Spinal Cord Stimulation for the Treatment of Motor Deficits in People With Spinal Muscular Atrophy
Phase: NA
Conditions: Spinal Muscular Atrophy Type 3, Spinal Muscular Atrophy Type 4
Sponsor: Marco Capogrosso

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
January 13, 2025 
SPINAL CORD STIMULATION FOR THE 
TREATMENT OF MOTOR DEFICTS IN 
PEOPLE WITH SPINAL MUSCULAR 
ATROPHY 
A SINGLE-CENTER, OPEN-LABEL, INESTIGATIONAL PILOT TRIAL TO EXPLORE POTENTIAL 
EFFECTS OF EPIDURAL SPINAL CORD STIMULATION ON LEG MUSCLE STRENGTH IN PATIENTS 
WITH TYPE 3 OR TYPE 4 SPINAL MUSCULAR ATROPHY.  

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
 
 
 
 
 
STUDY AIMS 
Spinal cord stimulation (SCS) has shown remarkable efficacy in restoring motor function in people with 
spinal cord injury by recruiting afferent input to enhance the responsiveness of spared neural circuits to 
residual cortical inputs. This pilot will test if SCS can show evidence to improve motor deficits in people with 
type 3 or 4 spinal muscular atrophy (SMA). We will enroll up to six subjects with Type 3 or 4 SMA aged 16 or 
older that show quantifiable motor deficits of the legs but are able to stand independently. We will then 
implant the subjects with percutaneous, bilateral, linear spinal leads near the lumbar spinal cord for a period 
of up to 29 days. Although these leads are not optimized for motor function but rather for their clinically 
approved indication of treating pain, we believe they provide a safe technology enabling our team to perform 
scientific measurement necessary to evaluate potential for effects of SCS in motor paralysis with SMA. After 
the end of the study, the leads will be explanted. The results of this pilot study will be used to refine the 
design of follow-up trials that will test the safety and efficacy of the long-term use of a fully implantable 
system tailored to SMA Type 3 or 4 patients. 
 
HYPOTHESIS 
Hypothesis 1: SCS immediately improves hip muscle weakness in subjects with SMA 
 
Hypothesis 2: SCS immediately improves motor control in subjects with SMA 
 
Hypothesis 3: SCS delivered over the course of 29 days induces measurable changes in spinal circuits and 
motoneuron recruitment properties 
 
OBJECTIVES 
The main goal for this pilot study is to assess Hypothesis 1 as well as verifying safety of the SCS procedure in 
SMA. For this we will measure variables that indicate an immediate improvement in selected motor control 
variables that are predictive of the potential efficacy of SCS to improve motor control in long-term efficacy 
studies. If no improvement is shown in these selected variables, then a conclusion can be made that SCS will 
not be effective in improving motor control in people with SMA. Selection of these variable is based on 
previous pre-clinical and clinical studies of SCS for motor control and tailored to the specific population of 
subject included in this study (see inclusion criteria). Additionally, we will evaluate safety of electrical 
stimulation. Please note that in this context safety does not refer to the specific devices, but to the delivery of 
electrical stimulation to the spinal cord in SMA. 
Specifically we will evaluate: 
 
● Muscle weakness - isometric torque: measure the isometric torque produced by the subject at the hip 
during hip-flexion. 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
 
● Safety of electrical stimulation: classify and report all adverse events, if any. 
 
Secondary Goals: 
Secondary goes in this pilot study are aiming at acquiring scientific evidence of the mechanisms that may 
allow an improvement of motor performances in subjects with Type 3 or 4 SMA by testing Hypothesis 2 and 3. 
 
Test hypothesis 2: Quantify motor control performances during SCS 
 
We will quantify motor control variables and performances when enrolled subjects are using SCS. The goal is 
to acquire as much information as possible to inform the design of a follow-on, long-term study that will 
couple SCS to physical exercise if this pilot study is successful. All measured variables are focused on 
locomotion and leg-motor control. 
 
Test hypothesis 3: Quantify variables indicative of early signs of neural plasticity occurring in the central 
nervous system. 
The following variables aim at identifying early signs of plasticity occurring in the central nervous system that 
could be associated to measured effects on motor control. These measurements will be critical to verify that 
potential improvement in motor function correlate with electrophysiological variables and not only with 
exercise and/or placebo. 
Neurostimulation is a successful clinical solution in the treatment of degenerative conditions such as 
Parkinson’s disease(Deep-Brain Stimulation for Parkinson’s Disease Study Group 2001). Coupled to 
pharmacological interventions, electrical stimulation of the basal ganglia ameliorates symptoms and 
decelerates progressive worsening(Bronstein et al. 2011). In contrast, application of neurostimulation to 
motor deficits in consequence of neurodegenerative motor syndromes such as Spinal Muscular Atrophy, 
Amyotrophic Lateral Sclerosis and Muscular Dystrophies has not been successful(Fehlings et al. 2002). 
Reasons for this mostly lie in the lack of clear neural targets for the neurostimulation to ameliorate 
sensorimotor functions. 
 
Here we posit that neurostimulation of the primary sensory afferents in the spinal cord can ameliorate motor 
deficits and improve quality of life in degenerative motor syndromes 
 
Success of SCS in traumatic motor syndromes: Electrical stimulation of the spinal cord (SCS) combined with 
physical training has shown remarkable results in the ability to restore motor abilities in people with 
complete and incomplete traumatic spinal cord injuries (SCI)(Angeli et al. 2014, 2018; Gill et al. 2018; 
Harkema et al. 2011a; Wagner et al. 2018). More importantly, long-term use of SCS led to unprecedented 
neurological improvements in patients with chronic spinal cord injury(Angeli et al. 2018; Wagner et al. 2018). 
Our group is currently running a clinical trial exploring the use of SCS to restore motor control in subjects with 
chronic stroke (IRB: 19090210). Studies in rodents showed evidence that plastic changes occur in the 
proximity of the lesion as well as in the supraspinal centers (Asboth et al. 2018; van den Brand et al. 2012). 
This re-adaptation of the sensorimotor network triggered by the combined action of neurostimulation and 
physical training optimizes the use of spared neural resources. The injured system reshapes existing 
connections to use SCS excitatory inputs for the production of movement. Key to this mechanism is the right 
target of stimulation (Capogrosso et al. 2013, 2018). 
 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
Identification of neural targets for motor control: In a series of studies combining computer models, animal 
studies and human studies, our group identified the large primary afferents in the dorsal roots of the cervical 
and lumbosacral spinal enlargements as the optimal neural target for SCS in sensori-motor applications 
(Barra et al. 2020; Capogrosso et al. 2013, 2016a, 2018; Greiner et al. 2021; Wagner et al. 2018). Electrodes in 
the epidural space artificially recruit primary dorsal root afferents and convey mono and poly-synaptic 
excitatory neural activity to the motoneurons(Formento et al. 2018; Moraud et al. 2016). Unlike other types of 
neurostimulation technologies, excitation of the motoneurons via these pre-synaptic sensory pathways 
allows a natural recruitment of the motoneurons thus producing fatigue-resistant large forces and reinforcing 
spinal circuit activity by augmenting feedback inputs. 
 
