) and the Neuromuscular Stimulator System is an 
investigational device developed by Battelle (Columbus, Ohio) that has been reviewed by a 
registered IRB and has been used with human participants with no related adverse effects 
reported.  (See the Device Description section for further details.) 

 
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Figure 1. a) Overall Neural Bridging System Diagram; b,c) Neuromuscular stimulation 
sleeve and glove 
. 
 
Study Rationale 
This study will extend the previous work in neural decoding and allow the investigators to better 
understand how the human nervous system can be augmented or bridged when trauma or disease 
has occurred which decouples the nervous system from the voluntary control of muscles. 

 
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Previous work allowed participants to imagine various limb movements and control a computer 
cursor or other devices (Bouton 2009).  The key extension in this study is to allow participants 
with tetraplegia to regain voluntary control of a paralyzed limb. The system will use re-coding 
algorithms to first decode brain activity in the motor cortex and then re-encode the signals for 
high definition stimulation of the selected muscles.  “Neural bridging”, as it is termed, involves 
signal monitoring (in the nervous system with a Neuroport microelectrode array), decoding of 
the information present, and then re-encoding appropriate stimulation signals for non-invasive 
insertion in another location in the nervous system, in this case directly to the muscles of interest.  
The insertion of signals back into the nervous system will be achieved through a non-invasive 
function neuromuscular stimulation system (NMES) (Bouton et al 2012).  The NMES will be in 
the form of a cuff/array or a sleeve consisting of a flexible circuit that has electrodes of 12mm 
diameter.  In the case of the sleeve, the cuff and electrodes are housed in a spandex fabric. A 
non-toxic FDA-approved conductive lotion forms the interface between the electrodes and the 
skin allowing stimulation of small and large muscles in the arm and hand to evoke a wide variety 
of movements. The optional glove (Figure 1, b and c) connects to the sleeve and provides 
information back to the system about the position of the hand and arm in space, as well as the 
flexion and extension of the fingers and wrist. The glove does not provide stimulation and is for 
positional information gathering only.   
 
Neurostimulation systems have been developed to restore functional movement in chronic 
paralysis population. The approach that provides the most functional multidimensional 
movement control utilizes a combination of a brain-computer interface (BCI) with implanted 
cortical sensors.  However, to date, human applications of implanted BCI technology have been 
limited to assistive technologies such as power chairs or robotic arms. An implanted BCI 
neuroprosthetic system designed to produce functional upper limb movement was only recently 
tested in an animal.  
 
The system described in this study is unique in that the BCI system translates intended action 
into human motion. Unlike the animal study previously referenced where the functional 
movement was generated through an implanted functional electrical stimulation system, this 
study will deliver surface stimulation through the NMES. 

 
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Team Expertise  
This investigation will be conducted at the Neuromodulation Center at The Ohio State 
University. This Center represents a collaborative effort between faculty in the Departments of 
Neurological Surgery, Neurology and Physical Medicine and Rehabilitation. The OSU functional 
neurosurgery team led by the PI, Dr. Milind Deogaonkar is internationally renowned for 
expertise with functional and stereotactic neurosurgery, Dr. Deogaonkar’s surgical team has 
performed over 2,500 neurological system implants in the past 16 years for various neurological, 
chronic pain and other applications.  
 
The study participants will be recruited from the Spinal Cord Injury Rehabilitation Service, 
which is a CARF accredited spinal cord injury rehabilitation program within the Department of 
Physical Medicine and Rehabilitation  (PM&R). The PM&R program at OSU is nationally 
recognized as a preeminent rehabilitation program. Dr. Jerry Mysiw is the Chair of PM&R and a 
study co-investigator.  
 
Battelle has extensive experience in developing commercial medical products for human use and 
in neural decoding in paralyzed human participants (Bouton 2009).  Battelle has also developed 
training methods to enhance the ability of participants to evoke targeted neural activity in the 
primary motor cortex  for various imagined arm and hand movements. Battelle has also tested 
the study components (cuff, sleeve, conductive lotion and stimulator system) in a Battelle IRB-
approved Study (Battelle IRB 0466) without adverse effects or complications.   
 
 
PART II - INVESTIGATIONAL PLAN 
 
1. Investigational Purpose 
The purpose of this clinical study is to allow the investigation of the Neural Bridging System for 
participants with tetraplegia to assess if the investigational device can reanimate a paralyzed limb 
under voluntary control by the participant’s thoughts. 
 

 
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2. Protocol Overview and Design 
The target population will be people with C4-C6 ASIA A spinal cord injuries (motor and sensory 
complete neurologic injuries) who are more than 1 year post injury and who are neurologically 
stable.   
 
3. Protocol Specifics 
3.1 Participation Criteria 
This study will plan to enroll up to 5 participants who have been diagnosed with tetraplegia. 
Study participants will be persons of any race, ethnic group, or gender. Participants who enter 
will be free to withdraw from the study at any time without affecting their access to other 
treatments at OSU and affiliated hospitals. The first 5 eligible and consenting participants will be 
accepted into this study. No gender or minority is intended to be excluded. However, since the 
sample size is small, there may be inadequate representation of ethnicities, genders, and race in 
the study sample. 
 
3.1.1 Inclusion and Exclusion Criteria 
Inclusion Criteria: 
• Must be 21 years or older. 
• Must be tetraplegic (C4- C6 ASIA A) 
• 12 months post injury and neurologically stable 
• Participant is willing to comply with all follow-up evaluations at the specified times. 
• Participant is able to provide informed consent prior to enrollment in the study.  
• The participant is fluent in English. 
• Participant must have a caregiver willing to participate in the study who will provide care 
for the surgical site. 
 
Exclusion Criteria: 
• No active wound healing or skin breakdown issues. 
• No history of poorly controlled autonomic dysreflexia. 
• Medical contraindications for general anesthesia, craniotomy, or surgery. 
• Diagnosis of acute myocardial infarction or cardiac arrest within previous 6 months. 

 
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• Participants with any type of destruction and/or damage to the motor cortex region as 
determined by MRI.  
• Dementia  
• Psychiatric disturbances 
• Other implantable devices such as heart/brain pacemakers 
• Participants who rely on ventilators 
• Co-morbid conditions that would interfere with study activities or response to treatment, 
which may include:  
o Life  expectancy < 3 years  
o Severe chronic pulmonary disease 
o Confirmed seizure disorder that requires continued clinical care 
o Local, systemic acute or chronic infectious illness 
o Life threatening cardiac arrhythmias  
o Severe collagen vascular disorder  
• Kidney failure or other major organ system failures History of a neurological ablation 
procedure. 
• Labeled contraindication for MRI. 
• History of hemorrhagic stroke. 
• History of HIV infection or ongoing chronic infection (such as tuberculosis). 
• Pregnant or of child-bearing potential and are not taking acceptable methods of 
contraception. 
 
