Motor Point Stimulation and Its Role in Investigating and
Modulating Neural Circuits
Taro Yamashita
Thesis submitted in conformity with the requirements for the degree of
Master of Biomedical Engineering
Institute of Biomaterials and Biomedical Engineering
University of Toronto
Motor point stimulation and its role in investigating and
modulating neural circuits
Taro Yamashita
Master of Biomedical Engineering
Institute of Biomaterials and Biomedical Engineering
University of Toronto
Abstract
Neuromuscular electrical stimulation (NMES) is often used in the rehabilitation of people
with neurological disorders such as spinal cord injury. There are two methods to evoke muscle
contraction via NMES including peripheral nerve stimulation (PNS) or motor point stimulation
(MPS), delivered to the so-named motor points located at neuromuscular junctions. We
hypothesized that, based on the specific location of neuromuscular junctions and the distribution
of muscle spindles, PNS and MPS would differ in their activation of sensory and motor axons,
and that MPS would produce strong antidromic activation. Here we aimed to investigate (1) the
difference of Ia-sensory activation by MPS and PNS, and (2) the antidromic activation of motor
nerve by MPS. We demonstrated that (1) PNS and MPS showed different patterns of motor and
sensory recruitment curves, (2) PNS and MPS differed in inducing reciprocal inhibition, and (3)
MPS induces strong antidromic motor nerve firing sufficient to produce recurrent inhibition of
the SOL H-reflex. These results suggest that distinct differences exist in the motor and sensory
recruitment by PNS and MPS, in that MPS preferentially activates motor axons and induces
antidromic motor nerve firing, while PNS stimulates the sensory and motor branches of the
ii
mixed peripheral nerve. Our findings will help to deepen the current understanding of the
neurophysiology of NMES and hence will contribute to the improvement of therapies using
NMES in future.
iii
Acknowledgments
I thank my supervisor, Dr. Kei Masani, for his support and guidance throughout the completion
of this project.
I thank my committee members, Dr. Kei Masani, Dr. Paul Yoo, Dr. Jose Zarriffa, and Dr. Kristin
Musselman for their advice and supervision.
I thank Dr. Austin Bergquist my contributor for his encouragement and advice provided
throughout the project.
I thank Mr. Azim Rashidi, Ms. Esther Oostdyk, for providing administrative and technical
support at the Rehabilitation Engineering Laboratory.
I thank Mr. Jeffrey Little for providing administrative support through the Biomedical
Engineering program.
I thank the students and staff at the Rehabilitation and Engineering laboratory for making my
time well spent.
I thank the unnamed volunteers who participated in my experiment.
Finally, I thank my family members, my mother, father and sister, and close friends for their
unending support and encouragement.
iv
Table of Contents
Acknowledgments ......................................................................................................................... iv
Table of Contents ........................................................................................................................... v
List of Figures .............................................................................................................................. viii
List of Tables ................................................................................................................................... x
Chapter 1 ........................................................................................................................................ 1
1 Introduction............................................................................................................................. 1
1.1
Motivation .................................................................................................................. 1
1.2 Layout of Thesis ................................................................................................................ 2
Chapter 2 ........................................................................................................................................ 4
2 Literature Review .................................................................................................................... 4
2.1 Spinal Cord Injury ............................................................................................................. 4
2.2 NMES and FES................................................................................................................... 5
2.2.1 NMES and FES Applications ....................................................................................... 5
2.2.2 MPS and PNS ............................................................................................................. 6
2.3 FES-therapy ...................................................................................................................... 8
2.4 Paired Associative Stimulation ....................................................................................... 11
2.5 The H-Reflex ................................................................................................................... 13
2.5.1 H-Reflex and the muscle spindle stretch reflex ....................................................... 13
2.5.2 Recruitment Curves of M-wave and H-reflex (MH-recruitment curve)................... 14
2.6 Reciprocal Inhibition....................................................................................................... 15
2.6.1 The Reciprocal Inhibition Circuit ............................................................................. 15
2.6.2 Reciprocal Inhibition and Spasticity ........................................................................ 17
2.7 Recurrent Inhibition ....................................................................................................... 18
2.8 Clinical Evaluations of Recurrent Inhibition ................................................................... 20
2.9 Testing Recurrent Inhibition ........................................................................................... 20
Chapter 3 ...................................................................................................................................... 22
v
3 Research Objectives .............................................................................................................. 22
3.1 Hypotheses ..................................................................................................................... 22
3.2 Objective 1.................................................................................................................. 22
3.3 Objective 2.................................................................................................................. 22
Chapter 4 ...................................................................................................................................... 24
