Noninvasive Cervical Electrical Stimulation for ALS: Mechanistic and Safety Study
Phase: NA
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: VA Office of Research and Development

NCT03411863 
 
Noninvasive Cervical Electrical Stimulation for ALS: Mechanistic and Safety Study 
 
May 5, 2019 

PART II 
GUIDE TO RESEARCH PROPOSAL 
 
1. SPECIFIC AIMS 
Aim 1: Map the cellular and synaptic targets of cervical electrical stimulation (CES). 
CES circuit interactions at both the spinal and supraspinal levels will be characterized using a common 
structure comprising an electrical or magnetic conditioning stimulus followed by a test stimulus delivered 
at a range of intensities, sites, and interstimulus intervals (ISI). This will shed insight into which circuits 
CES activates, and how CES circuits interact with circuits activated by other exogenous neural stimuli. 
Hypothesis 1.1: Conditioning subthreshold CES will potentiate spinal motor neuron responses to test 
transcranial magnetic stimulation (TMS) pulses. Depending on the timing of the effect, this would support 
either the mechanism of heterosynaptic summation between segmental Ia input and descending 
corticospinal input1, or sensory cortical facilitation of motor cortex excitability2–4. 
Hypothesis 1.2: Conditioning CES will increase persistence (number of responses per 20 stimuli) of spinal 
motor neuron F-responses to retrograde stimulation over the median and/or ulnar nerve. This would 
indicate CES’s potential to modulate motor neuron excitability at the spinal level. 
Hypothesis 1.3: Conditioning CES will reduce amplitude of median (flexor carpi radialis) H-responses, 
indicating that CES traveling via sensory afferents homosynaptically depresses ensuing H-reflexes5,6. This 
would demonstrate the potential for CES to reduce hyperactive muscle stretch responses (spasticity)5 via 
segmental afferent interactions. 
Aim 2: Determine optimal CES and volitional movement combination parameters for acutely 
facilitating concurrent arm and hand movements. 
Volitional limb movements depend on the same corticospinal and motor neuron circuits as those 
activated by TMS and F-waves. Since preliminary data shows that subthreshold CES facilitates TMS 
responses, CES may also be able to facilitate volitional limb movements. The experiments in Aim 2 will 
shed light on this clinically applicable question. 
Hypothesis 2.1: Subthreshold CES will facilitate concurrent arm and hand muscle activation, further 
indicating CES’s ability to positively modulate corticospinal and/or motor neuron excitability. This would 
establish an opportunity to directly translate this paradigm for clinical benefit by combining repetitive 
subthreshold CES with repetitive task-oriented physical exercise training in a subsequent study. 
Hypothesis 2.2: High-intensity suprathreshold CES will transiently inhibit concurrent arm and hand 
muscle activation. If observed, this ‘spinal silent period’ would shed insight into mechanisms underlying 
the ‘cortical silent period’ noted when cortical TMS is delivered during volitional contraction7,8. 
 
2. BRIEF REVIEW OF RESULTS AND CURRENT STATE OF KNOWLEDGE 
Amyotrophic lateral sclerosis (ALS) is a spinal cord disease. Many of the most striking features of ALS – 
muscular atrophy, fasciculations, and findings of denervation on electromyography – demonstrate the 
consequences of damage to lower motor neurons within the spinal cord. The almost pathognomonic 
spasticity and hyperreflexia seen in atrophied limbs reflects degenerating corticospinal axons in the 
lateral spinal cord (“lateral sclerosis”). Remaining motor circuits are weak, uncoordinated, and spastic9. 
Therefore, ALS shares many key features with incomplete spinal cord injury (SCI). Thus, some of the 
therapies aimed at strengthening neural transmission in SCI may warrant testing in ALS as well.  
A large body of evidence in brain and spinal cord injury suggests that activating spared nerve circuits 
augments circuit and physiological function10–14. Impressive gains have been made in the SCI field by 
applying electromagnetic stimulation, including transcranial magnetic stimulation (TMS), direct current 
stimulation (DCS), and invasive epidural electrical stimulation10,15–21. However, drawbacks exist, such as 
the unfeasibility of combining TMS with active exercises, the inability to directly map the timing or 
circuitry of DCS effects, and the risks of invasive surgery for epidural stimulation, especially in the ALS 
population.  