Participation in another investigational device or medication trial  
 
3.1.2 Informed Consent  
Informed consent will be obtained by the PI or their designee with documented specific 
knowledge of the study. The informed consent form will be reviewed with the participant and all 
questions will be addressed before the participant signs the consent form. The participant will 
also be given a copy of the signed consent, and a copy of the consent will be placed in the 
patient’s medical record.  
 
3.2 Study Phases 

 
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The study design will consist of the following four (4) phases listed below. 
I. 
Baseline (approximately 8 weeks prior to surgery) 
II. 
Surgery (approximately 1-2 weeks) 
III. 
Decoding and stimulation   (approximately 60 months) 
IV. 
Follow-up (approximately 8 weeks post device explantation) 
 
3.2.1 Phase I - Baseline 
• Medical history review 
• Physical and neurological exam, and neuropsychological tests (see Section 3.2.5) 
• Functional Magnetic Resonance Imaging (fMRI) 
• Transcranial Magnetic Stimulation (TMS) 
• Neurophysiological recordings: 
• Electromyography (EMG)/Nerve Conduction Studies (NCS), Electroencephalography 
(EEG), Quantitative EEG (QEEG), and evoked response assessments involving the 
Event-related Potential (ERPs) and steady state sensory evoked potentials (SSEP) 
• Pre-test the external stimulator prior to implant 
 
3.2.2 Phase II - Surgery 
The patient will undergo a standard fronto-parietal image guided craniotomy to expose the 
sensory and motor cortex.  Subsequently, one or two Blackrock Microsystems Neuroport arrays 
will be implanted into the motor cortex in the standard fashion using the Neuroport pneumatic 
wand. 
The electrodes used in this study are manufactured by Blackrock Microsystems. The Blackrock 
Microsystems Neuroport array is a 4.4 by 4.2 mm, chronically implantable array containing 96 
electrodes, with an electrode spacing of 400 µm, capable of recording from areas of the central 
and peripheral nervous system for extended periods. The electrodes are Parylene-coated, silicon 
shanks with platinum or iridium oxide tips. The wires connecting the electrode array to the 
Blackrock connector are 25 µm gold alloy insulated wires collectively sealed as a bundle with 
silicone elastomer. The electrode and wire bundle lengths are user-specified and, once 
constructed, are not variable. The array of electrodes is biologically inert and can function 
implanted in cortex for three or more years. The electrodes typically have impedances in the 

 
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range of 100-800 kΩ (at 1kHz) and are capable of recording single and multi-unit action 
potentials with signal-to-noise ratios of up to 10 and peak-to-peak amplitude of greater than 1 
mV.  
 
Postoperative Management and Monitoring 
Post-operatively, participants will be taken to the neurosurgical step down unit and subsequently 
to the routine patient ward. Participants will also have a CT scan post operatively to evaluate the 
brain for intracranial air, hemorrhage and to assess the location of the electrodes.    
 
Surgical recovery  
Following surgery, participants will return to their home and enter into a postoperative recovery 
phase, which is normally expected to be 1-2 weeks from the initial implant, but may take longer 
depending on wound healing time. The pedestal site should be cleaned at least once every seven 
days or as required. This procedure will most likely require some assistance from a caregiver. To 
help reduce the risk of infection, it is important that all caregivers who touch the patient above 
the neck have clipped nails. The Pedestal Cap should remain on the Pedestal at all times and 
should only be removed by the physicians or trained investigators on the study. Caregivers 
should be careful not to touch the pedestal without first touching the patient elsewhere (skin to 
skin) to discharge any static electricity, and not to bump the Pedestal Connector.  
 
3.2.3 Phase III - Decoding and Stimulation  
Neural signals from the implant will be monitored and re-coded by the Neural Bridging System.  
Re-coding involves the process of decoding neural signals and then encoding the appropriate 
stimulation patterns for an intended movement. Decoding algorithms will decipher neural signals 
using pattern recognition methods to classify different movements imagined by the participant.  
The Battelle Neuromuscular stimulator will be setup and calibrated to evoke the imagined wrist 
and hand/finger movements. Encoding algorithms will use the calibration data and the decoded 
data to create the appropriate spatial and temporal stimulation patterns to evoke imagined 
movements. 
 

 
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Each subject will be asked to participate in test sessions, for up to 3 times a week for about 60 
months.  Each session will typically last less than 4 hours (including setup time).  The first 30 
minutes, approximately, will be needed for setup of the Blackrock and stimulator system.  Once 
the stimulator is calibrated, the participant will be asked to imagine wrist and hand movements 
and the decoding algorithms will identify the desired movements.  Once a select set of imagined 
movements have been identified, the stimulator system will apply the appropriate spatial 
stimulation patterns to the forearm to achieve motion in the paralyzed limb. This will give the 
patient voluntary control of the select movements in the paralyzed limb. Neurophysiological 
recordings and evaluations will also be conducted during these test sessions. Active stimulation 
time will be monitored to avoid fatigue.  Trained study personnel will set up and perform the 
device during the study visits. At the conclusion of the study, the patients will have the cortical 
implant removed via a second procedure. 
 
The participant(s) will receive haptic feedback above the level of their injury during motor tasks 
to enhance their motor performance. Haptic feedback simply provides a skin sensation (e.g. 
vibration), is well characterized in the literature (Shull & Damian, 2015), and is a well-studied 
and safe stimulus carrying no significant increase in risk. The apparatus will be electrically 
isolated from the participant. The participants currently receive electrical skin stimulation for 
feedback I the study. Haptic feedback is a non-electrical safer means of providing even more 
meaningful sensory information to enhance motor capability. 
 
During this phase of the study a virtual reality headset may be used to provide visualizations of 
imagined movements. If the virtual reality headset is not used, the virtual environment will be 
displayed on a screen. On occasion, the virtual reality headset may show the participant 
incongruent movements, that is, movements different from reality, to study the participant’s 
sense of agency. This reanimation study offers a unique opportunity to study the neural 
mechanisms of motor awareness, such as sense of agency or movement intentions. Agency is the 
sense that we control the actions of our own body (Gallagher, 2000; Jeannerod, 2003) and is a 
fundamental aspect of the experience of self. In this study, normal efferent and afferent 
sensorimotor information is replaced by the reanimation system and visual feedback, 
respectively. Congruent and incongruent visual feedback presented via virtual reality may 

 
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provide important information about the fundamental mechanisms of self-awareness. The 
importance of showing both congruent (the VR representation looks the same as the intended 
movement) and incongruent (the VR representation shows different movement than the 
participant’s intended movement, is important in understanding whether or not the participant is 
self-aware of the movements he is making with his paralyzed limb. This type of VR experiment 
is currently being done with the participant (i.e. showing congruent and incongruent 
movements), but on a flat screen which is a less immersive and less engaging environment. The 
addition of the device may remove some bias of the participant being able to see his limb, which 
is typically covered to some degree, but is never completely out of view. 
 