4 Methodology ......................................................................................................................... 24
4.1 Participants..................................................................................................................... 24
4.2 Apparatus ....................................................................................................................... 25
4.2.1 Digitimer Stimulator ................................................................................................ 25
4.2.3 Stimulation Electrodes ............................................................................................ 27
4.2.4 Electromyography ................................................................................................... 27
4.2.5 Data Acquisition System .................................................................................................. 28
4.2.6 Joint Dynamometer ................................................................................................. 28
4.3 Protocol .......................................................................................................................... 29
4.4 General Set Up ............................................................................................................... 30
4.5 Study 1: Recruitment Curves ..................................................................................... 32
4.6 Study 2: Reciprocal Inhibition ..................................................................................... 33
4.7 Study 3: Conditioning H-Reflex with different timings of MPS................................... 35
4.8 Study 4: Conditioning the H-Reflex with different intensities of MPS........................ 36
Chapter 5 ...................................................................................................................................... 37
5 Results ................................................................................................................................... 37
5.1 Study 1: Recruitment Curves .......................................................................................... 37
5.2 Study 2: Reciprocal Inhibition......................................................................................... 39
5.3 Study 3: Recurrent Inhibition with different timings of MPS ........................................ 41
5.4 Study 4: Recurrent inhibition with different intensities of MPS..................................... 42
Chapter 6 ...................................................................................................................................... 44
6 Discussion .............................................................................................................................. 44
6.1 Study 1: Comparing recruitment curves by MPS and PNS ............................................. 44
6.2 Study 2: Reciprocal Inhibition with MPS or PNS ............................................................. 46
vi
6.3 Study 3: Recurrent Inhibition of the Soleus H-Reflex with different timings of MPS ..... 47
6.4 Study 4: Recurrent Inhibition with different intensities of MPS .................................... 48
6.5 Potential Mechanism of FES therapy ............................................................................. 48
6.6 Limitations ...................................................................................................................... 51
6.7 Future Recommendations .............................................................................................. 51
Chapter 7 ...................................................................................................................................... 53
7 Conclusions............................................................................................................................ 53
References.................................................................................................................................... 54
vii
List of Figures
Figure 1 Modes of electrical stimulation, peripheral nerve stimulation (PNS), motor point
stimulation (MPS). ............................................................................................................... 8
Figure 2 Neural mechanism of FES-therapy PNS excites the entire nerve branch including the
sensory branch including the Ia sensory neuron and the motor branch. Sensory
activation can lead to activation, and reorganization of the sensorimotor cortex resulting
in adaptive plasticity at the cortical level. MPS activates the motor nerve
orthodromically and antidromically. .................................................................................. 10
Figure 3 Paired Associative Stimulation targeting the spinal cord. TMS of the motor cortex
generates a motor valley that travels orthodromically towards the spinal cord (1). A
volley generated by PNS travels antidromically (2) and reaches the spinal cord after the
TMS motor volley to strengthen the synapse leading to long term potentiation (LTP). ... 12
Figure 4 Representative H-reflex pathway(A), At stimulation intensity sufficient to evoke a
large H-Reflex the M-wave is small, however as the M-wave approaches it’s maximal
value no H-reflex is present (B). The M-H Recruitment curves for a single subject are
shown in (C) panel (i) the abscissa shows intensity of stimulation measures in multiples
of motor threshold while the ordinate shows the amplitude of the traces in % Mmax.
(Cii) shows the size of the H-reflex relative to the size of the M-wave, the same data are
shown in panel I and II. (Knikou, 2008). .............................................................................. 14
Figure 5 Testing reciprocal inhibition with different intensities of the test Sol H-reflex with
conditioning stimulation of TA by PNS ISI – 0ms for both conditions. An example of a
single subject from a pilot study conducted in our lab. With a test reflex amplitude of
20% of the maximal H-reflex, no reciprocal inhibition was measured. With a 5% test
reflex, the conditioned H-reflex is significantly depressed due to reciprocal inhibition
(p<0.05). ............................................................................................................................... 16
Figure 6 Reciprocal inhibition circuit from tibialis anterior (TA) to Soleus. .............................. 17
Figure 7 Recurrent inhibition circuit in the soleus muscle. ........................................................ 19
Figure 8 Schematic including the two circuits described in the studies, Ia Reciprocal Inhibition
and Recurrent Inhibition of the Soleus H-Reflex. EMG traces including the M-wave, Hreflex, and F-wave. .............................................................................................................. 21
Figure 9 Digitimer stimulator DS7A............................................................................................. 26
Figure 10 Master 8 Stimulator (left) an Iso-Flex stimulator (right). ........................................... 26