Noninvasive electrical spinal stimulation lacks these drawbacks. We have developed a novel method of 
noninvasive cervical electrical stimulation (CES). Our technique draws on lessons learned from other 
forms of noninvasive spinal stimulation, mostly focused on the lumbar cord5,22–26. However, these studies 
need to be supplemented with experiments that further investigate CES circuit interactions, not only 
within the spinal cord, but also between the cord and other parts of the nervous system. This proposal 
will address gaps in mechanistic and therapeutic understanding in the field of noninvasive spinal cord 
stimulation, and will establish the rationale for applying our novel technique in individuals with ALS. 
ALS has been neglected by the field of neural stimulation. To our knowledge, the small body of work 
using neural stimulation in ALS has centered on the brain [[or phrenic nerve]], not the spine, and most 
studies have performed diagnostic rather than therapeutic stimulation27–32. A literature search revealed 
only seven primary studies of therapeutic repetitive TMS or transcranial DCS for ALS, the majority 
performed by the Di Lazzaro group in Italy, which have not shown a clear benefit in ALS progression33–39. 
A search of “amyotrophic stimulation” on the clinicaltrials.gov database showed one study with unknown 
active status recruiting ALS patients for therapeutic DCS in Italy, two studies recruiting ALS patients for 
diagnostic TMS in France, and our own unfunded pilot study of TMS paired with electrical stimulation at 
the James J. Peters VA Medical Center (see Preliminary Data). Both of these searches were last 
conducted on 21 February 2017. Thus, except for our own ongoing unfunded pilot study, there are no 
active clinical studies anywhere in the world of spinal stimulation for ALS. Given the limited therapeutic 
options available for ALS, this technology warrants testing even though electromagnetic stimulation may 
not halt or reverse underlying processes that contribute to ALS pathology such as inflammation, axonal 
transport defects, and protein aggregation40.  
Significance 
ALS incidence is up to twice as high in Veterans from all eras of active duty41. Therefore, ALS is a 100% 
VA Service-Connected condition, and the experiments proposed here strongly align with RR&D’s mission. 
Treatments are extremely limited, and there remains no cure. Individuals with ALS and their loved ones 
are generally eager to seek out new options – unfortunately, this is often exploited by unethical purveyors 
of ill-defined mixtures of stem cells or herbal remedies42–44. Therefore, rational, ethical, IRB-approved 
research studies are desperately needed. This pilot study, focused on mechanisms, safety, and short-term 
biomarkers of efficacy, represents an essential – and original – first step toward subsequent evidence-
based studies of combined CES-exercise programs that will aim to improve clinical function in individuals 
with ALS. 
This proposal focuses on non-invasive electrical stimulation over the spinal cord. Below, we will detail the 
state of this field, highlighting the gaps in mechanistic understanding and therapeutic application toward 
ALS and other conditions. We will thereby establish the rationale for testing and applying our novel 
technique of non-invasive cervical electrical stimulation. 
Non-invasive brain stimulation 
Transcranial magnetic stimulation (TMS) uses a transient focal magnetic field to induce action potentials 
in the underlying brain. TMS over the motor cortex transduces action potentials to descending corticospinal 
fibers45,46. Repetitive TMS (rTMS) at 1 Hz is generally inhibitory, whereas at 5 Hz or greater, rTMS is 
generally excitatory47. Higher-frequency (usually 50 Hz) ‘theta burst’ TMS may induce longer-lasting effects 
that are either inhibitory or excitatory based on burst patterns46,48. Seminal TMS mechanistic studies will 
serve as guides for some of the experiments in this proposal45,46,48–50. 
Direct current stimulation (DCS) delivers a low-power electric current that modulates neuronal excitability51. 
In distinction from TMS, DCS delivers exclusively tonic, subthreshold stimulation52. Various cranial and 
spinal DCS configurations have shown promising effects in neurological and psychiatric disorders, as well 
as enhancement of normal function15,20,53–62. However, there is no technique to directly map how the low-
energy current distributes within the body, or to determine how individual variations in injury characteristics 
affect that distribution63. Furthermore, the continuous nature of DCS makes it difficult if not impossible to 
elucidate timing-dependent synaptic changes. Therefore, although DCS has therapeutic potential, its 
underlying mechanisms are quite likely to remain a black box.  
Invasive spinal stimulation 

Epidural electric stimulation through implanted lumbar electrodes delivers tonic, motor-subthreshold 
stimulation, usually targeted toward the locomotor central pattern generator. In rodent SCI models, epidural 
stimulation combined with physical training and monoaminergic drug stimulation has led to recovered 
ability to walk on previously paralyzed hindlimbs19,64,65. This work has been translated into humans with 
chronic motor-complete spinal cord injury as high as the C7 level, resulting in regaining some volitional leg 
movement while stimulation is turned on10,17. These incredibly encouraging results support the utility of 
subthreshold spinal stimulation to improve neural circuit function. However, stimulator implantation carries 
the risks of invasive surgery – these risks are significantly higher in the cervical than lumbar spine.  
Non-invasive spinal stimulation  
Multiple transcutaneous spinal stimulation approaches have been developed, largely targeted at 
thoracolumbar locomotor circuits. Tonic stimulation over the T11 level at 3 Hz induces coordinated walking 
movements in uninjured volunteers23. Adding simultaneous stimulation at the C5 and L1 levels increases 
motion coordination and range22. High-intensity phasic stimulation over the C7-T1 or T10-L1 levels 
activates efferent fibers in ventral motor roots to elicit action potentials in arm or leg muscles, 
respectively24,25. 
Transcutaneous biphasic stimulation can also elicit action potentials through afferent fiber pathways6. 
Subthreshold transcutaneous stimulation over T11-T12 for 30 minutes at 50 Hz led to reduced leg 
spasticity and evidence for improved motor function in three subjects with motor-incomplete SCI5. This 
effect was most likely mediated by activation of afferent spinal roots and their segmental interneuronal 
connections. We plan to exploit subthreshold cervical transcutaneous stimulation targeted at similar 
afferent pathways. 
Temporally linked (paired) neuronal firing can lead to lasting effects on synaptic and neuronal excitability 
through Hebbian-like mechanisms such as long term potentiation and synaptic summation66–69. These 
paired stimulation techniques include paired associative stimulation (PAS), transspinal-transcortical 
stimulation, spinal associative stimulation, spike timing-dependent plasticity, and others2,70–77. In a 
demonstration of spike timing-dependent plasticity in the cervical cord, TMS over the hand motor cortex 
was paired with high-intensity electrical stimulation over the ulnar nerve at the wrist70. When repetitive (0.1 
Hz, 100 repetitions) paired pulses were timed so the anterograde TMS signal arrived at cervical motor 
neurons 1-2 ms before the retrograde ulnar nerve signal, both able-bodied volunteers and subjects with 
SCI demonstrated increased TMS-evoked potentials in hand muscles and improved hand dexterity for at 
least 30 minutes after the end of paired stimulation70. This suggested that synapses between upper and 
lower motor neurons underwent Hebbian-like strengthening. Other studies have found more evidence for 
the highly timing-dependent nature of synaptic effects, both at cervical and lumbar levels74,76,77.  
The advantages of non-invasive cervical electrical stimulation (CES) 
Our group recently developed a novel configuration of transcutaneous CES. Our technique draws on 
lessons learned from other forms of non-invasive spinal stimulation referenced above. We have already 
applied for and received FDA designation as non-significant risk, and we are conducting two other IRB-
approved human pilot studies to establish basic CES mechanisms and safety. As presented in the 
preliminary data, CES (Figure 1) comfortably elicits action potentials over multiple spinal cord segments 
simultaneously in both arms. CES activates spinal motor neurons indirectly via nerve roots, targeting either 
afferent or efferent fibers depending on stimulus intensity. This afferent or efferent root-stimulation 
approach provides a flexible portal to access synapses between upper and lower motor neurons, even in 
contexts of damaged motor circuitry78.  
While we are excited to test CES paired with either peripheral nerve stimulation or TMS, TMS requires 
bulky, expensive equipment that makes it highly impractical to use in conjunction with concurrent physical 
exercise. In this proposal, we will take a more in-depth mechanistic approach to the CES technique itself, 
with the goal of establishing a single-modality stimulation paradigm that mediates beneficial synaptic 
plasticity in conjunction with physical exercise.  