Motor deficits in Spinal Muscular Atrophy: A variant in the survival motor neuron 1 (SMN1) gene results in 
progressive degeneration and death of the spinal motoneurons causing the clinical syndromes of spinal 
muscular atrophy (SMA)(Arnold et al. 2015). Type I SMA presents with a severe phenotype at or shortly after 
birth. The milder presentation of Type II and Type III SMA comprises progressive muscle weakness that 
impairs quality of life through the deleterious effects on motor skills such as standing and walking. Type II 
SMA results in premature death. Physical therapy and strength training are interventions that can preserve 
and improve strength, ameliorate motor deficits and delay muscle atrophy. However, similar to the 
experience with physical interventions for SCI, trials testing efficacy of physical therapy for SMA have shown 
low quality evidences of efficacy(Bartels et al. 2019). Surprisingly, no study has attempted to complement 
physical training by artificially sustaining muscle tone and neural circuit activity with neurostimulation. It is 
important to note that anatomical evidences show that mouse models of SMA demonstrate reduced 
synaptic connectivity between sensory afferents and motoneurons. While the reasons for these deficits are 
unclear, they demonstrate that SMA also affects spinal circuitry organization leading to severe motor 
deficits. Our technology directly targets primary afferents and reinforces precisely these disrupted 
connections. Therefore, SCS offers a tool to selectively and directly target the affected spinal circuit 
infrastructure that is responsible for the motor deficits in SMA. 
 
Systematic literature analysis on SCS and SMA 
We performed a systematic literature search on May 7th 2020 to search for clinical works exploring the use of 
Spinal Cord Stimulation (SCS) or Functional Electrical Stimulation (FES) in people with Spinal Muscular 
Atrophy (SMA). We searched the dabase PubMed for keywords without time span limits and looking for all 
references of which full text was available (Table 1). 
 
Only 13 entries (excluding 1 duplicate) were found that contained the selected keywords. We then performed 
a weighting analysis of these 13 papers based on inspection of the abstracts to identify only those that 
concern human studies (no in vitro) and that explored the effects of electrical stimulation for therapeutic 
use. Only 3 papers passed the criteria none of which concerned the use of SCS. 
 
Paper 1 (Fehlings et al. 2002) 
Evaluation of therapeutic electrical stimulation to improve muscle strength and function in children with 
types II/III spinal muscular atrophy 
This study tested whether low-intensity direct electrical stimulation of muscles delivered overnight would 
increase muscle mass and strength in children with Type II/III SMA. The authors recruited 13 subjects (of 
which 9 completed the study) of 9.9 yo average age. The study was a placebo-controlled, randomized 
prospective study. The authors evaluated upper arm muscle mass and strength over a period of 12 Months 
against placebo group. The therapy consisted in the delivery of low-intensity electrical stimulation overnight. 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
There was no statistical difference between the tested group and the placebo group in either strength or 
muscle mass, hence the authors concluded that muscle stimulation alone is not effective to improve the 
quality of life of children with SMA. 
 
Paper 2 (Norton et al. 2013) 
Preservation of motor evoked potentials under anesthesia in children with spinal muscular atrophy type II 
undergoing spinal deformity surgery. 
This study does not concern directly the application of electrical stimulation to therapeutic treatment. 
However, it constitutes an important evidence of the survival of cortico-spinal excitability. The authors 
measured motor evoked potentials induced by transcranial electrical stimulation during neuromonitoring 
procedures for spine surgery in patients with svere paralysis in consequence of SMA. They showed that the 
aplitued of motor evoked potentials was comparable with control group, demonstrating that cortico-spinal 
tracts are intact in SMA. This is an important conclusion as spared cortico-spinal connectivity is critical to the 
efficacy of SCS. 
 
 
Paper 3 (Gobbo et al. 2019) 
Exercise Combined with Electrotherapy Enhances Motor Function in an Adolescent with Spinal Muscular 
Atrophy Type III 
This is a single case study. The authors analyzed the combined effect of motor training and FES on an 
adolescent with type III SMA. As opposed to Fehlings 2002, FES in combination with training significantly 
improved both muscle mass and motor performances even increasing subject’s independence in daily-like 
activities such as stair climbing. This anecdotical study shows that the combination of electrical stimulation 
with physical activity can improve motor performances in people with SMA. 
 
 
Given the lack of works related to the use of SCS in SMA we included here a report of the latest clinical 
results that report on the use of SCS in humans with motor paralysis in consequence of spinal cord injury. 
The results of our own stroke study currently ongoing at the University of Pittsburgh are excluded as they are 
not yet published. 
 
PRIOR ART OF SCS IN TRAUMATIC SPINAL CORD INJURIES 
The efficacy of spinal cord stimulation (SCS) to improve motor deficits in people with SMA has never been 
tested (see document SCS-SMA-Literature). However, recent clinical studies showed unprecedented results 
in patients with complete and incomplete spinal cord injury (Angeli et al. 2014, 2018; Gill et al. 2018; 
Harkema et al. 2011b; Wagner et al. 2018). These studies reported that 100% of patients immediately 
regained the ability to produce voluntary muscle activity in previously fully paralyzed muscles immediately 
after surgical implantation of the leads. Then, after long-term rehabilitation protocol combined with SCS, 
patients improved their ability to stand, move and walk, with and without SCS 
 
All studies achieved similar clinical outcomes albeit with different timings that can be attributable to the 
efficiency of parameter optimization and optimal stimulation protocols (Angeli/Wagner). However, in terms 
of clinical and scientific outcomes the results are remarkably consistent. 
All studies reported on the efficacy of SCS as a prosthetic intervention to enable movements of previously 
paralyzed joints since day 1 after implant. Second, when subject initiated physical training focused on 
walking and standing, subjects progressively acquired abilities of increasing complexity. At week 1 the ability 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
to stand with SCS on was reported in all subjects, starting from the second week, studies started reporting on 
the ability of subject to walk or move the legs over while using a treadmill. And After 20 weeks of training, 5/8 
subjects were able to walk overground with only minimal level of support. The three subjects that did not 
achieve this goal were classified as ASI A. More importantly, for the first time, partial regain of function was 
reported in subjects even when stimulation was OFF by the end of the trial. Specifically 4/8 subjects (AIS B 
and C) could now activate muscles that were previously completely paralyzed even without SCS. 2/8 
subjects (AIS C) were instead capable of performing single joint movements and even standing without 
stimulation or support. 
 
RATIONALE FOR STUDY DESIGN AND SUCCESS CRITERIA 
Clinical data in SCI shows that SCS has 2 effects: 
1 an immediate effect: increase in the ability of subjects to move limb joints and produce forces 
2 a long -erm effect: when physical exercise is combined with SCS over several weeks, functional 
improvements in motor control are observed, with and without SCS. 
 
Our pilot study will focus on demonstrating immediate effects. Given previous results in SCI if, immediate 
effects are shown also in people with SMA, then a follow up study involving long-term implantation of spinal 
cord stimulation devices combined with targeted rehabilitation has chances of success. 
Alternatively, if these immediate effects are not observed in this pilot study, then chances that a 
rehabilitation protocol would work are limited. 
 