Figure 11 AMT-8 recording EMG system..................................................................................... 27
Figure 12 Powerlab-30 data acquisition system ......................................................................... 28
Figure 13 Biodex-System 3 dynamometer .................................................................................. 29
Figure 14 Study protocol design for each participant. Four studies were divided evenly
between two sessions. In each session, studies were separated by 10 minutes and
sessions were separated by a minimum of two days. Note that the order of Session 1 and
2 were counter-balanced among participants, so this figure indicates the case when
Session 1 was first. .............................................................................................................. 30
Figure 15 General set up for all tasks, all assessments were made on the right leg. ................ 31
viii
Figure 16 Stimulation (MPS) (square electrodes) and recording electrodes (circular electrodes)
for Soleus (A), Stimulating electrodes for TA and SOL (B) Recording electrodes for TA and
PER (C). ................................................................................................................................. 32
Figure 17 Typical examples of recruitment curves by PNS (left) and MPS (middle) from a
representative individual, and MPS group data (right) Data normalized to PNS M-max
value . ................................................................................................................................... 38
Figure 18 The exerted torque data during PNS and MPS for a single participant (left) and the
group (right). ........................................................................................................................ 38
Figure 19 Group data for the Soleus H-Reflex by conditioning TA stimulation delivered
through PNS or MPS. ........................................................................................................... 40
Figure 20 The maximal reciprocal inhibition of Sol H-reflex induced by TA activation by MPS
and PNS. ............................................................................................................................... 40
Figure 22 Normalized H-reflex amplitude from a representative participant for each ISI (left),
and group data for the M-wave (middle) and H-reflex (right) amplitudes. The
conditioning intensity of stimulation was 0.8X the intensity required to evoke Mmax and
the corresponding M-wave was normalized to this value. The intensity of test H-reflex
stimulation was set to 0.8X the intensity required to evoke H-max and the corresponding
H-reflex was normalized to this value. * denotes significant difference from the
unconditioned value (p<0.05). ............................................................................................ 42
Figure 23 Time course of the conditioned SOL H-reflex with different intensities of MPS, pitch
10 mA, MPS first. ................................................................................................................. 43
Figure 24 Testing Recurrent inhibition by conditioning the Sol H-reflex with different
intensities of MPS ................................................................................................................ 43
Figure 25 Example of SOLl EMG during MPS .............................................................................. 45
Figure 26 MPS is able to stimulate the motor efferents orthodromically and generate an
antidromic pulse which can produce an F-wave (top) PNS stimulates the entire nerve
branch leading to stimulation of the Ia afferents which at low stimulation intensities can
generate the H-reflex. ......................................................................................................... 45
Figure 27 Overall model of electrical stimulation by PNS and MPS in relation to sensory
and motor contributions of NMES. .................................................................................. 50
ix
List of Tables
Table 1 Demographic information of the 10 participants. The group mean ± standard
deviation (SD) were described at the bottom. ................................................................... 25
Table 2 Summary of differences between MPS and PNS recruitment curves between M-waves
and H-reflexes . All traces normalized toe the size of the PNS evoked Mmax * denotes
significant difference (p<0.05). ........................................................................................... 38
Table 3 Intensity of the conditioning stimulation for reciprocal inhibition of the Sol H-Reflex
using MPS and PNS .............................................................................................................. 39
x
1
Chapter 1
1 Introduction
1.1 Motivation
Spinal cord injury (SCI) results in pervasive lifelong impairment for individuals and a
substantial cost on the healthcare system. Even people with incomplete spinal cord injuries
(SCI), where individuals maintain some function below the level of injury and which account for
a majority of patients, incur tremendous financial burden. For example, individual costs of
incomplete spinal cord injury can be as high as $347,000 in the first year alone, with lifelong
costs exceeding $1,000,000 (Government of Canada, 2013); In Canada it is estimated that more
than 85,000 people live with SCI and that 11,000 new injuries occur each year (Government of
Canada, 2013); The financial burden is echoed by the personal suffering accompanying SCI with
nearly all SCI patients reporting clinically significant levels of depression (Lim et al., 2017).
Therefore, there is a high motivation to develop therapies that can improve motor function in
individuals with SCI and to reduce the secondary complications of SCI.
Neuromuscular electrical stimulation (NMES) is a technology whereby an electrical
current is applied to the peripheral nervous system to induce muscle contractions in paralyzed
muscles. When NMES is applied to muscles to induce functional activities, such as walking, it is
called as functional electrical stimulation (FES) (Masani & Popovic, 2011). FES can be applied
broadly in two major applications: prosthetic and therapeutic. Prosthetic use of FES replaces or
augments functional motor tasks during patients’ daily lives such as helping foot drop in stroke
survivors. Therapeutic FES can drive motor-relearning, in these applications NMES serves as a
training stimulus which provokes an adaptation of the nervous system, directing beneficial
neuroplasticity (Milos R. Popovic, Masani, & Micera, 2016). Although FES therapy has been
2
shown to be a viable treatment option for patients with neurological impairment including but
not limited to those with spinal cord injuries and stroke, the clinical viability offers exciting
potential for rehabilitation and motor re-learning but to date the neural mechanism of the benefits
is not well understood (Robbins, Houghton, Woodbury, & Brown, 2006).