We emphasize that CES is inherently different 
from popularly used types of non-invasive 
electrical stimulation such as direct current 
stimulation (DCS, described above) and functional 
electrical 
stimulation 
(FES). 
FES 
targets 
peripheral nerves with suprathreshold pulses 
designed to directly stimulate motor units within 
one or more large muscles at a time. Separate 
FES electrodes are required for each targeted 
nerve/muscle. Critically, FES engages motor units 
in non-physiological order, from largest to smallest 
– this causes excessive muscle fatigue79. In 
contrast, CES targets multiple root levels and both 
sides simultaneously, with the goal of using 
subthreshold intensity to amplify endogenous 
volitional neural circuit signaling. 
Gaps in mechanistic understanding of spinal stimulation 
As opposed to stimulation configuration and pairing with other modalities, the effect of timing between 
successive spinal cord stimuli has received less attention in comparison to similar experiments in the field 
of TMS. Extensive studies have defined rTMS effects over a range of pulse frequencies and patterns, in a 
broad variety of injury and disease contexts. A similarly rigorous definition of spinal stimulation timing 
effects has not yet been achieved. One reproducible finding has shown that at low suprathreshold 
intensities, a conditioning spinal pulse inhibits a second spinal pulse given 20-50 ms later1,5,6,80. These 
findings, which we have confirmed in our own studies, indicate that at these intensities, spinal stimulation 
triggers afferent sensory fibers that activate motor neurons via synapses that are subject to homosynaptic 
depression. However, these studies need to be supplemented with experiments that more deeply 
investigate basic mechanisms of circuit interactions. In the TMS field for example, conditioning pulses 
inhibit test pulses given either 1-3 or 100-200 ms later, and facilitate test pulses given 8-15 ms later. The 
effects of these time intervals have revealed important brain circuit interactions termed short-interval 
cortical inhibition (SICI), long-interval cortical inhibition (LICI), and intracortical facilitation (ICF), 
respectively46,50. Using conditioning and test stimuli over a broad range of time intervals, site, and modality 
combinations, we now expect to define similar types of circuit interactions mediating the response to CES. 
Our team is optimally positioned to address these gaps – we already conduct studies involving electrical 
and magnetic stimulation in a well-run clinical research center; and we have already obtained FDA and 
IRB clearance to conduct human studies using our novel CES technique. 
PRELIMINARY DATA 
This preliminary data derives from an ongoing 
study investigating basic parameters of CES and 
its interaction with TMS. That study does not 
involve volitional movement, and lacks many of 
the basic mechanistic experiments proposed in 
the current application. 
Noninvasive, 
non-noxious 
cervical 
electrical 
stimulation (CES) 
We 
have 
designed 
a 
surface 
electrode 
configuration that effectively stimulates motor 
responses 
from 
multiple 
cervical 
levels 
simultaneously at non-noxious current outputs. 
One 5x10 cm cathode is placed longitudinally over 
 
 
Figure 1. CES schematic. Biphasic electrical pulses are 
delivered noninvasively over the cervical spine. The 
cathode is placed posteriorly over T1-T3 levels, and the 
anode is placed anteriorly over C4-C5 levels. Ground 
electrodes are placed over the distal clavicles. Depicted 
schematically on left, photographically on right. 
 
 
Figure 1. CES schematic. Biphasic electrical pulses are 
delivered noninvasively over the cervical spine. The 
cathode is placed posteriorly over T1-T3 levels; the 
anode is placed anteriorly over C4-C5 levels. Two 
ground electrodes are placed over the distal clavicles. 
Depicted schematically on left, photographically on right. 
 

the midline with the top edge 2.5 cm caudal to the C7 
spinous process (~T1-T3 vertebral levels posteriorly). 
Another 5x10 cm anode is placed horizontally 
centered over the thyroid cartilage, corresponding to 
the C4-C5 levels anteriorly (Fig 1). Two 5x10 cm 
ground electrodes are placed over the distal clavicles. 
Pulses are delivered via biphasic waveforms of 2-ms 
duration. In our ongoing pilot study comparing 
combinations of TMS with either CES or peripheral 
nerve stimulation, 19 subjects (5 with SCI, 3 with ALS) 
have undergone over 120 sessions of CES without 
procedure-related significant adverse events or 
intolerance. All subjects have had easily obtainable 
CES responses. Of 7 ALS subjects screened to date, 
5 had hand motor responses to TMS, a requirement 
for inclusion in the ongoing study (Table 1). One 
subject did not wish to pursue further testing, and 
another subject presented with visual hallucinations 
before his first scheduled study visit, so we aborted 
his participation. Thus, 3 ALS subjects have undergone CES, without any significant adverse events. 
CES activates 
multiple arm 
muscles 
simultaneously 
Surface recording 
electrodes 
were 
placed in a non-
disabled 
volunteer over the 
biceps 
(C5-C6), 
flexor 
carpi 
radialis (FCR, C6-
C7), 
extensor 
carpi 
radialis 
(ECR, C6-C7), triceps (C7-C8), and abductor pollicis brevis (APB, C8-T1). At intensity levels sufficient to 
stimulate both proximal and distal arm muscles, relative latencies corresponded to the distance of each 
recording electrode from the cathode (Fig 2A). The hand myotomes more directly underlying the cathode 
A  
 
 
 
B  
 
 
         C 
 
 
Figure 2. CES activates multiple muscles simultaneously. A) CES waveforms in one non-disabled volunteer 
depicted in raster format. CES stimulus at ~200% threshold. Note the proximal to distal gradient of latencies and 
amplitudes. B) Intensity-response curves of five different arm muscles, showing distal muscle selectivity. C) CES 
symmetrically activates homologous muscles on both sides [[updated, 10 non-disabled subjects]]. FCR, flexor carpi 
radialis; ECR, extensor carpi radialis; ADM, abductor digiti minimi; APB, abductor pollicis brevis. 
 A                  
B  
              C 
 