Use of VR will advance our current “screen-limited” understanding of the reasons that influence 
ownership or control a person with tetraplegia may have over a hand or limb they cannot feel. It 
is anticipated that improving visualization and subjective feeling of movement during training 
will enhance training efficiency and make it easier for participants to move their limbs. We will 
explore whether brain-computer interface training using virtual reality decreases training time 
compared to standard (non-VR) training protocols. 
 
A brain machine interface is expected to function at all times, interpreting brain activity and 
producing movements. One way our brain limits the production of activity from neural activity 
in the motor cortex is by gaiting the signal emanating from motor cortex during various state of 
consciousness. Therefore the brain machine interface should be able to understand different brain 
states and adjust its function appropriately. Currently we have very limited knowledge about the 
activity of motor cortex during sleep in primates. Some have suggested that the activity of 
neurons during certain parts of the sleep cycle may be related to motor learning. EEG/EMG 
recordings and intracortical data from our participants will allows us to better understand the 
relationship between brain activity and motor output during various stages of sleep. 
 
Additional to the weekly test sessions, the participant will be admitted to The Ohio State Wexner 
Medical Center for overnight sleep evaluations. We will ask the participant to perform a variety 
of motor tasks. Those will be similar to the ones that the participant performed during the 
recording sessions. While the participant is performing the motor tasks we will record EMG 

 
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from biceps, triceps, and deltoids along with recording the EEG and intracortical activity. We 
will continuously record this activity throughout the night in order to correlate it with various 
sleep stages. 
 
3.2.4 Phase IV - Follow-up 
The subject will have the device explanted when the study team and Principal Investigator have 
determined the subject is healthy enough to undergo explantation. After explantation surgery, 
participants will be ask to complete the same fMRI, neurophysiological recordings, 
neuropsychological tests, and TMS procedures as they did during the baseline phase.  
 
3.2.5 Study Specific Procedures 
 
Neuropsychological Tests 
Neuropsychological tests are useful to us to help categorize whether there are minimum 
neuropsychological criteria for successful patient selection and to determine safety (i.e., whether 
the procedure carries risk of decline in neuropsychological function post-explant). 
Neuropsychological tests will include but not limited to: 
• Motor-Free Visual Perception Test (MVPT-3) 
• Wechsler Adult Intelligence Scale (WAIS-III) 
• Wechsler Memory Scale (WMS-III) 
• Delis – Kaplan Executive Function System (DKEFS) 
 
Neurophysiological Recordings 
The neurophysiological recording and evaluations will include Electromyography (EMG)/Nerve 
Conduction Studies (NCS), Electroencephalography (EEG) EEG, Quantitative EEG (QEEG), 
and evoked response assessments involving the Event-related Potential (ERPs) and steady state 
sensory evoked potentials (SSEP). These studies are non-invasive and are routinely performed in 
the hospital and the clinic by the Ohio State Neurophysiology, PM&R and epilepsy teams. These 
studies will be performed at various times and will involve spontaneous recordings as well as 
recordings linked to decision making paradigms as well as auditory, tactile and visual non-

 
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invasive stimuli. These evaluations may also be performed in conjunction with intraoperative 
microelectrode recording and stimulation. 
 
Electroencephalography (EEG) is a routine physiological measure of cerebral function that has 
been used to evaluate TBI as well as to prognosticate survival and global outcome after TBI. 
Quantitative EEG (QEEG) methods evaluate brain functions and task specific EEG changes that 
can provide information about patterns of brain activity related to attention, learning and 
behavior. QEEG results in the same patient before and following cortical array implantation will 
allow changes in brain function to been quantified. Event-related potentials (ERPs) reflect 
processing that involves selective attention, memory, comprehension and other types of 
cognitive activity in the brain. ERP provides a non-invasive method of studying cognitive 
processes in both normal and pathological states. Comparing recordings before, during, and 
following cortical array implantation will allow changes in cognitive activity to be quantified. 
P300 is an ERP elicited by visual stimuli. The characteristics of the P300 have been used as 
metrics of cognitive function. Steady state evoked potentials to periodic stimuli and 
somatosensory evoked potentials can be used to quantify and characterize the strength of sensory 
signals that reach the brain for processing. This information is critical for phenotyping the degree 
of disruption of sensory tract inflow of spinal cord injured patients, evaluating the somatosensory 
contribution to motor ERPs and intracortical motor unit activity, and determining whether 
plasticity changes sensory tract inflow between pre- and post-implant conditions. 
 
Electromyography (EMG) and nerve conduction studies (NCS) evaluate peripheral sensory and 
motor nerve pathway integrity, which can be lost to different degrees by patients with different 
levels and severity of spinal cord injury.  EMG of the patient’s limbs will be collected pre- and 
post-implant and during decoding/stimulation to quantify and characterize the strength of 
voluntary motor signals that reach limb muscles. This information is critical for phenotyping the 
degree of disruption of motor tract outflow of spinal cord injured patients, evaluating voluntary 
vs. brain-machine interface stimulated motor patterns that can be elicited, and determining 
whether study participation is associated with plasticity changes in motor tract outflow from 
brain through the spinal cord. Nerve conduction studies (NCS) will be collected pre and post-

 
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implant to characterize the integrity of peripheral sensory and motor pathways, which further 
helps to phenotype patients with spinal cord injury.  
 
Functional magnetic resonance imaging (fMRI) 
We are collecting pre-implantation fMRI in order to localize the neural representations of 
movements of the upper limb, wrist, hand, and/or fingers. This information will be combined 
with anatomical information, clinical judgment, and intraoperative stimulation and recording to 
select the cortical implant placement site. After explantation surgery, we will be collecting fMRI 
to determine if training and use of the Neural Bridging System has resulted in any change in the 
locations of neural representations of movements of the upper limb, wrist, hand, and/or fingers. 
In both pre-implantation and post-explantation fMRI sessions, we will ask the participant to 
complete a task with visual and/or auditory stimuli designed to evoke neural representations of 
the movements of interest. 
Transcranial magnetic stimulation (TMS) 
To complement the fMRI motor mapping of the motor cortex that is being used for pre-surgical 
implant location planning and post-explant evaluation of motor cortex plasticity, we will also 
include transcranial magnetic stimulation (TMS) pre-implant and post-explant to map the hand 
and arm area of the motor cortex. TMS is a non-invasive brain stimulation method that delivers a 
magnetic pulse through the surface of the skull to the motor cortex. This induces a depolarization 
of neurons in the corticospinal tract, which results in a twitch of peripheral limb muscles 
innervated by that brain region. This modality is commonly used clinically as an alternative to 
fMRI for pre-surgical motor mapping to assist in planning prior to brain surgery. It is used 
experimentally to investigate corticospinal tract plasticity associated with motor recovery, e.g., 
after stroke. Potential risks include seizures (2%, mostly among patients who were previously 
known to have seizures) and headache.  Mapping of the hand/arm area with MRI-navigated TMS 
in patients with spinal cord injury serves 3 purposes: 1) it validates the cortical motor maps 
obtained through fMRI; 2) it distinguishes the sectors of cortical motor maps that are capable of 
controlling voluntary motion through the corticospinal tract in the spinal cord from areas that 
have been rendered mute from cord injury; and 3) it allows for quantification of plasticity, or 
change in sectors of motor maps that are capable of controlling voluntary motion through the 
corticospinal tract after stimulator explant. 