There are two methods to evoke muscle contraction via NMES including peripheral
nerve stimulation (PNS) or motor point stimulation (MPS), delivered to the so-named motor
points located at neuromuscular junctions. While the neural mechanism induced by PNS has
been well-documented, the one by MPS has not been investigated well. As MPS is often used for
NMES as well as FES, especially FES therapy, the neural mechanism of MPS needs to be
investigated to further understand the mechanism of FES therapy as well as to improve the FES
therapy to assist patients with neurological disability.
1.2 Layout of Thesis
The present thesis includes seven chapters. The first chapter introduces electrical
stimulation as a therapeutic modality of interest to the population of patients with SCI and the
current gap in the knowledge with respect to its neurological mechanism. The second chapter
provides the requisite review of the literature and background information to understand the
current project. The third chapter details the specific purposes of the research and presents the
research hypothesis. The methodology is presented in chapter four, including the apparatus,
experimental protocols, and statistical analyses for the four studies included in the project. The
fifth chapter details the results obtained from the four experiments and the relevant findings and
statistical significance of the data. The results are interpreted and contextualized in the sixth
3
chapter, the discussion. The seventh chapter concludes the project. Additional sections include
Acknowledgments, List of Abbreviations, References and an Appendix.
4
Chapter 2
2 Literature Review
2.1 Spinal Cord Injury
SCI is a serious and life-changing event which can affect every facet of patients’ lives
and imposes an enormous cost on the health care system. Greater than half of all SCIs result in
an incomplete lesion with at least some function retained below the level of injury. For
incomplete SCI (iSCI), the healthcare costs can be as high as $347,000 in the first year with a
lifetime cost of approximately $1,500,000 (Krueger, Noonan, Trenaman, Joshi, & Rivers, 2013) .
To date there exists no treatment which can completely cure the effects of spinal cord injury
(Lim et al., 2017). Treatment strategies will typically include surgical, pharmacological, and
physical methods to help reduce symptoms and regain motor function (McDonald & Sadowsky,
2002). For those patients with iSCI who retain limited motor abilities, physical therapy will
include compensatory strategies aimed to replace lost motor function, with assistive devices, and
restorative strategies designed to encourage motor recovery (Nowak, Euler, & Rupp, 2017). In
these patients, the residual function offers the possibility of motor recovery and improvement in
quality of life post injury. Furthermore, motor recovery can enable patients to participate in
behaviours, such as standing, which help to reduce secondary complications such as pressure
sores, low impact bone fractures, urogenital infections and deep venous thrombosis (BieringSørensen, Hansen, & Lee, 2009). Following from this line of reasoning, there is a substantial
economic and individual gain to developing therapies that can help patients own their recovery,
minimize costs associated with SCI and regain motor function and independence.
5
2.2 NMES and FES
2.2.1 NMES and FES Applications
Neuromuscular electrical stimulation (NMES) uses short trains of electrical pulses to
generate muscle contractions (Sheffler & Chae, 2007). NMES has been used to treat the
symptoms of neurological disorders including SCI (Ragnarsson, 2007). NMES has been
successfully applied in pain management, muscle strengthening, muscular atrophy prevention,
prevention of deep venous thrombosis, improvement of hemodynamic functioning and
cardiopulmonary conditioning (Peckham & Knutson, 2005).
When NMES is used to induce functional movements, it is called FES. There are two
broad classes of FES treatment: Functional (prosthetic) FES and therapeutic FES (Masani &
Popovic, 2011) (Milos R. Popovic et al., 2016). Functional FES is used in assistive devices
where the electrical pulses are coordinated to produce actions; if the user wishes to perform the
function they are dependent on the stimulator as a neuroprosthesis (Masani & Popovic, 2011)
(Milos R. Popovic et al., 2016). Orthotic applications of FES include assistive devices which aid
patients in the acts of standing, walking, reaching, grasping, swallowing, rowing and cycling.
(Sheffler & Chae, 2007)(T. Adam Thrasher, Zivanovic, McIlroy, & Popovic, 2008)((Wheeler et
al., 2002)(Decker, Griffin, Abraham, & Brandt, 2010)(Steele, Thrasher, & Popovic, 2007).
Therapeutic applications of FES are used to address secondary complications from injury and
promote motor relearning. FES has been used as a training tool to produce motor re-learning by
promoting adaptive plasticity in the CNS. This use is called as FES-therapy. In these applications
FES has been successfully applied to re-train grasping in patients with SCI (Milos R. Popovic et
al., 2016)(P. N. Taylor et al., 1999). Motor recovery reduces patients’ dependence on assistive
devices and affords the opportunity for patients to regain functional independence and autonomy
6
leading to improve their quality of life. The development of these therapies demands an
explanation of the neural mechanism through which they promote adaptive neuroplasticity.