 
D 
 
Figure 3. The CES circuit pathway is adjustable via stimulus intensity. APB recordings 
of double CES stimuli at 40 ms intervals. A, At high intensity (200% of resting motor 
threshold), repeat CES stimulus (red lines) shows no decrement. B, At peri-threshold 
intensity, repeat CES stimulus results in significant amplitude decrement. C, Second 
stimulus response increases as stimulus intensity increases, indicating direct axonal 
activation, not synaptic transmission. Average ± SEM in 8 non-disabled subjects. D, CES 
activates sensory afferent roots (red) at lower intensity, and motor efferent roots (green) at 
higher intensity. Red 20 ms-scale bar same for A and B.  
Age 
Gender 
Duration 
FRS 
MEP 
Resting 
Threshold 
(% MSO) 
62 
M 
1.5 yr 
37 
+ 
84 
60 
M 
4 yr 
30 
+ 
59 
51 
F 
1 yr 
42 
- 
n/a 
48 
M 
4 yr 
43 
- 
n/a 
42 
F 
1.5 yr 
42 
+ 
83 
54 
M 
3 yr 
34 
+ 
44 
58 
M 
1.5 yr 
35 
+ 
50 
Table 1 – Demographics and average TMS resting 
motor threshold to hand muscles in subjects with 
ALS. FRS, ALS Functional Rating Scale (out of 48); 
MEP, motor-evoked potential; MSO, maximum 
stimulator output. 

responded at lower thresholds than the arm myotomes (Fig 2B). Additionally, muscles in both arms 
simultaneously and symmetrically respond to CES in non-disabled subjects (Fig 2C).  
CES targets different circuits at different intensities 
When single CES pulses are delivered at peri-threshold intensity, latencies to the APB muscle are up to 
3-5 ms longer than when delivered at higher stimulation intensity (not shown). When two CES pulses are 
given 40 ms apart at low intensity, the second pulse amplitude is strongly reduced, whereas at higher 
intensity, there is little to no decrement (Fig 3). These findings indicate that the CES circuit pathway can 
be selected by titrating intensity: at low intensity, CES travels a longer route from afferent to efferent 
neurons via synapses susceptible to post-activation depression1,6. At higher intensity, CES directly (non-
synaptically) activates efferent fibers (Fig 3D).  
Subthreshold 
CES 
acutely 
facilitates 
muscle 
responses to cortical stimulation 
To test whether subthreshold CES (80-90% of motor 
threshold) could facilitate response to suprathreshold 
TMS (120% of motor threshold), CES was delivered 
either alone or paired such that the CES pulse arrived 
at cervical motor neurons 10 ms prior to TMS pulse 
arrival or 1.5-5.0 ms after TMS pulse arrival. 
Preliminary results show that subthreshold CES 
facilitates the response to TMS when the TMS pulse 
arrives first (Fig 4), with similar trends among non-
disabled, SCI, and ALS subjects. Since TMS travels 
via the same corticospinal pathways that mediate 
volitional movement, the fact that subthreshold CES 
facilitates TMS suggests that it may also facilitate 
volitional movement. This is a finding with potential for 
direct clinical translation. Note, only three different 
interstimulus intervals (ISI) were tested in this 
experiment. A much wider range of intervals needs to be tested to better understand and optimize this 
phenomenon. 
 
Rationale:  
This proposal includes experiments designed to achieve both mechanistic insight and demonstration of 
therapeutic principle. CES is innovative: the delivery patterns, configurations, and subject population 
proposed here are novel. CES is practical: non-invasive stimulation carries significantly lower cost, lower 
risk, and greater ability to widely implement than surgically implanted stimulation, especially at the cervical 
level. Unlike TMS, surface electrical stimulation may be easily combined with simultaneous physical 
exercise. This approach is broadly applicable: it could be used for individuals with other neurological 
injuries such as stroke, spinal cord injury, multiple sclerosis, or traumatic brain injury. Finally, CES is 
compatible: it could be combined with drug or cell-based treatments to hopefully produce synergistic 
functional benefits in the future. 
 
Please note that this IRB application involves similar neural stimulation procedures as already 
reviewed and approved in study HAR-15-001, HAR-16-042, and HAR-17-017. This application directly 
parallels the protocol of HAR-17-017, but in a different subject population and funded by a different 
agency, requiring separate IRB applications. 
 
 
Figure 4. Subthreshold CES acutely facilitates 
TMS-evoked potentials. Suprathreshold (120%) 
TMS and subthreshold (80-90%) CES were given 
alone or in combination. Response amplitudes were 
normalized to the response to TMS alone. 
Subthreshold CES facilitated the response to TMS 
alone when the TMS pulse arrived prior to CES, but 
not when the timing was reversed. Amp, amplitude. 

3. PROCEDURES, METHODS AND EXPERIMENTAL DESIGN. 
Participants: Ages between 21 and 75. n=24 subjects with ALS. n=27 non-disabled volunteers. 
Inclusion criteria 
Non-disabled participants 
1. Age between 21 and 75 years; n=15 for Aim 1, n=12 for Aim 2; 
2. No known central or peripheral neurological disease or injury. 
ALS participants 
1. Age between 21 and 75 years; n=12 for Aims 1 and 2; 
2. Diagnosis of definite or probable ALS by Escorial Criteria; 
3. Weakness (not paralysis) or either hand: Score of 2, 3, or 4 (out of 5) on manual muscle testing of 
wrist extension, wrist flexion, finger extension, finger flexion, or finger abduction in left or right 
hand; 
 
Exclusion criteria  
1. History of other serious injury or disease of central or peripheral nervous system; 
2. History of seizures; 
3. Ventilator dependence or patent tracheostomy site; 
4. Use of medications that significantly lower seizure threshold; 
5. History of head trauma with evidence of brain contusion or hemorrhage or depressed skull 
fracture on prior imaging; 
6. History of implanted brain/spine/nerve stimulators, aneurysm clips, ferromagnetic metallic 
implants, or cardiac pacemaker/defibrillator; 
7. Significant coronary artery or cardiac conduction disease; 
8. History of bipolar disorder or suicide attempt or active psychosis; 
9. Heavy alcohol consumption (> equivalent of 5 oz of liquor) within previous 48 hours; 
10. Open skin lesions over the face, neck, shoulders, or arms; 
11. Pregnancy; 
12. Unsuitable for study participation as determined by study physician 
 