 
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We will perform TMS pre-implant (baseline, phase I) and post-explant (follow-up, phase IV). 
We will deliver navigated TMS based on the patient’s brain MRI scans to stereotactically 
identify and target near the “hand knob” of the primary motor cortex on the central sulcus. 
Recording EMG electrodes will be placed on the skin surface above the most distal upper limb 
motor groups under voluntary control by the patient, as defined by the pre-implant EMG study, 
as well as the extensor digitorum communis (EDC) and the abductor pollicis brevis (APB). We 
will find motor threshold, defined as the lowest stimulation intensity that produces a motor 
evoked potential, or EMG twitch response, of 100-500uV in the target voluntary muscle group 
on at least 50% of trials. We will start at an intensity of about 35% of stimulator output, adjust 
intensity up if needed until we are able to see twitch responses, then use a staircase method to 
adjust intensity up/down to find the motor threshold. The staircase will lower stimulation 
intensity 1-2% for trials with an EMG peak-to-peak response >500 uV or increase the intensity 
1-2% for trials with EMG responses <100 uV. 
Using the 110% of the MT intensity defined in the previous step, we will determine the spatial 
extent of the upper limb cortical motor map by stimulating over a grid overlaying the central 
sulcus, precentral gyrus, postcentral sulcus and precentral sulcus and reporting locations with 
motor evoked potentials (MEPs). 
 
3.3 Outcomes and Data Analysis 
Statistical analysis will be conducted with a biostatistician consultant. Continuous outcome 
variables will be summarized by the mean, median, standard deviation, minimum and maximum.  
Adverse effect data will be reported continuously, including all serious and non-serious adverse 
effects, as well as effects related to the surgical procedure and device-related.   
 
Primary and Secondary Outcomes 
The primary outcome measure of this study is the achievement of voluntary movement of the 
upper extremity.  Based on previous neural decoding that has been demonstrated in humans 
(Bouton 2009), it is expected that many of the following movements will be recognizable and 
classifiable in the motor cortex and can be achieved physically through the multichannel 

 
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stimulator: wrist flexion, extension, adduction, and abduction; forearm pronation/supination; 
flexion and extension of fingers.   
The targeted primary and secondary outcomes are therefore as follows: 
• Primary outcome- consistent and repetitive voluntary movement in the targeted muscle 
groups 
• Secondary outcome- consistent movement in the targeted muscle groups that is functional 
(manipulate or pick up an object)  
 
4. Risk Analysis 
4.1 Risks 
The surgical risks for implantation are the same as for any intracranial craniotomy, image guided 
procedures and implantable device such as a deep brain stimulator or a motor cortex stimulator 
procedure. This includes hemorrhages (intraparenchymal, subdural or epidural hematoma), 
paralysis, coma and/ or death, stroke, leaking of fluid surrounding the brain, seizures, infection, 
allergic reaction, temporary or permanent neurological complications, confusion or attention 
problems, pain at the surgery sites and headaches.  
Training and therapeutic sessions involving BCI regulated functional electrical stimulation will 
need to be monitored for autonomic dysreflexia signs and symptoms. 
As with any muscle stimulator, there can be a risk of excessive current and skin irritation or 
burns.  The stimulator in the Neural Bridging System, however, limits the average output current 
density to less than 2mA/cm2 at the skin and the average power density to less than 0.25W/cm2 
to provide safe levels and avoid tissue damage. Despite these built-in safety limits, current and 
power density could exceed FDA guidelines if electrodes lift off the skin. This has the potential 
to cause causing minor irritation or first degree burns locally. The research investigator will 
monitor frequently during test sessions for wrinkles and misalignment of the sleeve, and any 
signs of electric shock, skin irritation, and/or burns.  
 
The sleeve material itself is spandex, with registration marks printed on it. The material itself has 
been formally tested for biocompatibility, both in vitro and in vivo, prior to printing and 
laundering. The printed, laundered sleeve was tested in Battelle’s IRB-approved Able-bodied 
study for up to 8 hours, with and without similar nontoxic conductive lotion. No adverse skin 

 
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reactions were observed. The investigator, who will already be monitoring frequently for signs of 
irritation from electric shock, will also monitor for signs of allergic skin reaction.  
 
 
When using virtual reality (VR) systems, there is the risk of feeling nauseous, disoriented or 
dizzy, similar to sensations of motion sickness. About 1 in 4,000 people using VR systems have 
a risk of seizures, similar to the risk of having a seizure while watching TV. Showing 
incongruent movements on the virtual reality headset may causeconfusion or frustration. The 
researchers will monitor participants closely for signs or symptoms of confusion that may occur. 
 
The study Sponsor-investigator and co-investigators will be responsible for the evaluation, 
monitoring, and documentation of events meeting the criteria and definition of an adverse event 
(AE) or serious adverse event (SAE) as provided in this clinical investigation.  The study 
participants will be evaluated for any possible AEs from the time written study informed consent 
is obtained until study closure or the subject exits the study.   
• Any normal expected postoperative complaints or symptoms, unless the event involves a 
clinically significant change in a patient’s severity or duration of symptoms, or that 
requires clinical intervention other than the ordinary postoperative care. The following 
are some expected postoperative outcomes that may occur: headache, autonomic 
dysreflexia, incision pain, nausea, vomiting, low grade fever, dizziness, sleepiness, 
nervousness, insomnia, constipation, urinary retention, confusion, etc.  
• Any pre-existing condition unless a worsening of that condition in terms of nature, 
severity, or frequency develops.  
• Medical or surgical procedure unrelated to the clinical protocol (i.e., dental or cosmetic 
procedure) 
• Technical observation or a device events that does not result in a medically undesirable 
situation for the subject  
 
4.1.1 Safety Endpoints 
The study safety endpoints will include a characterization of all adverse events (AE) for all 
participants, including those related to the implant surgical procedure, the implantable device, 

 
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and stimulation of patients with tetraplegia.  In addition, these safety profile elements will be 
compared across the various phases of the study. Furthermore, patients with clinically significant 
complications related to surgery (hemorrhage, stroke, infection) will not undergo implantation or 
further participation in the study. 
Participants may choose to withdraw from the study at any point, in addition, the study 
investigators may decide to conclude a patient’s participation in the study for the following 
medical reasons: 
• Onset of epilepsy; 
• Significant decrement in neurological exam; 
• Development of serious adverse events, physical or psychological, including 
negative behavioral symptoms, major depression, or suicidal ideation; 
• Intra- or extra-cranial infection unresponsive to antibiotic treatment; 
• Serious infection around the percutaneous connector unresponsive to 
antibiotic treatment; 
• Development of intracranial hematoma requiring evacuation; and 
• Need for urgent Magnetic Resonance Imaging (MRl) of any kind (brain or body). 
 