2.2.2 MPS and PNS
In many NMES applications including FES applications, electrodes are placed
noninvasively on the skin surface. There are two sites at which NMES can be applied
superficially: 1. over the nerve branch in PNS, and 2. over the muscle belly in MPS (Figure 1)
PNS has been applied therapeutically to foot extensor and flexors to correct drop-foot in
patients who suffer stroke (Granat, Maxwell, Ferguson, Lees, & Barbenel, 1996) (P. N. Taylor et
al., 1999)(Wieler et al., 1999). In PNS, the nerve stimulation flows from cathode to anode and
stimulates the entire nerve branch including the sensory and motor pathways (Bergquist, Wiest,
& Collins, 2012). Motor point stimulation has been often used in FES-therapy in upper limbs (T.
Adam Thrasher et al., 2008) (Alon, Sunnerhagen, Geurts, & Ohry, 2003) (Kowalczewski,
Gritsenko, Ashworth, Ellaway, & Prochazka, 2007) (D. B. Popovic, Popovic, Sinkjær, Stefanovic,
& Schwirtlich, 2004) (M. B. Popovic, Popovic, Sinkjaer, Stefanovic, & Schwirtlich, 2003) (M. B.
Popovic, Popovic, Sinkjær, Stefanovic, & Schwirtlich, 2002) (Milos R. Popovic et al., 2011) (M.
R. Popovic et al., 2005) and lower limbs (T. A. Thrasher, Flett, & Popovic, 2005)(T. A. Thrasher
& Popovic, 2008)(Wieler et al., 1999). Compared to PNS, MPS can be applicable to more
surface muscles, leading the ease of use in FES-therapy (Gobbo, Maffiuletti, Orizio, & Minetto,
2014a). In contrast, PNS can be applicable only when the peripheral nerves innervating the target
muscles are superficially accessible. This limits the availability and potential effectiveness of
PNS as a therapeutic tool. Despite the differences in clinical application the majority of research
into the neural mechanism of FES-therapy has focused on PNS (Everaert, Thompson, Chong, &
Stein, 2010) (Khaslavskaia & Sinkjaer, 2005) (Aiko Kido Thompson & Stein, 2004) (Aiko K.
7
Thompson, Lapallo, Duffield, Abel, & Pomerantz, 2011a)(Aiko Kido Thompson & Stein, 2004).
Meanwhile only one has investigated MPS (Barsi, Popovic, Tarkka, Sinkjær, & Grey, 2008).
The different location of stimulation by PNS or MPS is accompanied by
neurophysiological differences in the two modes of stimulation. Distinct differences in the
pattern of surface EMG traces have been observed including the appearance of the M-wave, the
electrophysiological measurement of muscle contraction and the H-wave which is the electrical
manifestation of the muscle spindle stretch reflex (Bergquist et al., 2012). These differences have
been explored in the context of how these two modes of electrical stimulation recruit motor
axons. It’s believed that PNS activates motor axons through central pathways by activating Iaafferents which produce direct monosynaptic connections with the alpha motor neurons in the
spinal cord (Yoshino Okuma, Bergquist, Hong, Chan, & Collins, 2013). This is in contrast with
MPS in which the axons of the motor neurons are directly depolarized by the electrical
stimulation and thus act through peripheral pathways. The differences in motor recruitment are
important for understanding applications of FES in functional applications, to minimize fatigue,
and discomfort while maximizing the ability to generate contractions. However, the mechanisms
through which PNS and MPS recruit sensory and motor neurons may affect how they can be
used to modify the nervous system in FES-therapy
Distinctions between MPS and PNS are important for optimizing therapeutic applications
of NMES and maximizing the effectiveness, and feasibility of therapy. MPS can be applied to all
muscles and thus offers the ability to help restore function, in therapy, to a greater number of
muscles and in a greater number of movements than PNS. The neurophysiological evidence
points to an important distinction between sensory and motor stimulation by these two
modalities. An implication of these differences would be the target of neuroplastic changes
8
directed by NMES. Sensory stimulation can lead to changes in the sensorimotor cortex while
motor stimulation, which can propagate antidromically, can create changes in the spinal cord.
Understanding these differences is critical to the understanding of how therapies that use NMES
can create lasting, beneficial neuroplastic changes and where these changes occur.
Sensory neuron
PNS
Motor neuron
Antidromic Activation
MPS
Muscle
Figure 1 Modes of electrical stimulation, peripheral nerve stimulation (PNS), motor point
stimulation (MPS).