In consequence the success criteria of this study are focused on the immediate effects: 
Increase in strength with SCS-on 
 
HYPOTHESES 
Hypothesis 1: SCS immediately improves muscle weakness in subjects with SMA 
 
Hypothesis 2: SCS immediately improves motor control in subjects with SMA 
 
Hypothesis 3: SCS delivered over the course of 29 days induces measurable changes in spinal circuits and 
motoneuron recruitment properties 
 
SUMMARY AND RATIONALE FOR THE USE OF SCS IN SMA 
 
Rationale for Hypothesis 1 and 2: Immediate improvements of motor ability 
The first and most important goal of SCS therapy for SMA is to be a supportive treatment to improve the 
quality of life of people with SMA by a large, significant, and immediate reduction of motor and respiratory 
deficits resulting from SMA. This is similar to DBS for Parkinson’s Disease. 
 
In order to achieve this goal, SCS must be able to show immediate improvement in motor performances. 
Albeit no study has assessed the efficacy of SCS for SMA, we do know that motor deficits in SMA result from 
a combination of motoneuron degeneration, progression of the disease, and finally secondary cascade 
effects created by immobilization or poor use of muscles (Arnold et al. 2015). 
 
What is the evidence that SCS can enhance motor performance in individuals with severe motor deficits? 
Three groundbreaking clinical trials in Louisville (Angeli et al. 2018), the Mayo Clinic (Gill et al. 2018) and EPFL 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
in Switzerland (Wagner et al. 2018) independently demonstrated that SCS can immediately restore voluntary 
control of legs in people with complete paralysis as a result of damage to the spinal cord (i.e. spinal cord 
injury). When the stimulation is turned on, every patient tested could immediately control paralyzed legs and 
even walk over ground with some supportive device. 
 
How does SCS work and why will it work in SMA? 
We discovered that SCS engages motoneurons through the recruitment of primary sensory afferents 
(Capogrosso et al. 2013, 2016b, 2018). In turn, this conveys excitatory inputs to spared motoneurons 
increasing their sensitivity to spared cortico-spinal projections (Formento et al. 2018; Harkema et al. 2011b; 
Moraud et al. 2016). Therefore, SCS is a neuromodulation technology that artificially enhances the neural 
activity of surviving motoneurons by making them more sensitive to descending controls and sensory 
feedback. In SMA types II and III, part of the spinal motoneurons degenerate (Arnold et al. 2015), thus the 
brain is not able to excite enough muscle fibers, thereby leading to motor deficits and paralysis. This also 
affects involuntary activity such as respiration because spinal respiratory reflexes as well cannot excite 
enough spared motoneurons. However, different from in the setting of SCI, spinal interneurons and cortico-
spinal pathways are fully preserved (Norton et al. 2013). 
Therefore, SCS in SMA will artificially enhance the activity of spared motor units to artificially higher levels, 
thus increasing muscle strength and motor output (Capogrosso et al. 2016b; Lu et al. 2016). In parallel, fully 
preserved cortico-spinal connectivity in SMA will enable subjects to gain full control over hyperexcitable 
muscles. Indeed, we demonstrated that SCS even enhances motor output in completely intact monkeys 
(Capogrosso et al. 2016b) (Video 2). Moreover, compared to a non-specific excitatory drug, SCS will target 
only the sensory-motor circuits, and it can be continuously and daily tuned in intensity and even turned off 
(for example during sleep) to immediately reduce circuit excitability. 
 
Rationale for Hypothesis 3: Long term effects 
The third and equally important outcome is whether SCS will have any effect on the rate of degeneration of 
the disease. While there is no direct evidence that SCS can enhance the survival of motoneurons, certainly 
similar supportive therapies increase life span and long-term life quality in people with neurodegenerative 
disorders such as Parkinson’s Disease. The key to success is the identification of the right target for the 
stimulation. 
 
Our hypothesis is that in SMA, the spinal motoneurons are affected, hence neurostimulation should be 
directed at supporting residual motoneuron activity. This support must occur through engagement of input 
pathways that can increase the responsiveness and general excitability of the cell without driving it 
completely, thus enabling voluntary motor control. 
 
Sensori-motor circuits in SMA and the target of SCS 
We know that SMA affects the primary afferents-to-motoneuron connectivity, likely as the result of 
immobility (Mentis et al. 2011). Abnormal sensory-to-motoneuron synaptic activity further alters an already 
compromised system leading to faster degradation of motor abilities and other spontaneous functions (such 
as respiration) that rely on spinal reflexes. Since SCS directly targets this compromised system (Capogrosso 
et al. 2013), we have strong scientific support for the hypothesis that SCS will strengthen this compromised 
system, thereby resulting in long term improvements effects. 
 
Combined neurostimulation and physical therapy in SMA 
Additionally, anecdotical findings in SMA suggest that the use of Functional Electrical Stimulation 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
(FES)(which we know is less effective than SCS in sustain motor function) in combination with physical 
therapy enhanced motor abilities and independence in an adolescent with SMA type III (Gobbo et al. 2019). 
In patients with a Spinal Cord Injury, when SCS was combined with physical therapy, all treated patients not 
only regained immediately their motor control, but they showed long term neurological improvements that 
lead to increased motor abilities even when the stimulation was turned off!! (Angeli et al. 2018; Gill et al. 
2018; Wagner et al. 2018). 
Despite studies in rodents demonstrating a potential key role of spared descending inputs to explain these 
long-term recovery effects (Asboth et al. 2018; van den Brand et al. 2012; Takeoka et al. 2014), direct 
evidence in humans is still lacking. However, since patients with SMA have a full sparing of cortico-spinal 
connectivity (Norton et al. 2013), we can argue that similar long-terms effect should also occur in patient 
with SMA. 
 
Therefore, the second goal of our pilot study is to quantify the long-term effects of the use of SCS in patients 
with SMA as well as studying why these may occur. 
 
RESEARCH ACTIVITIES 
 
Both patients with SMA and healthy volunteers will be enrolled in this study. Healthy volunteers will be 
considered a control group and will not complete all sections of the protocol. Activities documented below 
will reflect healthy volunteer participation. 
 
DEVICES: 
In this study we are proposing the quantification of potential effects on motor control of spinal cord 
stimulation in people with spinal muscular atrophy. All the following research activities are geared towards 
the acquisition of this pilot scientific evidence and they involve motor tests and recordings of muscles 
activity during the delivery of electrical stimulation to the lumbosacral spinal cord. 
 
To stimulate the lumbosacral spinal cord we will utilize FDA-appoved percutaneous spinal cord stimulation 
leads that are indicated for use to treat syndromes of refractory pain. The percutaneous leads will be 
connected to external stimulators that are either FDA-approved for use in humans, or human-grade research 
stimulator with strict safety features. 
 
Below we describe the devices chosen for this study. Annexed documents provide further descriptions of 
these devices and their FDA approvals. 
 