4.1.2 Serious Adverse Events  
A Serious Adverse Event (SAE) is an adverse event that is fatal or life-threatening, permanently 
disabling, requires or prolongs hospitalization, or results in significant disability, congenital 
anomaly, or birth defect (OSU IRB Policy v 12/19/16).  
 
4.1.3 Unanticipated Adverse Device Effects 
An unanticipated adverse device effect (UADE) is defined as any serious adverse effect on 
health or safety or any life-threatening problem or death caused  by, or associated with the device 
[and/or stimulation therapy] if that effect, problem, or death that was not previously identified in 
nature, severity, or degree of incidence in the investigational plan or 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 participants (21 CFR 812.3(s)). 
Any UADE will result in an evaluation of that effect as soon as is possible, and will then be 
reported to the IRB within 10 days (OSU IRB policy v 12/19/16) and to the FDA within 10 

 
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working days after the sponsor-investigator first receives notice of the effect(s). [21 CFR 
812.46(b), 812.150(a)(1), 812.150(b)(1)] 
 
Device Malfunction  
A device malfunction is the failure of a device to meet its performance specifications or other 
performance as intended.  Performance specifications include all claims made in the labeling for 
the device.  The intended performance of a device refers to the intended use for which the device 
is labeled or marketed (21 CFR 803.3(k)).  
 
4.1.4 Documentation of Adverse Events  
All AEs from the time the study informed consent is signed through the time of device 
explantation will be recorded as AEs on the study adverse event log; each event being 
documented separately.  Any adverse event occurring after this time and is considered related to 
the device or therapy by the Principal Investigator will be reported.  AEs and SAEs will be 
followed until: 
• AE is resolved and has returned to normal/baseline or has stabilized 
• Subject has withdrawn from the study 
• AE is judged by the investigator to be no longer clinically significant 
• Study closure at which time, the responsibility for following any ongoing AEs will be 
transferred to the incoming clinical care team. 
 
The Principal Investigator will serve as point of contact to which the team will report adverse 
events.  All non-serious adverse events will be reported to the FDA and to The Ohio State 
University Institutional Review Board (IRB) during the annual reporting period. 
 
Relatedness will be determined for all events according to the following criteria: 
• Definitely related: The event is resolved by discontinuing stimulation and another cause 
cannot be identified.  
• Probably related: The event resolves upon discontinuing stimulation and cannot be 
reasonably explained by the subject’s current clinical state or any other cause. 

 
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• Possibly related: The event was likely caused by the subject’s current clinical state, , 
however, the effect of stimulation cannot be ruled out. 
• Unlikely related: The event did not occur temporally to stimulation and can be explained 
by the subject’s current clinical state or any other cause. 
• Unrelated: The event is explained by the subject’s current clinical state or any other 
cause. 
 
For purposes of determination of a UADE the following categories will be considered related: 
“definitely related” and “probably related”.  
 
4.1.5 Reporting of Serious Adverse Events 
SAEs reported during the protocol defined reporting period per section 4.1.4 will be: 
• Evaluated for their relatedness per section 4.1.4; 
• Reported to the Data Safety Monitoring Committee;  
• Included in the IRB Continuing Review; and 
• Included in the FDA Annual Report. 
 
4.2 Procedures for Minimizing Risks 
Investigators involved with this study have a great deal of expertise with the management of 
tetraplegic patients and with craniotomies. The surgical team has over 16 years of experience 
with deep brain stimulation implants with over 1600 DBS implants for various indications. The 
study inclusion/exclusion criteria have been developed to select those who would most likely 
benefit from this study as well as excluding those with higher risks. Study participants will be 
monitored after surgical implantation in neurosurgical and physiological monitoring units with 
personnel experienced in the care of complex neurosurgical participants and monitoring 
neurological status. In the case of cerebrospinal (CSF) leakage or pain, patients will be managed 
per the standard clinical practice. In case of infection that is not responsive to antibiotic treatment 
or allergic reaction to the implanted device, the device will be explanted.  
 
Upon completion of the study, participants will have the entire cortical implant system surgically 
removed. The procedure for removing the device is similar to those of the implant procedure. 

 
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Risks for removal are similar to insertion: infection, bleeding, need for further surgery, and 
seizures.  
 
Post-surgical removal the participants will be asked to come for post-surgery follow up 
appointments to remove stitches/sutures and wound caring. 
 
Risks are minimized in all of the non-surgical procedures including blood drawing and the 
neuroimaging procedures by having trained and highly experienced personnel performing all 
those tasks.  
 
Participants may also terminate from the study if they wish at any time. Study participants may 
also wish to discontinue participation for any reason. Cortical implant systems will also be 
removed if the participant/representative asks for removal. Participants who prematurely 
withdraw from the study due to an adverse event will be followed (e.g. telephone contact, and/or 
follow-up visits, etc.) until resolution of the event. In addition, a designated investigator will 
have access to treatment status at all times and provide that information to appropriate medical 
personnel in the event of medical emergencies. Risks to confidentiality are negligible in this 
protocol, since participants will not be identified by name, or by any personal data, in any 
summary reports or publications. CRFs will be maintained in locked files and password-
protected databases behind the Ohio State University Wexner Medical Center firewall. Data and 
safety monitoring activities for this study will continue until all participants have completed their 
participation in the study.  
 
4.3 Potential Benefits 
The intended purpose of neuroprosthetics is to develop devices to replace or improve the 
function of an impaired nervous system.  Thus far, BCI systems have been successful in 
controlling power chairs, robotic devices and more recently, upper limb movement in animals. 
Functional electrical stimulation (FES) systems have been created that stimulate muscles and 
restores functional movement in paralyzed limbs. This is the first study in humans to combine 
both systems, a BCI and functional electrical stimulation, to produce real-time control of a 
paralyzed limb.  