Recruitment: 
Veterans with ALS will be recruited from the multidisciplinary ALS clinic at the James J. Peters VA Medical 
Center, Bronx, NY. After our ALS veteran population has been given first option to participate, eligible non-
veterans with ALS will be permitted to participate. This will allow for a larger pool of subjects, and will help 
to ensure balanced allocation among treatment groups. Individuals who indicate desire to participate in 
clinical research will be referred from colleagues at ALS clinics at New York-Presbyterian Hospital and 
Mount Sinai Health System. We will not contact anyone unless referring physicians provide assurance that 
the individual would be interested in receiving further information about this study. Individuals who contact 
us through online postings at clinicaltrials.gov, which are distributed by various ALS online communities, 
will also have the opportunity to participate. Participants will be recruited without regard to gender, racial, 
or ethnic status. We will not contact any patients unless referring physicians provide us with assurance 
that the patient would be interested in receiving further information about this study.  
Eligibility Screening: 
Persons interested in participating will be assigned a number beginning at 1. To determine eligibility, 
interested participants will be asked the “yes” or “no” questions listed below. Persons who answer “no” to 
any of the following questions will not be eligible for the study: 
 
 
Do you have amyotrophic lateral sclerosis, or are you an able-bodied volunteer? 
 
Are you between the ages of 21 to 75 years? 
 
If the potential participant answers “yes” to all questions, then the informed consent process will continue 
by inviting the participant for an in-person interview.  
 

Enrollment: 
At the in-person interview, the study will be explained by one of the study team members. All study team 
members will be trained to obtain consent. The study will be explained in its entirety. Along with explaining 
each of the testing and evaluation procedures, the study team member will explain every possible risk that 
the participant may encounter. The potential participant will be told that there is a possibility that he or she 
will not be eligible if any of the exclusion criteria are found to be true (i.e. a screening failure). This is an 
investigational, observational study. As such, no direct permanent benefits will be expected. 
Potential participants will be encouraged to ask questions throughout the process. Potential participants 
will be informed of their right to withdraw at any time and that choosing to not participate will not infringe 
on any of their regular VA benefits or medical care. Once he/she has no further questions and the study 
team is confident that the potential participant fully understands the protocol and its risks, then the 
participant will be asked whether he or she is willing to sign the ICF.  
 
Procedures: 
General: All procedures are performed in a seated position with elbows at roughly 90 degrees and hands 
resting on a pillow in pronated position. Electrophysiological measurements are made using the dominant 
or stronger affected arm. Safety (blood pressure, heart rate, pulse oxygenation, peak expiratory flow rate, 
and structured symptom questionnaire) and tolerability are closely monitored throughout all experiments 
(see Human Subjects section).  
Electromyography (EMG): EMG is recorded using surface sensors with 300x preamplification, 15-2,000 
Hz bandwidth, and internal grounding (Motion Lab Systems). EMG input is collected at a sample rate of 
5,000 Hz via digital acquisition board and customized LabVIEW software (National Instruments). Muscles 
recorded may include abductor pollicis brevis (APB), abductor digiti minimi (ADM), first dorsal interosseous 
(FDI), flexor carpi radialis (FCR), extensor carpi radialis (ECR), and/or biceps brachii. 
TMS: TMS is performed using a MagPro X100 stimulator (MagVenture). The hand motor cortex ‘hotspot’ 
is found while monitoring EMG motor response. Location of the hotspot and all subsequent TMS stimuli 
are tracked using a neural navigation system (Brainsight). Resting motor threshold is determined by 
delivering pulses with increasing intensity until motor responses of ≥ 50µV are observed in the APB or FDI 
muscle in at least 5 out of 10 stimuli.  
CES: CES is performed using two DS7A nerve stimulators or a dual DS8R stimulator (Digitimer) linked to 
deliver biphasic pulses (1 ms each phase; cathodal first). The cathode is a 5x10 cm surface electrode 
(Natus) placed longitudinally with the top edge ~2.5 cm caudal to the C7 spinous process (~T1-T3 vertebral 
levels posteriorly). The 5 x 10 cm anode is placed horizontally over the thyroid cartilage, corresponding to 
the C4-C5 levels anteriorly. Two 5x10 cm common ground electrodes are placed over the distal clavicles. 
Stimulus intensity ranges from 0-80 mA. Motor threshold is determined analogously to the method used in 
TMS. Blood pressure, heart rate, pulse oximetry, and peak expiratory flow rate are monitored every three 
minutes. 
Peripheral nerve stimulation: Stimulation is delivered using a DS7A or DS8R nerve stimulator and dual 
surface electrodes (20 mm apart). M-wave and F-reflex responses are triggered over the median and ulnar 
nerves at the wrist, recording over the APB and FDI muscles, respectively. F-wave pulse intensity is ~110-
120% of the intensity that results in maximal compound motor action potential (CMAP). H-reflex responses 
are triggered over the median nerve at the elbow, recording over the FCR muscle. H-reflex pulse intensity 
will be calibrated to result in H-reflex amplitude ~20-25% of maximal CMAP81. Pulse width is 0.2 ms for 
M/F wave stimulation and 1.0 ms for H-reflex stimulation. 
Autonomic monitoring: In addition to standard vital sign monitoring of blood pressure, heart rate, pulse 
oxygenation, and forced vital capacity, real-time changes in cardiovascular and respiratory function will be 
monitored: A three lead electrocardiogram (ECG) (UFI; Morro Bay, CA. #Resp1EKG) will be used to 
determine HR and heart rate variability (HRV); recording electrode will be in the V6 position. These data 
will be intermittently monitored during study visits. The ECG data will be viewed in real-time and stored on 