Percutaneous Spinal Cord Electrodes: 
We will use 2 to 4, octopolar Medtronic leads (see documents in annexes) temporarily implanted in the 
epidural space of the T12 to L2 spinal vertebra. These devices have an extensive history of use in humans 
with minimal adverse effects. During the study, two to four FDA-approved spinal cord stimulator leads 
(Medtronic Vectris Leads) will be placed in the lumbar epidural space of participants and steered laterally 
towards the dorsal spinal roots under fluoroscopic guidance. This approach is identical to the FDA-approved 
procedure in which these devices are placed in the epidural space for treatment of trunk, back and limb pain. 
As in that procedure, the device will be tunneled percutaneously through the skin and secured in place with 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
tape. Therefore, in this trial we will implant the electrodes in the same region of their clinical indication and 
we will also externalize them for a maximum duration of 29 days. Which is also consistent with clinical 
practice. Surgical procedures are described below in specific paragraphs. 
 
 
External stimulators: 
During research activities the leads will be connected to an external stimulator. The Natus Medical 
Protektor32 IOM is FDA-approved under 510k Number K093304 (attached). This stimulator is commonly used 
for intra-operative neurostimulation and monitoring during neurological and neurosurgery procedures 
involving the recording of multiple neurophysiological signals as well as the delivery of electrical stimulation 
to the central nervous system. 
Alternatively, the stimulation will be delivered through the Digitimer DS8. 
The DS8 is an external isolated stimulator system for human research use. The DS8 is not a medical device 
but its safety specifications comply to standard for clinical devices utilized for transcutaneous electrical 
stimulation of human peripheral nerves. The device is non-invasive, non-toxic, and interaction with other 
componentry is unlikely and therefore it is rare to harm a patient. It is not intended as an implant nor does it 
present a potential for serious risk to the health, safety, or welfare of a subject. It is not purported or 
represented to be for use supporting or sustaining human life. It is not potentially for a use of substantial 
importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of 
human health. 
 
During the study, we will use the Syde device from Sysnav which records high precision motion data and has 
been previously used in clinical trials. The side device consist in an elastic ankle band similar to a modern 
"Apple Watch" device that can be wore at the ankle. We will use this data to assess changes in gait quality 
during the study. Participants will wear two devices, one in each ankle, during the entire day. To pre-process 
data, the Syde sends fully anonymized, encrypted raw kinematic data to the Sysnav data center via web 
transfer for preprocessing purposes after which it will be sent back to us for analysis. No identifiable 
information is included in these data transfers, and Sysnav will not have access to any patient information. 
The data will be transferred encrypted using https with protocol TLS 1.2. At night, participants will charge the 
devices in a charging station. If participants have access to internet connection, data collected during the 
day will be sent to Sysnav from the charging station. Otherwise, we will send the data weekly or at the end of 
the experimental sessions. There is no risk associated with the device, as only raw data is transmitted and 
analyzed. 
 
In all sessions with spinal cord stimulation, the participant and the Syde device wearable monitors on the 
ankles are isolated from the stimulation. The participant and Syde device are isolated from the stimulator 
and electrical circuitry so that the stimulation is isolated to the leads to the implanted electrode array and 
back to the stimulator machine [termed: uninterrupted circuit]. 
 
For the research activities that do not require the synchronization of the stimulation with other variables, we 
will use the external wireless stimulator of the Intellis system from Medtronic. The Medtronic external trial 
stimulator is an FDA-approved medical device (PMA: P840001/S344) and routinely used for the stimulation of 
the same leads we use in this study via the same type of percutaneous connections and with the same 
parameters. Since this stimulator is wireless, it is more comfortable and convenient for patients when 
performing certain motor tasks such as locomotion. 
 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
 
STIMULATION PARAMETERS: 
FDA approved parameters for the Medtronic stimulation electrodes for use in humans are: 
Stimulation amplitude for each pulse should be lower than 25.5 mA 
Pulse frequency should be lower than 1200 Hz 
Pulse width should be comprised between 60 and 1200 µs 
These parameters can be found in the Medtronic stimulation IFUs in the annexed 
 
In our protocol we will never exceed the following ranges 
Stimulation amplitudes will be comprised between 0.2 and 10 mA 
Stimulation frequency will be comprised between 0.1 and 500 Hz 
Pulse width will be comprised between 100 and 400 µs 
 
Therefore, our stimulation parameter ranges are well within the FDA approved stimulation limits for the 
electrodes used and in no case will exceed the clinically approved maximum values for any of the three 
parameters. To ensure this condition we defined standard operating procedures that are summarized in the 
stimulation system checklist and stimulation reporting protocols attached in the annexes. These documents 
were reviewed and approved by the DSMB for the STUDY19090210: sIRB SCS for Stroke 
 
Below we describe all the research activities that we will perform as part of this protocol: 
 
-SCREENING (after consent, prior to surgical procedures): 
Once written informed consent is obtained, the subject is enrolled in the study and is assigned a unique 
subject ID. A physician-investigator/sub-investigator will verify the eligibility of the subject by assessing most 
of the eligibility criteria after consent via self- report. This will be documented on an "Eligibility Checklist" 
form, included in this protocol. 
After informed consent and after the participant's verbal self-report of eligibility criteria, an in person clinical 
evaluation will be performed, including a detailed history and physical examination, and a detailed 
musculoskeletal and neurologic examination. A history form will be completed to detail the dynamic and 
onset of their SMA. The The Physical Activity Disability Survey (PADS) will be administered. The Revised 
Hammersmith Functional Scale (RHS) and the 6 Minute Walk test will be performed as well as an evaluation 
of the ability of the subject to stand independently for at least 3 seconds. Moreover, also the other primary 
and secondary outcomes will be evaluated. Additional medical records may be accessed if more information 
is required to perform pre-operative planning and review pertinent medical history, allergies, medications 
and radiology images. Both healthy volunteers and individuals with SMA will be required to successfully 
complete screening procedures. Pre-surgical procedures and device placement for participants with SMA 
will occur within 6 months after the subject undergoes screening procedures. We will work with each 
individual to determine the optimal testing schedule. The schedule will be designed to meet study goals, and 
complete specific study tasks which will change over the duration of the study. The participants' 
engagement, and training preferences will also be considered in this process. We will photograph or 
videotape portions of the experimental session. Appropriate UPMC permission will be obtained as needed 
for any photographs or videotaping of participants. For participants who will need to travel a significant 
distance, any screening procedures that can be done prior to any travel will be done to decrease burden 
placed upon the participants who may not be eligible. Experimental procedures are described below. 
 
-MRI screening: 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
All individuals with SMA, and some healthy participants, will be required to undergo MRI. Prior to undergoing 
an MRI for this study, a person will be asked about any implanted metal in their body and will undergo a MRI 
safety screening. We have attached a 3 page screen at the end of this. The screen covers items that would 
possible exclude a participant from the study. This screen has been used in previous MRI studies. The 
completed MRI screens will be kept in a locked file cabinet which will be located in a locked office to assure 
subject confidentiality. 
 
 
- 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 and their current level of motor and sensory abilities, 
as well as recent history. We will also ask questions related to improvement of quality of life. A complete 
copy of the questionnaire is included. Both healthy volunteers and individuals with SMA will be required to 
successfully complete demographic and medical history questionnaires. 
 