 
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4.4 Study Justification 
The target population will be people with C4-6 ASIA A spinal cord injuries (motor and sensory 
complete neurologic injuries ) who are more than 1 year post injury and who are neurologically 
stable.  This population has no potential for additional neurological recovery of functional 
movement. People with this level of paralysis are totally dependent in all aspects of self-care. 
Restoration of functional movement in this population requires exploration of neuroprosthetic 
applications to increase functional movement that has quality of life implications. This BCI 
system is the first attempt to utilize cortical sensors and a high resolution stimulation system to 
bypass the injured spinal cord and produce volitional movement in humans. 
 
The sleeve configuration of the NMES represents an incremental step toward portability for the 
system. The sleeve provides a less operator-dependent, more convenient application and removal 
of the electrode cuff. The electrodes and circuitry are otherwise identical to the cuff.  
 
This reanimation study offers a unique opportunity to study the neural mechanisms of motor 
awareness, such as sense of agency or movement intentions. Agency is the sense that we control 
the actions of our own body (Gallagher, 2000; Jeannerod, 2003) and is a fundamental aspect of 
the experience of self. In this study, normal efferent and afferent sensorimotor information is 
replaced by the reanimation system and visual feedback, respectively. Congruent and 
incongruent visual feedback presented via virtual reality may provide important information 
about the fundamental mechanisms of self-awareness. This is clinically relevant to developing 
neuroprosthetics that maximize user acceptance by enhancing integration with the users’ body 
image. In addition, we will study whether using virtual reality (VR) can provide a more efficient 
way to train motor cortex neural decoders.  
 
 
4.5 Device Description 
The Neural Bridging System (as shown in Figure 2) is comprised of a Blackrock Microsystems 
Neuroport device, a personal computer (PC) which runs the re-coding algorithm, and a non-
invasive Neuromuscular Stimulator.  The Neuromuscular Stimulator has been reviewed and 

 
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approved by a registered IRB for use in a study with human participants.  In this study both wrist 
and individual finger movements have been demonstrated (Bouton and Annetta 2012).   
 
The Neuromuscular Stimulator, designed by Battelle Medical Products, is a non-significant risk 
investigational device; however it is included in this submission for completeness (since the two 
devices will be used together in the study).  In addition, note the Neural Bridging System will be 
used in support of an IDE study to demonstrate proof-of-concept in a clinical environment. As 
such, the results from this IDE study will be used to determine feasibility of the product concept 
and will not be used to support a regulatory clearance or approval submission.   
 
4.5.1 Clinical Safety  
Safety risk management for the Battelle BCI-NMES (updated and inclusive of VR device) was 
performed in accordance with Battelle Process and Product Development SOP 65, Safety Risk 
Management Procedure, which complies with the requirements of ISO 14971:2007, Medical 
devices – Application of risk management to medical devices.  A safety risk management plan 
was put in place, and potential hazards associated with the use of the device were identified.  The 
risks of the identified hazards were evaluated against the risk acceptability criteria documented 
in the plan, and controls identified for risks that exceeded the acceptability thresholds. The 
identified risk controls were incorporated into the product design or clinical trial protocol, as 
appropriate. A summary of the analysis is included below. 
Hazard Analysis Summary (Without VR Device) 
 
A hazard analysis was conducted in accordance with D8208-020 (a document within Battelle 
Medical Devices Quality System), Neurobridge Clinical Trial Safety Risk Management Plan, 
and identified the following potential hazards associated with the use of the device: 
• Electromagnetic energy 
• Thermal energy 
• Biological 
• Chemical  
• Biocompatibility 
• Functional 
• Use error 

 
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• Installation/Service/Calibration 
• Warnings 
 
Analysis of potential hazard causes and evaluation of the risk of potential harm was conducted in 
accordance with D8208-020.  The potential hazards required risk controls and the implemented 
risk control measures are detailed in the following table. 
 
Potential Hazard 
Potential Harm 
Risk Control Measures 
Electromagnetic energy 
Participant/Operator 
electrical shock; burns 
1. Design in accordance with 
Clause 8.5.1 of IEC 60601-1:2005 
 
2. Current limiting safety circuit 
(on every channel) 
 
3. Fuse on high voltage power  
4. Clinical trial protocol excludes 
participants requiring use of life 
supporting/sustaining equipment 
 
5. Clinical trial protocol excludes 
participants requiring use of critical 
health monitoring equipment 
 
6. Electrostatic discharge warning 
label applied to device in area of 
NSC connectors 
 
Participant injury or 
unnecessary medical 
intervention 
1. Clinical trial protocol excludes 
participants requiring use of life 
supporting/sustaining equipment 
Biological 
Participant contact dermatitis 
or infection 
1. NSC materials and conduction 
enhancer in contact with the 
Participant are compliant with ISO 
10993-1 requirements for limited 
exposure skin contact. 
 
2. Clinical procedure specifies to 
not reuse the conduction enhancer. 
Chemical 
Participant/operator allergic 
reaction or infection 
1. The conduction enhancer in 
contact with the Participant are 
compliant with ISO 10993-1 
requirements for limited exposure 
skin contact 
 

 
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2. The NSC materials in contact 
with the Participant are compliant 
with ISO 10993-1 requirements for 
limited exposure skin contact  
 
3. Participant monitored for allergic 
reaction to conduction enhancer 
that could result in classification as 
clinical adverse event 
Biocompatibility 
Participant/operator allergic 
reaction or infection 
1. The conduction enhancer in 
contact with the Participant are 
compliant with ISO 10993-1 
requirements for limited exposure 
skin contact  
 
2. The NSC electrode material in 
contact with the Participant are 
compliant with ISO 10993-1 
requirements for limited exposure 
skin contact  
 
3. Conduction enhancer 
formulation stable when subjected 
to anticipated storage conditions  
 
4. Conduction enhancer 
formulation stable when subjected 
to electrical current 
Function (inappropriate 
output) 
Participant electrical shock; 
burns 
1. Current limiting safety circuit 
 
2. Fuse on high voltage power 
supply  
 
3. Incoming parts inspection to 
verify electrode size 
User error (improper 
operation) 
Participant electrical shock; 
burns 
1. Current limiting safety circuit 
(on every channel) 
 
2. Fuse on high voltage power 
supply  
Installation, service or 
maintenance 
Participant electrical shock or 
burns 
1. Operator trained on clinical 
procedure to ensure application of 
conduction enhancer 
 
 
 

 
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The risks of harm for all other identified potential hazards were deemed broadly acceptable 
under the risk acceptability criteria established in D8208-020.  Details of the potential hazards 
identified and evaluation of the risk of potential harm are provided in D8208-022, Neurobridge 
Clinical Trial Hazard Analysis.  
 