2.3 FES-therapy
Although motor re-learning following FES-therapy in patients with iSCI is believed to be
the result of neuroplasticity, the exact mechanism is not known (Milos R. Popovic et al.,
2016)(Rushton, 2003)(Sheffler & Chae, 2007). It has been shown that functional recovery
following FES-therapy is superior to conventional physical therapy in patients with iSCI (Milos
R. Popovic et al., 2011). This result casts doubt upon the the possibility that recovery is
9
exclusively due to the result of improved muscular strength and range of motion (Rushton,
2003). Alternatively, it’s been shown that while effective, FES does not differ from conventional
therapy in stroke rehabilitation (McCabe, Monkiewicz, Holcomb, Pundik, & Daly, 2015). Thus
there is a need to understand how FES therapy exerts its effects when it should be applied in
rehabilitation. It is speculated that some adaptations in the central nervous system can take place
at a cortical level or in the spinal cord (
Figure 2).
Changes in cortical neural circuits have been investigated for PNS for wrist extensors
(Spiegel, Tintera, Gawehn, Stoeter, & Treede, 1999) and for MPS with knee extensors (Smith,
Alon, Roys, & Gullapalli, 2003). These studies have found that the sensory and motor cortical
activities were increased following FES-therapy, suggesting FES-therapy can facilitate motor relearning at the cortical level.
It has been hypothesized that FES-therapy induces plastic changes at the spinal level too
(Rushton, 2003). These changes are believed to occur through Hebbian plasticity in which a
synapse becomes strengthened when pre- and post-synaptic events occur within a specific
temporal window (Dan & Poo, 2006) . The modification of spinal synapses provides an elegant
explanation for the adaptations that occur following FES-therapy. It accounts for the unique
neural mechanisms engaged by FES, namely the antidromic (back-propagating) activation of
motor nerve axons. Moreover, it accounts for the temporally sensitive features of successful
FES-therapy.
Evidence for changes in corticospinal excitability, otherwise stated as changes in the
excitability of the cortex and/or the spinal cord have been observed in FES applications using
MPS and PNS (Barsi et al., 2008)(Everaert et al., 2010). With MPS, it was demonstrated that
FES for grasping increases corticospinal excitability, measured as an increase of motor evoked
10
potential induced by transcranial magnetic stimulation (TMS), only when electrical stimulation
was paired with voluntary effort (Barsi et al., 2008). Similar results have been obtained with
drop-foot stimulators, which use PNS, in healthy subjects (Khaslavskaia & Sinkjaer, 2005),
(Aiko K. Thompson, Doran, & Stein, 2006) (Aiko Kido Thompson & Stein, 2004), in patients
with iSCI (Aiko K. Thompson, Lapallo, Duffield, Abel, & Pomerantz, 2011) and in stroke
survivors (Everaert et al., 2010).
Thus for a spinal mechanism to be an important target for the adaptive neuroplasticity
observed with FES-therapy MPS must target these spinal synapses through antidromic firing of
the alpha motor neuron in the spinal cord. Additionally, the absence or effect of Ia afferent firing
calls into question the viability of a cortical mechanism for the neural adaptations of FEStherapy.
Figure 2 Neural mechanism of FES-therapy PNS excites the entire nerve branch including
the sensory branch including the Ia sensory neuron and the motor branch. Sensory
activation can lead to activation, and reorganization of the sensorimotor cortex resulting in
adaptive plasticity at the cortical level. MPS activates the motor nerve orthodromically and
antidromically.
11
2.4 Paired Associative Stimulation
Paired Associative Stimulation (PAS) uses the orthodromic pulse generated by TMS and
the stimulation of peripheral nerves to target specific synapses, and strengthen or weaken them
depending on the specific temporal window within which the two stimuli arrive at the synapse
(Stefan, Kunesch, Cohen, Benecke, & Classen, 2000) (Error! Reference source not found.).
This technique has been used to measure changes in the sensory and motor cortices following
afferent stimulation of peripheral nerves. More recently it has been used to target spinal
synapses, which we call here as PASspinal (Taylor &Martin). By selecting interstimulus intervals
(ISIs) that allow presynaptic TMS and postsynaptic antidromic motor nerve firing to arrive at
spinal synapses, PAS takes advantage of the spike timing dependent plasticity (STDP) (Dan &
Poo, 2006). This allows for the tight control of long term potentiating or depressing effects
depending upon the order at which pre and post synaptic signals reach the synapse, which is
potentially usable for a therapy aiming to induce the neuroplasticity at the spinal neural circuit.