- Pre-operative labs and screening: 
We will obtain pre-operative complete blood count with differential, prothrombin time and international 
normalized ratio (PT/INR), and partial thromboplastin time (PTT) within two weeks prior to the device 
placement procedure. Pre-operative screening may also include a MRSA test, electrocardiogram, x-rays, 
and/or additional labs and tests as required by the neurosurgery team to determine safety of the surgical 
procedure. These preoperative procedures will apply to participants with SMA only. 
 
-Pre-operative high-resolution MRIs: 
We will perform a pre-operative MRI of the spine without contrast, to generate a high resolution scan of the 
spinal cord and spinal roots in patients with SMA. This MRI will be performed at the Magnetic Resonance 
Research Center at UPMC Presby or at the BRIDGE Center. We may use a neck brace during this MRI to 
ensure the subject's neck is in a similar position for both scans. 
We will additionally perform high-resolution structural images of the brain. Specifically, we will acquire: high-
resolution T1 weighted images, high-resolution T2 weighted images and Diffusion Tensor Imaging (DTI). The 
same brain images will be acquired also at the end of the study to document possible structural changes in 
fiber tracts that might correlate with brain plasticity and motor recovery. 
Finally, we will perform a spinal cord functional Magnetic Resonance at rest and during muscles 
contractions. The same images will be acquired also at the end of the study to document possible changes in 
functional connectivity of the brain and spinal cord that might correlate with plasticity and motor recovery. 
The total duration of the MRI session should not exceed the 2 hours. 
 
-Passive Mobilization and Tendon Vibration: 
Subjects will be asked to perform a task in the MRI scanner. Muscle spindle afferents from specific leg 
muscles will be recruited by stretching the muscles in which they are embedded (the limb is mobilized by a 
physiotherapist, aided with audio cues), and in separate runs by applying muscle tendon vibration using MR-
compatible pneumatic vibrators (synchronized with MRI triggers). We will target the gastrocnemius medialis/ 
soleus, tibialis anterior, quadriceps, iliopsoas, gluteus and 
biceps femoris muscles of only the right leg. Two runs are required for each pair of agonist/antagonist 
muscles per joint per muscle recruitment method. In each run, passive mobilization or tendon vibration, the 
flexor muscle and the extensor muscle are alternatively activated in blocks of 15 seconds followed by a block 
of rest for 10 to 15 seconds with a run lasting 7 minutes in total. To avoid any bias, the order of the runs are 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
randomized. Both healthy participants completing the MRI and those with SMA will be completing this 
activity. These activities will be done pre-implantation and post-explantation. Several scans may be repeated 
post-explant at the investigator's discretion for participants with SMA. 
 
-MRI Scan for Characterization of Brain and Spinal Networks: 
SMA and healthy subjects without contraindications for MRI may undergo MRI, at PI discretion, depending on 
the number of subject MRIs needed for a complete dataset. Depending on facility and subject availability, the 
MRI scan will take place at the Magnetic Resonance Research Center, which is part of the University of 
Pittsburgh, main campus, and is located on the 8th floor of UPMC Presbyterian Hospital, or the CMU-Pitt 
BRIDGE Center, located at Carnegie Mellon University. MRI data will be acquired in a 3T Prisma System 
(Siemens, Erlangen, Germany). A 64-channel coil will be used with a head stabilizer to limit head motion. For 
spine scans we will use a spine coil. We will acquire the following sequences: 
- T1-weighted structural scan of the brain 
- T2-weighted structural scan of the lower thoracic/lumbar area of the spinal cord 
- DWI scan of the brain 
- Functional MRI of the brain and of the lower thoracic/lumbar area of the spinal cord both at rest and while 
performing the same runs described in the “Passive mobilization and tendon vibration session”. 
T1-weighted structural scan of the brain will be used to pre-process the fMRI data and the DWI data. 
T2- structural scan of the spinal cord will be used to pre-process the fMRI data. 
We will extract resting-state and task networks of the brain and of the spinal cord for patients and healthy 
subjects separately. We will compare the spatial and temporal organization of these networks between the 
two population groups. This type of analysis will allow to understand whether there are measurable changes 
in spinal circuits and motoneuron recruitment properties induced by SCS. This MRI will take approximately 3 
hours to complete and will occur during a separate visit than other testing. This 3 hours can be split over two 
sessions if the 3 hours is too long to complete in one session for the patient. These activities will occur pre-
implantation and post-explantation. Post-explant fMRIs may be repeated multiple times at the investigator's 
discretion. 
 
-Measurements of active proprioception capacity: 
Since SCS recruits proprioceptive afferents in the dorsal roots, it is important to assess the ability of each 
subjects to consciously and unconsciously process proprioceptive feedback. We (Dr. Pirondini) will assess 
subject’s capacity by performing leg movement assessments in the Humac Norm system at baseline, during 
the 29 day trial and follow up visits. The HUMAC NORM system is a clinical system used to assess isokinetic, 
isotonic and isometric joint movements and torques in patients. The participant will be seated in a chair with 
their legs supported by specific braces that are different for each of the tested joints (e.g. hip, knee, ankle). 
The participant will be asked to actively perform isometric movements as well as isokinetic and passive 
movements with and without visual aid to reach a specific target of force. This will allow us to measure the 
ability of a subject to assess the level of force applied at a joint or movement and velocities. Surface EMG 
from the main leg muscles will be recorded. We will assess the capacity of the subjects to assess limb 
position and joint movements. We will also assess subject’s capacity by performing arm movement 
assessments in the KINARM system (Kinarm, Kingston, ON, Canada) at baseline and follow up visits. The 
KINARM is a human research intended system used to evaluate motor performances in subjects with stroke. 
The participant will be seated in a chair with their arms supported against gravity. The participant will be 
asked to actively perform isotonic elbow extension and flexion, e.g. movements, against an opposing 
constant force of 0%, 10%, 20%, and 30% of the maximum voluntary surface electromyogram (EMG). Surface 
EMG from the main arm muscles will be recorded. Throughout the experiment the participant’s arm and hand 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
will be occluded from vision with a protective screen built in in the KINARM system. We will assess the 
capacity of the subjects to assess limb position and joint movement. These exercises may be done pre-
implantation, during implantation, and in the follow-up phase of trial participation. Both healthy subjects and 
participants with SMA will be asked to perform these activities. 
 
-Single Joint movement and torques: 
To quantify the range of motion of leg joints and the joint torques produced with and without SCS we will use 
the clinical isokinetic testing system: HUMAC NORM by CSMi. This data may be captured at baseline, during 
the 29 days of the implantation period, and at the follow up visit. Both healthy subjects and participants with 
SMA will be asked to perform these activities. 
 
-Pre-operative antibiotics: 
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 1 hour before the surgery and will be maintained as directed by the study physiatrist and their 
clinical team. Thirty minutes prior to the procedure, the patient will be given dose appropriate cefazolin (1-2g; 
IV), or vancomycin (1g; IV) if there is an allergy to cefazolin (anaphylaxis or airway swelling). 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. These procedures will greatly minimize the risk of infection. This 
activity applies to participants with SMA only. 
 
- Pre-operative Sedation: 
The subject will see an anesthesiologist for the eventual administration of very minimal procedural sedation. 
Traditionally, very small doses of Fentanyl and Versed will be administered intravenously. Please note that 
this may vary based on the anesthesiologist's clinical judgement. This activity applies to participants with 
SMA only. 
 