a secured desktop computer for future analysis using LabVIEW graphical software for instrumentation 
(National Instruments, Austin, TX, USA). Beat-to-beat finger BP will be monitored using photo-
plethysmography for assessment of BP variability and baroreceptor reflex activity (CNSystems 
Medizintechnik; Graz, Austria; # CNAP Monitor 500). Impedance plethysmography will be used to monitor 
respiration rate (Biopac Systems, Inc.; Goleta, CA.; # RSP100C). These data will be viewed in real time 
and stored on a secured desktop computer for future analysis using LabVIEW.  
Timing: Peripheral motor conduction time is calculated using F-wave and M-wave latencies using the 
formula (LatencyM+LatencyF – 1) ÷ 282. Central motor conduction time is calculated as the TMS-evoked 
potential latency minus the peripheral conduction time. These values are used to precisely synchronize 
arriving TMS, CES, and peripheral pulses at cervical motor neurons in the relevant experiments. 
Replication: For Aim 1, testing will occur over three sessions. For Aim 2, testing will occur over two 
sessions. This will allow confirmation of key intensity and timing parameters defined for each subject over 
different sessions, improving reliability of the findings. 
Aim 1: Map the circuit and synaptic targets of cervical electrical stimulation (CES).  
This Aim investigates fundamental CES mechanisms using a classic conditioning-test stimulus paradigm. 
An electrical conditioning stimulus will be paired within 0-300 ms of a test stimulus delivered at a range of 
intensities and sites. This will shed insight into which circuits CES activates, and how CES circuits interact 
with inhibitory and facilitatory endogenous neural feedback pathways. 
CES-TMS interactions:  
• Hypothesis 1.1: Conditioning subthreshold CES will potentiate spinal motor neuron responses to test 
TMS pulses.  
• Methods: Test TMS pulse intensity will be set at 120% of motor threshold (or 80-90% of maximal 
stimulator output if threshold not detectable). Conditioning CES pulse intensity will be set between 30-
95% of CES motor threshold. For conditioning CES, either single or “theta bursts” (3 pulses at 50 Hz)48 
will be delivered. All pulse combinations will be delivered at a rate of 0.1 Hz, in pseudorandom parameter 
order, until 8 responses per parameter have been recorded.  
• Interpretation: Depending on the timing of the observed effect, this would support either the mechanism 
of heterosynaptic summation between segmental Ia input and descending corticospinal input (facilitation 
expected to occur at ISI between 2-15 ms)1, or sensory cortical facilitation of motor cortex excitability 
(facilitation expected to occur at ISI between 20-60 ms2–4). This would also set the basis for using 
subthreshold CES to facilitate spinal cord motor responses during physical training (see Aim 2). 
CES-peripheral nerve interactions:  
• Hypothesis 1.2: Conditioning CES will increase persistence of F-responses (per 20 stimuli) to retrograde 
stimulation over the median or ulnar nerve. 
• Hypothesis 1.3: Conditioning CES will reduce amplitude of median (flexor carpi radialis) H-responses. 
• Speculative hypothesis 1.2: Conditioning suprathreshold CES will block spinal motor neuron F-
responses delivered up to 10 ms later.  
• Methods: If obtainable, F-wave pulse intensity will be ~110% of the intensity that results in maximal 
compound motor action potential (CMAP). H-reflex pulse intensity will be calibrated for amplitude ~20-
25% of maximal CMAP81. Conditioning CES pulse intensity will be set between 30-175% of motor 
threshold. For subthreshold conditioning CES, either single or “theta bursts” (3 pulses at 50 Hz)48 will 
be delivered. All pulse combinations will be delivered at a rate of 0.1 Hz, in pseudorandom parameter 
order, until 8 (CES-H combinations) or 20 (CES-F combinations) responses per parameter have been 
recorded. 
• Interpretation: Hypothesis 1.2 would indicate that CES positively modulates motor neuron excitability at 
the spinal level; Hypothesis 1.3 would indicate that CES traveling via sensory afferents 
homosynaptically depresses ensuing H-reflexes6. This would demonstrate the potential for CES to 
reduce hyperactive muscle stretch responses (spasticity) via segmental interactions5,6; ; and speculative 
hypothesis 1.2 would demonstrate that high-intensity CES pulses traveling anterogradely via efferent 
nerve roots collide with retrogradely traveling F-waves. 

 
Aim 1 data analysis: Peak-to-peak amplitude (or F-wave persistence) of conditioned pulses will be 
normalized to that of unconditioned pulses. For each interaction paradigm, repeated-measure analysis of 
variance (ANOVA) with factors of subject group, conditioning stimulus intensity, interstimulus interval, and 
muscle will be performed. Post hoc pairwise comparisons will be made using Tukey’s method. 
Aim 1 Timeline: 
Each subject will undergo two testing sessions on separate days, with a minimum of 24 hours and a 
maximum of two weeks between visits. Per subject, Aim 1 participation would therefore take 2 to 15 days. 
27 subjects will be enrolled, resulting in 54 total testing sessions. A very conservative projection of 
completing 1.5 testing sessions per week would result in a timeline of 36 weeks or 9 months for completing 
Aim 1, not including recruitment. 
Aim 2: Determine optimal CES parameters for acutely facilitating concurrent arm and hand 
movements. 
Volitional limb movements depend on the same corticospinal and spinal motor circuits as those activated 
by TMS and F-waves. Therefore, since preliminary data shows that subthreshold CES facilitates TMS 
responses, CES may also be able to facilitate volitional limb movements. The experiments in Aim 2 will 
shed light on this clinically applicable question. 
Volitional motor tasks: Maximal voluntary effort will be defined as the largest response from 3 attempts 
prior to testing. Effort will be measured using a customized dynamometer or the root mean square (RMS) 
of electromyographic activity in the target muscles. The tasks are: thumb-third finger opposition (C8-T1 
levels), or wrist extension by extending the dorsal hand laterally against a mounted load cell (C6 level). A 
combined finger opposition/wrist extension task will also be tested. Subjects will be instructed to perform 
tasks at target effort levels based on real-time display of ongoing EMG or force output. 
CES-motor task interaction: While performing volitional motor tasks at 100%, 50%, or 15-20% of maximal 
effort, conditioning CES (or sham) pulses will be delivered at a range of intensities between 30%-175% of 
resting motor threshold. For subthreshold CES, either single or “theta bursts” (3 pulses at 50 Hz)48 will be 
delivered. The effect of CES pulses on RMS electromyographic activity over the subsequent 200 ms will 
be measured at several different arm and hand muscles and divided by the baseline RMS from the 
preceding 100 ms. At least 10 seconds will elapse between each CES/motor task combination. Effort level 
and CES pulse parameters will be varied in pseudorandom order, until 8 responses per parameter have 
been recorded.  
Aim 2 Outcomes: 
• 
Facilitation: At each muscle, the effect of CES pulses on RMS electromyographic activity over the 
subsequent 200 ms (in 25 ms bins) will be measured and normalized to the baseline RMS from the 
preceding 100 ms. 
• 
Silent period: At each muscle, the duration of electromyographic silence is measured from the end of 
the CES-evoked potential until the resumption of volitional muscle activity (defined as mean rectified 
EMG amplitude less than or greater than mean baseline activity + 2 standard deviations83, 
respectively). 
Hypothesis 2.1: Subthreshold CES will facilitate concurrent wrist and hand muscle activation. 
Hypothesis 2.2: High-intensity CES will transiently inhibit concurrent wrist and hand muscle activation. 
Interpretation: Confirmation of Hypothesis 2.1 would substantiate the findings of Hypotheses 1.1 and 1.2 
and our updated preliminary data that indicate CES’s ability to positively modulate corticospinal and/or 
motor neuron excitability. We expect optimal facilitation when subthreshold CES is delivered at closer to 
motor threshold intensity. We do not know whether the effects will differ depending on intensity of volitional 
effort, but if so, further experiments could investigate the roles played by peripheral, spinal, and supraspinal 
components of effort intensity84. Most importantly, confirmation of Hypothesis 2.1 would represent an 