 
 
Figure 2.  Overall System Diagram with Additional Details. 
 

 
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Figure 3.  Neuromuscular Stimulator in Able-Bodied Study 
 
Hazard Analysis Summary (With VR Device): 
An analysis was conducted by Battelle concerning the use of the VR device with  the Battelle 
BCI-NMES(D8208-051). The risks of adding the Oculus Rift virtual reality headset to the NBS 
may increase the risk of electrical shock, however, due to the design of the NBS, the risk is not 
perceived to be significantly increased over wearing the headset without the NBS. 
 

 
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Figure 4. Block diagram of the virtual reality headset used with the Neural Briding System 
 
Risks Associated with the Oculus Rift Virtual Reality Device Alone: 
• Seizures (1 in 4000 people) 
• Electrical shock 
• Repetitive stress injury such as muscle, joint, or skin pain 
• Eye discomfort, eye muscle twitching, visual problems 
• Dizziness  
• Skin irritation 
 
Risks associated with VR use will be mitigated by close patient monitoring, exclusion of patients 
with history of seizure or pacemaker, electrical isolation from the Neural Bridging System, and 
periodic device monitoring by the OSU Clinical Engineering Department. The VR device has 

 
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passed Clinical Engineering inspection to verify that no significant current is leaking from the 
electrical components of the device. 
 
4.5.2 Interaction between Devices 
The Neuroport device will collect neural signals as a subject imagines various movements, the 
data will be processed in real-time, and corresponding stimulation patterns will be sent to the 
Neuromuscular Stimulator.  For example, a subject will imagine the flexion of their wrist and the 
stimulation patterns required to cause wrist flexion will be provided (after a short delay). 
 
The Neuroport device will continuously monitor neural activity, passing the data to the re-coding 
algorithms running in Matlab (Natick, MA) on the PC.  These algorithms will first decode the 
neural data (as was done in the BrainGate study), and then will provide the spatial and temporal 
stimulation patterns required to the subject to achieve the imagined movement. The spatial and 
temporal stimulation patterns for each subject will be different due to differences in anatomy, but 
will be determined during a ‘calibration’ session to map the various electrodes to the desired 
movements. 
 
Once the neural activity resulting from an imagined movement is recognized and re-coded to 
determine the appropriate stimulation patterns, the stimulation pattern commands are sent to the 
Neuromuscular Stimulator via a USB connection (that is electrically isolated).  The 
Neuromuscular Stimulator will then activate the appropriate electrodes in the NMES to evoke 
the desired movement. Furthermore, the Blackrock Neuroport device is electrically isolated from 
mains power to the patient.  In addition, the Neuromuscular Stimulator is electrically isolated 
from mains power and earth ground and is compliant with the applicable patient and touch 
leakage currents in accordance with IEC60601-1:2005.  Therefore, the two Neural Bridging 
subsystems that are in contact with the patient are electrically isolated and do not provide an 
unsafe current leakage path through the patient.   
 
4.5.3 Stimulation Parameters 
The stimulation parameters of the Neuromuscular Stimulator are as follows:  
 
 Maximum peak current is 20mA with a maximum pulse width of 0.5ms. 

 
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 Maximum pulse frequency is 50 pulses per second. 
 
 Nominal output voltage is 200V ± 10% with maximum output of 300V. 
 
 Maximum average current density is 2 mA/cm2 at the NMES    
 electrode surface. 
 
 Maximum average power density is 0.25 W/cm2 at the NMES   
electrode surface. 
 
 
4.5.4 Battelle Quality System 
Battelle Medical Products is an operational entity within Battelle in Columbus, Ohio. Medical 
Products’ operations are guided by a set of operating budgets and goals that are defined and 
updated on an annual basis. As such, Battelle Medical Products is operationally accountable for 
all projects assigned to the group, administratively accomplished under its organization code(s), 
which identify Medical Products as the controlling entity for the contractual obligation with our 
customers. 
 
All projects conducted within Battelle Medical Products fall under the Quality System (QS). The 
Battelle Medical Products QS is certified to ISO 13485:2003 and ISO 9001:2008,in addition to 
being compliant with the FDA's Quality System Regulation (21CFR Part 820) and Electronic 
Records; Electronic Signatures Regulation (21CFR Part 11). 
 
 
4.5.5 Battelle Software Development 
The software used in this study in accordance with the Neural Bridge Software Development 
Plan (SDP), Document D8208-007 which is derived from the guidance provided by the 
ANSI/AAMI/IEC 62304:2006 Medical device software – Software life cycle processes standard. 
In addition, Battelle follows the FDA guidelines outlined in the Guidance for the Content of 
Premarket Submissions for Software Contained in Medical Devices (issued on May 11, 2005).  
 
 
 
 

 
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5. Monitoring Plan 
5.1 Plan Description 
The data management for this study will maintain a level of data integrity and confidentiality that 
will provide optimum adherence to all 21 CFR regulations, while providing a standardized 
method of data collection and recording to enable the investigators, sponsors and regulatory 
agencies to accurately reconstruct the events of a study, confirm protocol compliance, and 
produce data that is accurate and appropriate in demonstrating study results.  
 
Study coordinators at the Ohio State University will perform primary data collection based on 
source documented hospital chart reviews. Paper case report forms (CRFs) will be used to collect 
study data. Study coordinators will complete all appropriate sections of the CRFs. The study 
sponsor/PI will review the information documented in the CRFs and verify the information 
recorded is consistent with medical records and other source documents. Study staff will rectify 
errors or incomplete entries. Final CRFs will be reviewed and signed by the principal 
investigator and/or trained study personnel.  
 
A data and safety monitoring committee (DSMC) will be appointed by the principal investigator 
to evaluate the accumulating data in this trial (21 CFR 812.46). Members of the clinical trial 
DSMC, who will have pertinent expertise in their medical and/or scientific field, may be chosen 
from neurosurgery, neurology, physical medicine and rehabilitation, and neuropsychology. The 
DSMC can advise the principal investigator and make recommendations on the continuing safety 
of enrolled trial participants, as well as the continuing validity and scientific merit of the trial. 
 
Regulations and Ethical Conduct of the Study 
The study will be conducted according to the clinical investigational plan, and the laws and 
regulations of the United States, parts, 50, 54, 56 and 812 of the US FDA CFR. 
 
PART III – Other Study Information 
 
1. Manufacturing Information 

 
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Refer to documentation on file with FDA by Blackrock. For information on the specific devices 
to be used in this study, a right of reference letter written by Blackrock, granting permission for 
the FDA to access such documents will be provided. 
 