- Intraoperative lead placement protocol: 
Between two and four percutaneous linear leads will be placed in the lumbosacral epidural space near the 
spinal nerve roots (Medtronic Leads). Clinical practice commonly includes placement of either a single 
paddle lead or alternatively multiple cylindrical linear leads into the epidural space of the lumbar spine. All 
leads will be placed in the lumbar epidural space by Dr. Peter C. Gerszten in the operating rooms at UPMC 
Presbyterian Hospital. The procedure will be performed as described below. However, based on the 
surgeon’s professional judgement, he may make slight modifications to the surgical procedure in order to 
improve targeting and outcomes. 
Preferentially, the subject will be awake throughout the procedure, and 1% preservative-free lidocaine will be 
used for local anesthesia but according to surgeon evaluation and medical records of the subjects the 
subjects may be fully anesthetized. The subject will be taken to the operating room and placed in a prone 
position with a pillow under the abdomen to decrease the normal lumbar lordosis. Each staff member 
involved in the procedure will sterilely scrub in with sterile gowns and gloves using standard surgical 
technique. The skin overlying the lumbar area will be prepped and draped in aseptic fashion with either 
Hibiclens or betadine solution. 1% lidocaine on a 22-gauge 3.5 inch spinal needle will be used in the skin and 
subcutaneous tissue for local anesthesia. 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
Percutaneous sterile needles or surface electrodes will be acutely placed on the principal leg muscles 
bilaterally. These will include: iliopsoas, rectus femoris, semitendinosus muscles, gastrocnemius medals, 
soleus and tibialis anterior. However, they may include other muscles of the leg and back if necessary. EMG 
leads will be connected to a standard clinical electrophysiology monitoring system. This monitoring is part of 
routine clinical practice as performed at UPMC Presbyterian Hospital (Protektor32). 
A small incision will be performed on the skin and for each of the spinal leads, a 14 gauge epidural Tuohy 
needle will be advanced through the L1-L2 space or a nearby intervertebral space to the epidural space via 
loss-of-resistance technique. Needle location will be confirmed in anteroposterior (AP), lateral, and 
contralateral oblique fluoroscopy views. An 8 contacts stimulator lead (Medtronic see device section), which 
is designed to span 2-3 spinal segments, will then be advanced into the T11-L1 posterior epidural space and 
steered laterally using the accompanying stylet under live fluoroscopic guidance in the AP, lateral, and 
contralateral oblique fluoroscopy views. The lead may be connected to an additional extension lead that is 
included in the approved epidural stimulation system (under PMA P030017). The external portion of the lead 
will be connected to one an external electrophysiology monitoring machine. The machine, which is routinely 
used during clinical practice at UPMC is the Natus Medical Protektor32, which is an FDA approved 
neurological programmable intra-operative monitoring system able to deliver up to 16 channels of neural 
stimulation, and up to 32 channels of continuous monitoring including EEG and EMG signals. Connection to 
the Protektor32 will be performed using clinical connecting systems provided by Ad-Tech Medical Instrument 
Corporation, as also routinely used during clinical neuromonitoring and neurostimulation procedures (see 
Document Lead Connectors Example). 
We will then iteratively stimulate at frequencies of 1, 2, 5, 10 or 20 Hz, pulsewidth of 200 or 400 µs, and 
current amplitudes between 100µA and 7 mA. These are common stimulation parameters normally used in 
similar mapping procedures and fully within the FDA-approved stimulation parameters range for spinal cord 
stimulation leads (currents up to 20 mA, frequencies up to 500Hz, puslewidth up to 2 ms). 
The lead placement will be iteratively adjusted based on EMG recorded responses until evoked EMG 
responses occur in the hip as well as ankle muscles. The stylet will then be removed under live fluoroscopic 
guidance to ensure the lead does not move. The procedure will be repeated for the other side and other leg. 
Leads are then secured to the fascia overlying the L2-L3 spinous processes using lead anchors (supplied 
within lead placement kit) and 2x2-0 silk sutures (FIGURE 1). A subdermal pocket lateral to the insertion and 
anchoring site is created, and the strain-relief loop is placed within the said pocket. The incision will be 
closed with interrupted sutures. The leads may be connected to an additional extension lead that is included 
in the approved epidural stimulation system (under PMA P030017).The entire procedure is expected to take 
approximately two hours. 
According to the clinical judgement of the neurosurgeon and anesthesiologist present during the 
implantation procedure, general anesthesia may be used instead of local. After the procedure, the subject 
will be kept for up to 23 hours in the hospital to minimize the infection risk. This activity applies to 
participants with SMA only. 
 
-Post-operative antibiotics: 
We will follow the standard clinical procedures to minimize the risks associated with surgical implantation or 
removal of electrodes. Cefazolin will be given every 8 hours for 24 hours. Patients are sometimes treated with 
antibiotics for the duration of the time that the leads are implanted. These procedures should greatly 
minimize the risk of infection. This activity applies to participants with SMA only. 
 
POST IMPLANT PROCEDURES 
Immediately following lead placement and up to 5 times a week for the following 29 days, the following 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
experimental procedures will be performed. Each testing session will be limited to no more than 8 hours and 
will include breaks. Meals will also be provided to the subjects. Stimulation is performed with external 
stimulator (with the devices described in this protocol) using clinically approved interconnects. In normal 
clinical practice when the trial period is over the surgeon decide whether to implant the “battery or 
implantable stimulator” or to remove the lead. In our case we will remove the leads as per protocol. This is 
entirely identical to our other IRB protocol in STUDY1909021 and the studies STUDY19100220 and 
STUDY19100220 that use similar devices. Consistently with those protocols, the access point is monitored 
and cleaned weekly by Dr. Gerszten and his team. For the duration of the study the leads come out of the skin 
from the back about 10 to 20 cm away from the main incision point on the left or right side. For all procedures 
described below, stimulation parameters (pulsewidth, frequency and amplitude) will never exceed the FDA-
approved parameter ranges for the spinal leads utilized in this protocol. This activity applies to participants 
with SMA only. 
 