PASspinal has been shown to produce changes in corticospinal excitability that are
correlated with functional outcomes, such as strength of biceps brachii in able-bodied
participants (J. L. Taylor & Martin, 2009). Furthermore, the increases in corticospinal
excitability have been shown to be predictive of functional recovery in patients with iSCI
(Bunday & Perez, 2012). This technique offers exciting possibilities for rehabilitation given that
it can be used to drive neural adaptations to regain instead of reanimating or replacing motor
function. Also, it offers the potential for benefits that persist outside of the treatment session. The
extent and duration of lasting effects remain to be investigated in humans. However, encouraging
findings from animal studies suggest that corticospinal plasticity can lead to persistent motor
recovery (McPherson, Miller, & Perlmutter, 2015). All applications of PASspinal to date use PNS
12
to generate the antidromic motor pulse (J. L. Taylor & Martin, 2009)(Bunday & Perez,
2012)(Shulga et al., 2016). These applications do not account for the effects of sensory
stimulation that accompanies the motor activation, or the role that such stimulation could play in
the effects observed with this therapy.
As with FES-therapy, the neural mechanism which underlies this therapy has yet to be
explained in detail. Ruston’s hypothesis (Rushton, 2003) describes that the antidromic motor
nerve firing induced by MPS during FES-therapy arrives at the cell body shortly after the
descending voluntary motor command arrives, which strengthens the synapse. This mechanism
is equivalent to PASspinal , except for the voluntary command is replaced by TMS.
As with FES-therapy , PASspinal is believed to rely on the antidromic firing of the motor
neuron induced by electrical stimulation.
The ability of MPS to induce this stimulation would
allow it to be used in PAS spinal therapy.
The practicality afforded by MPS would expand the
use of this therapy and as such validation of the antidromic firing properties induced by MPS
remains a crucial step in the understanding of its role in PASspinal therapy.
Figure 3 Paired Associative Stimulation targeting the spinal cord. TMS of the motor cortex
generates a motor valley that travels orthodromically towards the spinal cord (1). A volley
generated by PNS travels antidromically (2) and reaches the spinal cord after the TMS motor
volley to strengthen the synapse leading to long term potentiation (LTP).
13
2.5 The H-Reflex
2.5.1 H-Reflex and the muscle spindle stretch reflex
The H-reflex is one of the most commonly studied reflexes in the human nervous system
and is the electrical analog of the muscle spindle stretch reflex (Knikou, 2008). H-reflexes are
generated through sub maximal stimulation of the afferent nerve leading to monosynaptic
excitation of the α motor neuron. Most muscles can generate H-reflexes however the one most
commonly investigated is the Soleus H-reflex. This is owing to the fact that its amplitude and
spinal inhibitory mechanisms have been used to assess movement, and spasticity in patients with
neurological injuries (Nagel et al., 2017). At low stimulation intensities electrical stimulation
preferentially stimulates the large diameter Ia afferents leading to the elicitation of the H-reflex.
Due to the fact that PNS is able to simulate the entire nerve branch it is capable of stimulating
the entire population of muscle spindles which contribute to the maxima H-reflex, H-max. These
muscle spindles are distributed throughout the muscle and can be uniformly distributed or
aggregated in patterns depending on the function of the muscle (Ovalle, Dow, & Nahirney,
1999). Animal histological analyses have revealed that muscle spindles are bundled in the
oxidative, slow twitch muscle fibers, which are not targeted by FES, which preferentially recruits
large diameter fast twitch muscle fibers (Maier, Simpson, & Edgerton, 1976) (Botterman,
Binder, & Stuart, 1978) Thus by stimulating the nerve branch it is possible to stimulate the
entire population of Ia-afferents. In order to stimulate the same population of afferents by
directly stimulating the muscle, electrical stimulation would need to stimulate the entire muscle
which is not possible with superficial electrical stimulation (Bergquist et al., 2012).
14
2.5.2 Recruitment Curves of M-wave and H-reflex (MH-recruitment
curve)
The H-reflex is elicited by applying electrical stimulation over a mixed peripheral nerve
which includes both the ascending limb of the afferent, sensory neuron and the descending motor
neuron (Figure 4A). At low stimulation intensities electrical stimulation is able to depolarize the
afferent nerve resulting in the H-reflex, which can be measured using electromyography (EMG)
(Figure 4B). As the intensity of stimulation increases the amplitude of the H-reflex increases
correspondingly. However, at higher stimulation intensities that are sufficient to depolarize the
motor nerve, the EMG will show the presence of an electrically evoked motor wave, i.e., Mwave, as well as the H-Reflex (
Figure 4C). With increases in stimulation intensity, the H-reflex will collide with the antidromic
component of the M-wave and thus shrink and eventually disappear from the EMG trace as the
amplitude of the M-wave approaches its maximal value, i.e., M-max. The resulting recruitment
curve has the characteristic sigmoidal shape (
Figure 4C).
Figure 4 Representative H-reflex pathway(A), At stimulation intensity sufficient to evoke a
large H-Reflex the M-wave is small, however as the M-wave approaches it’s maximal value no
H-reflex is present (B). The M-H Recruitment curves for a single subject are shown in (C) panel
(i) the abscissa shows intensity of stimulation measures in multiples of motor threshold while
the ordinate shows the amplitude of the traces in % Mmax. (Cii) shows the size of the H-reflex
relative to the size of the M-wave, the same data are shown in panel I and II. (Knikou, 2008).