2. Investigator Agreements 
Sample Investigator Agreement Document (As provided for in 21 CFR 812.43) 
I am a physician who is familiar with tetraplegic patients. 
I have never been involved in an investigation that was terminated. 
I am committed to conduct the investigation in accordance with the agreement, the investigational 
plan, the applicable FDA regulations and the conditions of the reviewing IRB and the FDA.  
I will supervise all testing of the device involving human subjects. 
I will ensure that the requirements for obtaining informed consent are met. 
I am committed to providing sufficient and accurate financial disclosure information and update 
information if any relevant changes occur during the investigation and for one year following the 
completion of the study. 
___________________________ 
       
Signature 
___________________________ 
Name (print) 
___________________________ 
Date 
_________________________________________________________ 
 
Witness 
 
 
 
 
 
 
 
 
 

 
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3. List of Investigators: 
Marcia Bockbrader, M.D., Ph.D. 
Principal Investigator, Physical Medicine and Rehabilitation 
The Ohio State University 
480 Medical Center Drive 
Columbus, Ohio 43210 
Phone: (614) 293-3127 
 
W. Jerry Mysiw, M.D. 
Co-Investigator, Physical Medicine and Rehabilitation 
The Ohio State University 
480 Medical Center Drive 
Columbus, Ohio 43210 
Phone: (614) 293-3433 
 
Dr. Vibhor Krishna, M.D. 
The Ohio State University 
480 Medical Center Drive 
Columbus, Ohio 43210 
Phone: (614) 366-2420 
 
Herbert S. Bresler, Ph.D.  
Co-Investigator 
Senior Research Leader, Consumer, Industrial and Medical Products 
Battelle  
505 King Avenue 
Columbus, Ohio 43201 
Phone: (614) 424-7129 

 
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4. Certification of Investigator Agreement 
I certify that all investigators have agreed to follow the applicable clinical investigator protocol 
in this application. I have submitted the written protocol to the Institutional Review Board. All 
participating investigators agree to conduct the investigation in accordance with the agreement, 
the investigational plan, the applicable FDA regulations, the conditions of the reviewing IRB and 
the FDA. I certify that the list of investigators in this application identifies all current 
investigators. Additional participating investigators will be added only when they have obtained 
IRB approval and have signed an investigator agreement. 
___________________________ 
       
Signature  
__________________________ 
Name (print) 
___________________________ 
Date 
 
 
5. IRB Information 
IRB Chairperson: 
Karla Zadnik, OD, PhD 
IRB Locations:  
Ohio State University 
Office of Responsible Research Practices 
300 Research Foundation Building 
1960 Kenny Road 
Columbus, OH 43210 
 
 
 
 6. Device Sales Information 
This study is an investigator/sponsor initiated study utilizing commercially available devices for 
an unapproved indication.  Study participants will not be charged for the device during the study, 

 
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and participants will not be paid to participate in the study. The conduct of this study does not 
involve the sale or commercialization of the therapeutic use of the devices.  
 
7. Device Labeling 
Caution: Investigational device. Limited by Federal law to investigational use only. 
Blackrock Microsystems Neuroport device is a commercially available device being used outside 
its FDA-approved indications for use (it is being used greater than 30 days). The array used in 
the Neuroport system has been successfully used in study participants well beyond 30 days, as 
for example, 1000 days in the Braingate study (Simeral et al, 2011). This investigational system 
in conjunction with the Battelle Neuromuscular Stimulator or its package will be labeled with the 
following information: the name and place of business of the manufacturer, packer, or distributor 
(in accordance with 801.1), the quantity of contents, if appropriate, and the following statement: 
"CAUTION--Investigational device. Limited by Federal (or United States) law to 
investigational use."  In addition, the label will describe all relevant contraindications, hazards, 
adverse effects, interfering substances or devices, warnings, and precautions. The labeling of the 
device will not represent that the device is safe or effective for the purposes for which it is being 
investigated. 
 
These devices will be treated as investigational-use devices since they are being used outside of 
approved indications and labeling.  Information on each device used in the study will be 
documented, and device accountability for each device used will be maintained. Only approved 
investigators will implant devices in participants participating in this study.  
 
8. Device Location 
The study is based at Ohio State University Wexner Medical Center. The Neuromuscular 
Stimulation device is external and will be taken off study participants after each session.  
 
9. Informed Consent Materials 
A sample of the revised participant informed consent document is provided.  Once this revised 
IDE is approved by FDA, the protocol and associated informed consent will be submitted to the 

 
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OSU IRB. All participant /legal representatives will sign an IRB approved informed consent for 
participation in research prior to enrollment in this study under this protocol. 
 
10. Contact and Correspondence Address  
Marcia Bockbrader, M.D., Ph.D. 
Principal Investigator, Physical Medicine and Rehabilitation 
The Ohio State University 
480 Medical Center Drive 
Columbus, Ohio 43210 
Phone: (614) 293-3127 
 
Email: marcia.bockbrader@osumc.edu 
cc:  Angela.Emerson@osumc.edu; Carson.Reider@osumc.edu 
 
REFERENCES 
Bouton C., "Decoding Neural Activity from an Intracortical Implant in Humans with 
Tetraplegia," Biomedical Science & Engineering Conference at Oak Ridge National Laboratory, 
vol. 1, no. 1, pp. 18-19, 2009. 
 
Bouton C., “Fusing Neural Decoding and Neuromodulation Technologies and Associated 
Engineering Challenges,” North American Neuromodulation Society, 15th Annual Meeting, Las 
Vegas, NV (8-11 Dec 2011). 
 
Bouton C., Annetta A., Arora S., Buck V., Eubanks C., Friend J., Glenn B., Mack N., Masters 
M., Schimmoeller A., “High Definition Neuromuscular Stimulation and Encoding,” IEEE 
Engineering in Medicine and Biology Conference Brain Machine Interface Workshop, San 
Diego, CA (Sep 2012). 
 
Bouton C. and Annetta N., “Neural Bridging: Recoding Motor Cortex Activity and Linking to 
High Resolution Neuromuscular Stimulation,” North American Neuromodulation Society, 16th 
Annual Meeting, Las Vegas, NV (6-9 Dec 2012). 
 
Sharma G. et al., “Using an Artificial Neural Bypass to Restore Cortical Control of Rhythmic 
Movements in a Human with Quadriplegia”, Scientific Reports 6 (2016): 33807. 
Spinal Cord Injury Facts and Figures at a Glance, National Spinal Cord Injury Statistical Center, 
Birmingham, Alabama https://www.nscisc.uab.edu February 2012. 
 

 
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Simeral J., Kim S., Black M, Donoghue J., and Hochberg L., “Neural Control of Cursor 
Trajectory and Click by a Human with Tetraplegia 1000 Days After Implant of an Intracortical 
Microelectrode Array,” Journal of Neural Engineering Volume 8 Number 2 (2011)