- Electrophysiology testing with spinal cord stimulation: 
We will conduct a series of electrophysiology tests to establish the relationship between epidural spinal cord 
stimulation and motor responses in participants with SMA. All experiments will occur either in a patient 
examination room at UPMC Presbyterian, or in the testing space within the Rehab Neural Engineering Lab at 
the University of Pittsburgh. During these tests the patients will be resting laying down on a bed or sitting in a 
relaxed position, and they will be asked to be as still as possible during the delivery of stimulation in order to 
make sure that recorded muscle activity is only coming from the stimulation. 
During electrophysiological stimulation trials, superficial EMG electrodes and gyroscopes to measure limb 
movements will be placed on the legs, the external digitimer stimulator will be connected to the SCS lead 
using interconnects that are used during routine clinical procedures to connect spinal and brain leads to an 
electrical stimulator with standard clinical connections (TouchProof). 
EMG responses and joint kinematics will be recorded in response to stimulation trains and the subject will be 
asked to respond to a set of standard psychophysical questions to assess possible levels of discomfort, as 
well as to provide any additional comments. In order to ensure quality signals are recorded, as well as to 
decrease any discomfort when removing the electrodes, some leg hair may be shaved. All precautions to 
avoid irritation/any cuts will be taken. 
Stimulus parameters to vary include: 
• Pulse amplitude (maximum of 10 mA per electrode) 
• Pulse width (maximum of 400 us;) 
• Pulse frequency (maximum of 500 pulses per second;) 
• Spatial effects: groups of electrodes will be stimulated simultaneously to investigate the effects of spatial 
summation 
• Temporal effects: the pattern of stimulus pulses will be varied to model naturally occurring neural patterns 
(e.g. muscle spindle changes to muscle stretches) or engineering patterns (e.g. sinusoidal modulation) 
In clinical practice, these devices are typically used throughout the day, with the exception of while driving or 
sleeping. As such, we do not expect that we will need to impose any upper limits on the total duration of 
stimulation applied throughout any experimental session or the entire study. As subjects will not be provided 
with a take-home stimulator, there is no risk that subjects will drive or sleep during stimulation. 
Participants may be asked to compare two or more successive stimulus trains and describe or compare the 
effects of stimulation. Examples of the kinds of comparisons that participants may be asked to make 
include: 
• Was the stimulus 1 more comfortable than stimulus 2? 
• Did stimulus 2 feel stronger or weaker than stimulus 1? 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
• Which of stimuli 1, 2, or 3 felt like it came from the foot? 
• Did you prefer stimulus 1, 2, or 3 in terms of ability to move your limb? 
These exercises may be done pre-implantation, during implantation, and in the follow-up phase of trial 
participation. 
 
- Initial Stimulation Parameters: 
When stimulation commences on an electrode that has not been previously used, stimulation parameters 
will be set conservatively in order to minimize the chance for eliciting an undesired response. Stimulation 
frequency will be set to 0.5 to 2 Hz maximum and pulse amplitude will be slowly increased until muscle 
responses are recorded. The patient will be continuously asked whether the stimulation is comfortable and 
amplitude increase will be limited to what the patient deems a comfortable range. If the patients think that a 
specific amplitude is uncomfortable we will immediately stop and limit the amplitude to comfortable level 
boundaries. Stimulation frequency will then be adjusted for the amplitude that elicits the most effective 
motor responses. Frequency will be increased starting from 10Hz and verifying that the sensation is 
comfortable at all time similarly to amplitude parameter search. These activities apply to participants with 
SMA after their implantation only. 
 
- X-Ray to Document Lead Migration: 
Every other week for a maximum of 2 X-ray sessions during the 4 weeks of the study, four total X-ray images 
(AP and lateral views) of the lumbar and thoracic spine will be captured to document the location of the leads 
and any movement that may have occurred. We will attempt to correlate movement of the electrodes with 
any documented changes in stimulation thresholds or the types of sensory percepts that are evoked by 
stimulation. These activities apply to participants with SMA only. 
 
-Single Joint movement and torques: 
To quantify the range of motion of leg joints and the joint torques produced with and without SCS we will use 
the clinical isokinetic testing system: HUMAC NORM by CSMi. This data may be captured at baseline, during 
the 29 days of the implantation period, and at the follow up visit. Both healthy subjects and participants with 
SMA will be asked to perform these activities. 
 
- EEG, EMG and transcutaneous muscle stimulation studies: 
Non-invasive electroencephalography (EEG), electromyography (EMG) and transcutaneous muscle 
stimulation may be used during the study (pre and post implant) to measure neural and muscular responses 
to electrical stimulation in participants with SMA. For EEG studies, electrodes will be placed on the surface 
of the scalp and, for EMG studies, electrodes will be placed on the surface of the skin on both the affected 
and contralateral limbs. Stimulation will be applied as described above. For Transcutaneous muscle 
stimulation studies, electrodes will be placed on the surface of the skin of the leg of the affected limb and 
electrical stimulation to stimulate hip and leg muscles will be delivered via Digitimer Stimulator. These 
exercises may be done pre-implantation, during implantation, and in the follow-up phase of trial 
participation. Both healthy subjects and participants with SMA will partake in EEG and EMG activities. 
 
- TMS measurements: 
Non-invasive transcranial magnetic stimulation (TMS) of the motor cortex may be used during the study (pre 
and post implant) to assess the residual motoneuronal function of each participant and the interaction 
between corticospinal axons and spinal cord stimulation. Subjects will be positioned in the HUMAC NORM 
machine configured for the leg joint to be examined. The robot will then execute passive single joint 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
movements spanning flexion/extension of the joint within a range of motion that will be adjusted to each 
subject according to specific biomechanics and comfort. The speed of movement will be set to slow rates 
(less or equal 0.5 Hz) that are comfortable for each subject. During movement TMS will be delivered by 
random and infrequent (<0.2 Hz) triggering so that pulses will occur at multiple joint-angles and evoked 
potentials in the leg and feet muscles will be measured. This will allow us to have a joint-angle dependent 
analysis of motor evoked potentials (MEP). This experiment will be performed prior to implant, during the 
course of spinal cord stimulation through the implant, and after explantation. 
During the period during which a participant is implanted, TMS will be delivered using the same method but 
while SCS is simultaneously delivered using parameters from the behavioral experimental sessions (see 
below). This will allow us to study the interaction between cortico-spinal inputs and SCS to test the 
hypothesis that SCS increases spinal responses to cortico-spinal neurons, thus enhancing voluntary motor 
control. We expect to see higher peak-to-peak MEP in legs and feet muscles and higher torques in the 
HUMANC NORM when TMS is delivered in conjunction with SCS. 
During this experiment, TMS intensity will be adjusted from initial low values (e.g. 10% maximum output) and 
progressively increased until MEP threshold is found, in case the threshold is lowered by SCS and to avoid 
potential side effects of simultaneous stimulation. Paired TMS and peripheral stimulation is a commonly 
used procedure to study cortico-spinal excitability (see for example Sunday, Urbin and Perez, Brain 
Stimulation, 2018). Here we will use an established experimental protocol to pair TMS with SCS which 
recruits sensory afferents from the posterior roots. Both healthy subjects and participants with SMA will 
partake in TMS activities. 
 
- Sit to stand transitions and standing: 
Periodically throughout the experimental sessions, we will ask each subject to stand up from a sitting 
position. During these trials SCS will be provided to verify its effects on motor task execution. Under constant 
supervision of Physical/Occupational Therapist, the subjects will attempt to stand from sitting position and 
hold the standing position for as long as they can while they are receiving SCS or in control trials without 
stimulation. EMGs of the legs will be recorded during these tests. Subjects will utilize standing supports and 
walkers to ensure safety and stabilization. These tests will be performed in testing space within the Rehab 
Neural Engineering Lab at the University of Pittsburgh. These exercises may be done pre-implantation, during 
implantation, and in the follow-up phase of trial participation. Both healthy subjects and participants with 
SMA will partake in these activities. 
 