opportunity to directly translate and test this paradigm for lasting clinical benefit by combining repetitive 
subthreshold CES with repetitive task-oriented physical exercise training in a subsequent study. 
If high-intensity CES inhibits concurrent volitional activity as predicted by Hypothesis 2.2, this would be 
analogous to the ‘cortical silent period’ (CSP) noted when cortical TMS is delivered during volitional 
contraction7,8. The early phase of CSP (the first 50-75 ms after onset of the cortical motor-evoked potential) 
is mediated by poorly understood spinal mechanisms7. Our observations of the onset and duration of a 
‘spinal silent period’ (SSP) in response to CES would shed mechanistic light on this phenomenon. 
Aim 2 Data analysis: Rather than peak-to-peak amplitude, the effects of CES on concurrent volitional 
muscle contraction will be measured using RMS. RMS in 25 ms bins over the 200 ms following each CES 
pulse will be normalized to the baseline RMS during the 100 ms prior to each pulse. Repeated-measure 
analysis of variance (ANOVA) with factors of subject group, volitional effort intensity, CES intensity, post-
stimulus timebin, and muscle will be performed. Post hoc pairwise comparisons will be made using Tukey’s 
method. 
Aim 2 Timeline: 
Each subject will undergo two testing sessions on separate days, with a minimum of 24 hours and a 
maximum of two weeks between visits. Per subject, Aim 2 participation would therefore take 2 to 15 days. 
24 subjects will be enrolled, resulting in 48 total testing sessions. A very conservative projection of 
completing 1.5 testing sessions per week would result in a timeline of 32 weeks or 8 months for completing 
Aim 2, not including results processing/dissemination. 
 
 
 
4. Possible RISKS and protective actions 
For subjects with ALS, there is a risk of falling during transfers between different testing positions. To 
minimize this risk, a clinician will be at the participant’s side at all times to assess comfort and provide 
manual assistance/stabilization as necessary.  
The surface electromyography recording and stimulating electrodes and tape have adhesive backing. 
Therefore, minimal risks such as transient skin irritation at the sites of surface electrode application may 
occur. Areas with excessive hair will be shaved prior to adhesive application. 
Electrical stimulation involves currents up to 100 milliamperes. Electrical pulses may be transiently irritating 
or painful. Stimulation intensity will be reduced, or testing halted, if a subject is too uncomfortable. Electrical 
stimulation of the upper spinal cord may theoretically alter activity in vagal or other autonomic circuits. The 
most likely adverse risks of autonomic activation would be nausea, light-headedness, diaphoresis, or 
syncope. There is no risk of current crossing over cardiac muscle with the electrode configurations used 
in this protocol. Nevertheless, to provide further caution against cardiac damage or arrhythmia, subjects 
who 
have 
significant 
coronary 
artery 
disease 
or 
cardiac 
conduction 
disease, 
implanted 
pacemaker/defibrillators will be excluded from participation. To provide further caution against any adverse 
cardiac or autonomic event, the procedure will be closely monitored for cardiac or dysautonomic side 
effects with continuous pulse oximetry, blood pressure, and spirometric measurements. Additionally, to 
better understand potential autonomic effects of stimulation, subjects may be monitored in real time for 
changes in cardiovascular and respiratory function using three-lead electrocardiography, photo-
plethysmography, and impedance-plethysmography. Any change in mean arterial pressure or pulse 
oximetry of greater than 15% from baseline, accompanied by symptoms such as sudden shortness of 
breath, chest pain, significant headache, or diaphoresis, will lead to immediate cessation of the protocol 
and further medical evaluation. Furthermore, if cardiac or dysautonomic side effects occur during the 
screening visit, the subject will be ineligible for further participation in the study. A medical doctor will be 
on the premises at all times during stimulation protocols. This technique has received formal designation 
by the FDA as Non-significant Risk (Q150053). 
Transcranial magnetic stimulation (TMS) carries several potential risks. Most of these risks are much 
greater during application of repetitive TMS (defined as pulses given at a frequency of 1 per second or 

more frequently), which will not be conducted in this study. We will be using a MagPro X100 device 
(MagVenture). This device has FDA 510(k) clearance (approval #K091940) for peripheral nerve 
stimulation, and has been cleared as a non-significant risk device by this and numerous other IRBs for 
research and clinical use. The most serious risk of TMS is induction of seizures. TMS-induced seizures 
are usually focal, but in some cases can become generalized. To minimize this risk, participants with 
underlying brain injury that increases the risk of TMS-induced seizures will be excluded from participation 
– this includes moderate or severe traumatic brain injury, stroke, tumor, multiple sclerosis, or abscess (see 
full list under Exclusion Criteria). Additionally, participants taking medications that significantly lower 
seizure thresholds, such as anti-psychotics, amphetamines, tricyclic antidepressants, bupropion, and 
dalfampridine will be excluded. Furthermore, the applied stimulus intensity will be kept below 200% of the 
motor threshold for each muscle. This intensity and single-pulse frequency fall far below the recommended 
safe guidelines delineated by an international workshop on TMS safety (Rossi et al. 2009). Furthermore, 
participants with implanted devices with electromagnetic properties, such as spine stimulators, deep brain 
stimulators, vagal nerve stimulators, cardiac pacemakers, cochlear implants, or aneurysm clips, will be 
excluded. The investigator who will be performing the TMS protocol (Noam Harel) is a neurologist 
experienced in treating seizures. There is no risk of seizure from electrical stimulation below the brain, as 
performed in this protocol. 
There is a theoretical risk of repetitive TMS causing acute psychotic or manic symptoms in patients with 
depression. This risk is not clearly above the risk for sham-TMS, and it is not clearly above the natural rate 
of psychotic or manic symptoms that may arise in subjects with depression. Regardless, this protocol does 
not meet the definition of repetitive TMS, and any subject with history of bipolar disease, active psychotic 
symptoms, or history of suicide attempt will be excluded 
TMS pulses generate loud auditory clicks. Hence, all participants will wear earplugs during the procedure. 
TMS may also cause scalp tingling sensations or pain that is almost always mild and transient. This occurs 
approximately half as frequently in participants exposed to sham-stimulation. This is much less common 
using single-pulse TMS than repetitive TMS. Our protocol will use only single-pulse TMS.  
The research team has delivered TMS pulses at 5 to 10-second intervals extensively in prior and ongoing 
IRB-approved clinical studies. A standardized form to assess TMS side effects is used at the end of each 
TMS session. To repeat, the use of only single pulse TMS, as well as all the other precautions and 
exclusion criteria we will follow in our TMS protocol, far exceed the recommended guidelines established 
by an international group of TMS experts85. 
The Brainsight optical TMS tracking system (Rogue Research) uses passive reflectors placed on the 
subject’s head and the TMS magnet to track the magnet’s position and orientation relative to the subject’s 
brain in real time. This is a passive detection device, with no penetrating electromagnetic stimulation. The 
infrared optical tracking portion of the system meets all applicable conformity standards (ANSI/AAMI 
ES60601-1:2005 +C1:2009 +A2:2010; see appendices), The infrared optical tracking portion of this system 
has been incorporated into numerous surgical tracking systems that have obtained FDA 510(k) approval 
in the setting of invasive brain and organ surgery. However, when used in combination with non-invasive 
TMS for research, it is not considered a medical device that requires FDA approval. There is no risk to the 
subject from using this tracking system. 
Study coordinators and research assistants will be trained to conduct all procedures in a safe and effective 
manner that produces reproducible results. Study personnel with experience working with SCI and ALS 
participants will supervise all sessions. All staff will have undergone the appropriate training to use the 
equipment properly and safely. All subjects will be thoroughly questioned after each procedure to ensure 
that all possible adverse events, expected and unexpected, are ascertained. Study personnel will refer 
participants to the proper medical or psychological resources for any identified conditions or problems as 
a consequence of the research. 
In the event of a serious adverse event, it will be reported to the IRB within 24 hours and study interventions 
will be discontinued until the study physician states that it is safe to resume the study. Adverse events will 

be recorded in a data sheet and reported annually to the IRB. When appropriate, necessary medical or 
professional intervention will be provided for any serious or regular adverse event warranting treatment. 
Any unexpected complications that may occur will be discussed with the study physician and/or the 
participant’s personal physician. Dr. Miroslav Radulovic, a board-certified internist, will serve as the study 
physician.  
 
Protection against Risk 
Most of the information that participants provide will not be identifiable. Participant data results will be 
stored on the VA network in a password-protected file. No identifiable information will be linked to this file. 
The study team members will have a separate file of participant contact information, also stored on the VA 
network. Participants will be assured that any “hard copies” of their contact information or data will be kept 
in a securely locked cabinet in a locked private office. This data will not be destroyed. There is minimal risk 
of a breach of confidentiality or data security.  
Study coordinators and research assistants will be trained to conduct all procedures in a safe and effective 
manner that produces reproducible results. Study personnel with experience working with SCI participants 
will supervise all sessions. All staff will have undergone the appropriate training to use the equipment 
properly and safely. All subjects will be thoroughly questioned after each procedure to ensure that all 
possible adverse events, expected and unexpected, are ascertained. Study personnel will refer 
participants to the proper medical or psychological resources for any identified conditions or problems as 
a consequence of the research. 
In the event of a serious adverse event, it will be reported to the IRB within 24 hours and study interventions 
will be discontinued until the study physician states that it is safe to resume the study. Adverse events will 
be recorded in a data sheet and reported annually to the IRB. When appropriate, necessary medical or 
professional intervention will be provided for any serious or regular adverse event warranting treatment. 
A formal Data Safety Monitoring Board will not be needed for this study. 
Provisions for keeping data confidential are established. All electronic data will be kept on the secure VA 
network. All intake forms are de-identified according to HIPAA regulations. Consent forms, along with any 
other forms containing identifiable information, are kept in a locked filing cabinet. Only members of the 
investigative team will be able to use the information. 
Any unexpected complications that may occur will be discussed with the study physician and/or the 
participant’s SCI physician. Dr. Miroslav Radulovic, a board-certified internist, will serve as the study 
physician.  
5. SIGNIFICANCE OF THIS RESEARCH. 
The experiments proposed here address important questions in an entirely unexplored context that 
strongly align with RR&D’s mission. ALS is a 100% VA Service-Connected condition due to its higher 
incidence and prevalence in Veterans41. There is no cure. There is no treatment that reliably reverses or 
halts progression. The rationally-based approach described in this Small Project In REhabilitation study 
will generate the data needed to advance this program to the next phase – the delivery of multiple sessions 
of facilitatory CES in conjunction with physical exercises to attempt to achieve lasting clinical benefit. The 
information obtained in this study may be useful scientifically to the subjects taking part in the study and 
to other researchers and patients. This could provide new information that leads to improved non-invasive 
techniques for strengthening nerve transmission after central nervous system injury and disease.  
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