-Overground locomotion: 
Periodically throughout the experimental sessions, we will ask each subject to walk a few steps over multiple 
occasions while kinematic and EMG data from their leg is recorded. During these trials SCS will be provided 
to verify its effects on motor task execution. Under constant supervision of a Physical/Occupational 
Therapist, the subjects will walk at their preferred pace while they are receiving SCS or in control trials 
without stimulation. We will utilize special extension cables to enable sufficient cable slack for the subject to 
execute a few steps. In the case that subjects cannot safely move according to judgment of the study PT, we 
will use a walking aide or remove the activity to ensure the safety of all subjects involved. These tests will be 
performed in testing space within the Rehab Neural Engineering Lab at the University of Pittsburgh. These 
exercises may be done pre-implantation, during implantation, and in the follow-up phase of trial 
participation. Both healthy subjects and participants with SMA will partake in overground locomotion 
activities. 
 
-Treadmill locomotion: 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
Periodically throughout the experimental sessions, we will ask each subject to walk on the AlterG Via, an 
antigravity treadmill, for as long as they can. The antigravity treadmill is a piece of rehabilitation equipment 
that uses air pressure to offset a percentage of body weight, relieving the user of some physical burden. 
Under the constant supervision of the study PT, we will adjust the percentage of body weight such that 
subjects can safely walk on the treadmill. During these trials SCS will be provided to verify its effects on 
motor task execution. Under constant supervision of a Physical/Occupational Therapist, the subjects will 
walk at their preferred belt-speed while they are receiving SCS or in control trials without stimulation. 
Superficial EMG electrodes and gyroscopes to measure limb movements will be placed on the legs, and 
external stimulators will be connected to the SCS lead. These tests will be performed in testing space within 
the Rehab Neural Engineering Lab at the University of Pittsburgh. These exercises may be done pre-
implantation, during implantation, and in the follow-up phase of trial participation. Both healthy subjects and 
participants with SMA will partake in treadmill locomotion activities. 
 
-Balance testing: 
Study participants will stand on a platform that can impart translational and rotational perturbations at the 
feet, and key elements of sensory feedback (e.g. visual feedback, ankle proprioception) will be manipulated. 
By providing sensory feedback that is either unreliable or incongruent with the actual perturbation, the test 
provides a method for isolating the influence of somatosensory, visual, and vestibular inputs on balance. We 
will test whether SCS improves balance and proprioception of subjects with SMA. These exercises may be 
done pre-implantation, during implantation, and in the follow-up phase of trial participation. Both healthy 
subjects and participants with SMA will partake in balance testing activities. 
 
-Recumbent bike: 
Periodically during the experimental session, we will ask participants to ride a Motomed recumbent bike for 
as long as they can while they are seated in a chair. During these trials SCS will be provided to verify its 
effects on motor task execution. Under constant supervision of a Physical/Occupational Therapist, subjects 
will ride at their preferred speed and resistance while they are receiving SCS or in control trials without 
stimulation. We will measure any possible torque asymmetries between legs, the time, distance and velocity 
that they are able to ride and the superficial EMG electrode. We will test whether SCS improves motor 
deficits of subjects with SMA. These tests will be performed in testing space within the Rehab Neural 
Engineering Lab at the University of Pittsburgh. These exercises may be done pre-implantation, during 
implantation, and in the follow-up phase of trial participation. Both healthy subjects and participants with 
SMA will partake in recumbent bike activities. 
 
 
-Stimulation parameters during sit-to-stand, overground and treadmill locomotions and balance test: 
Bursts of stimulation or continuous stimulation will be delivered through the SCS leads. Bursts will occur at 
various moments during the execution of attempted movement in order to study effects of different 
stimulation patterns on movement execution. Stimulation parameters will be restricted to those found to be 
more selective from the previously described procedures. Electrical stimulation will be either controlled 
manually by triggering pre-determined bursts or automatically. Automatic control will be based on residual 
EMG activity from leg muscles or gyroscopes as input signals. An attempted movement will trigger pre-
defined stimulation patterns. Stimulation patterns might be also delivered in pattern for each movement 
phase by segmenting the movement in different parts such as swing and stance. Finally closed loop control 
of stimulation using kinematic or EMG inputs might be implemented to control force. This applies to SMA 
patients after implantation only, and will only be done during their 29 day testing period. 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
 
 
- Electrode Impedance: 
Periodically during the experimental session, we may measure the impedance of the SCS leads as a means 
to ensure that the device is functioning properly. This functionality is included in the Protektor32 system. 
 
- Removal of SCS Leads: 
After completion of testing and no later than 29 days after device placement, the SCS leads will be removed 
at UPMC Presbyterian. To remove these devices, we will follow a similar procedure to the implant to 
minimize infections risks. In the operative room the subject will be positioned prone on the operating table, 
and using sterile technique, the lead will be gently pulled until it is removed after removing sutures. Similarly 
to the implant procedures, EMGs signals in response to test stimuli will be recorded for post-study controls. 
Visual inspection of the leads will confirm that they are intact and that no portion of the device remains under 
the skin. The skin will be sutured, cleaned with Hibiclens or betadine and dried with sterile 4x4 gauze 
dressings, and a sterile bandage will be placed on the site. A follow-up telephone call will be made to the 
patient within 48 hours of their discharge to make sure they are asymptomatic. A follow-up visit for suture 
removal will occur within 2 weeks after electrode removal. 
 
-Replacement of Electrodes: 
If, during the experiment, the electrodes move away from the target nerves, it may be necessary to remove 
the electrodes before the end of the 29-day 
period. If deemed appropriate by study staff, participants may undergo the electrode placement procedure 
one additional time, followed by an additional 29-day testing period. In this case, we may repeat any of the 
screening and experimental procedures described above. 
 
 
-Mid-study, post-study and follow up outcome measurements: 
Primary outcomes related to muscle strength will be assessed pre-study, at week 2, week 4 and post-study 
follow up (at least 4 weeks after completion) safety will be assessed throughout the study. 
Secondary outcomes will be assessed as follows: 
1. MRI Imaging: will be assessed pre-study and post-study 
2. Electrophysiology will be assessed, pre-study, throughout the study, and post-study 
3. Pain will be assessed throughout the study 
4. Motor function clinical scales will be assessed pre-study, at week 4 and post-study follow up 
 
Prior to any procedure that may potentially involve risk to an unborn child, we will ask females of child-
bearing potential to undergo a urine pregnancy test. 
 
Subjects may be be video recorded or photographed during any of the experimental procedures for research 
or educational purposes. The study team will track subjects' choices for PHOTOGRAPH / VIDEO at the time 
of consent and follow subjects' choices on disposition of samples after use for this study in a document with 
appropriate confidentiality protections. The PI will oversee this process. 
 
STATISTICAL ANALYSIS 

SCS in SMA 
Principal Investigator: Marco Capogrosso, PhD 
 
January 13, 2025 
 
This is a pilot proof of concept study. Because this is a pilot study, we feel that it is appropriate to begin with a 
small sample size in this initial investigation. Up to six participants will be enrolled in this proof-of-concept 
study. This pilot study is descriptive in nature and no formal statistical comparisons will be performed among 
groups instead, all data will be analyzed for all participants. 
 
The study is considered successful if 70% of enrolled subjects (e.g. rounded at 4/6) achieve success criteria 
in primary outcomes