15
2.6 Reciprocal Inhibition
2.6.1 The Reciprocal Inhibition Circuit
The reciprocal inhibition (RI) describes the spinal circuit which aids in the coordination
of the relaxation of the antagonist during a contraction of the target muscle (Figure 6). This
circuit was first described by Hoffman who showed that the soleus H-Reflex was decreased
when its antagonist, tibialis anterior (TA) was contracting (Hoffmann, 1952). Since it was
initially described this circuit has been identified to include a single inhibitory interneuron which
receives input from corticospinal, rubrospinal, and vestibulospinal tracts in healthy adults. It has
been observed that RI exerted from ankle dorsiflexors onto plantarflexors occurs as many as
50ms before the onset of contraction supporting the supraspinal initiation of this spinal inhibition
in humans (Knikou, 2008). In spinal cord injury it is believed that the regulation of this pathway
is disrupted by the lesion leading to reductions in RI which contribute to spasticity (C. Crone,
Nielsen, Petersen, Ballegaard, & Hultborn, 1994). Additional research into RI will help scientists
and clinicians better understand how to interpret and modify this circuit to treat patients.
The most commonly studied reciprocal inhibition circuit in humans is between ankle
extensors and flexors, specifically between SOL and TA (Elbasiouny, Moroz, Bakr, &
Mushahwar, 2010). To measure reciprocal inhibition, a conditioning-test paradigm is used
wherein the target muscle’s H-Reflex is elicited 0-4ms after a conditioning stimulus is delivered
to the antagonist at motor threshold (Knikou, 2008). This method has been used with some
success in able-bodied subjects at rest (Clarissa Crone, Hultborn, Jespersen, & Nielsen,
1987)(Kubota et al., 2013)(Perez, Field-Fote, & Floeter, 2003) . However, a substantial number
of groups have reported difficulties in observing reciprocal inhibition from TA to SOL in able-
16
bodied resting subjects (Baret, Katz, Lamy, Pénicaud, & Wargon, 2003)(Pierrot-Deseilligny,
Morin, Bergego, & Tankov, 1981). Two methodological concerns account for some of the
difficulty in studying reciprocal inhibition at rest: 1. The size of the test reflex, and 2.
Contamination of activation of peroneus muscle (PER), which is the muscle adjacent to TA and
which shares a facilitatory connection with SOL (Meunier, Pierrot-Deseilligny, & Simonetta,
1993).
These challenges have been addressed in the research with varying success. Several
groups have reported success with a small test H-reflex of less than 20% of Hmax (Kubota et al.,
2013) (Koyama et al., 2014). However, in our group’s pilot experiments, it was suggested that 20
% Hmax may in fact still be too large to observe the reciprocal inhibition initiated by the small
population of conditioning afferents activated (Figure 5).
EMG (mV)
RI at Different Test Intensities Single Subject
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
*
Unc
Con
20% Mmax
5% Mmax
Figure 5 Testing reciprocal inhibition with different intensities of the test Sol H-reflex with
conditioning stimulation of TA by PNS ISI – 0ms for both conditions. An example of a
single subject from a pilot study conducted in our lab. With a test reflex amplitude of 20%
of the maximal H-reflex, no reciprocal inhibition was measured. With a 5% test reflex, the
conditioned H-reflex is significantly depressed due to reciprocal inhibition (p<0.05).
17
Moreover, only one study has identified a method that is able to distinguish between the
activation of TA or PER (Kubota et al., 2013). This method calculated the ratio of muscle
activation between TA and PER to validate preferential activation of TA when stimulating over
the deep peroneal nerve, stemming from the common peroneal which innervates both TA and
PER. This method is limited by the anatomy of the deep and common peroneal nerves. In many
subjects, these nerves completely overlap, rendering this method ineffective. Furthermore, the
anatomy of the common peroneal nerve activates PER as it is closer to the skin surface.
Addressing these concerns is a challenge and potential benefit of the project.
Figure 6 Reciprocal inhibition circuit from tibialis anterior (TA) to Soleus.
2.6.2 Reciprocal Inhibition and Spasticity
Spasticity is a common symptom of disordered sensory-motor control patients with SCI,
stroke, and multiple sclerosis (MS). It is classically defined as a “motor disorder characterized by
a velocity dependent increase in tonic stretch reflexes with exaggerated tendon jerks, resulting
from hyperexcitability of the stretch reflex as a component of the upper motor neuron
syndrome”(Nielsen, Crone, & Hultborn, 2007). To reflect novel insights into the mechanisms of
18
spasticity the classical definition has been expanded to include “abnormal intra-spinal processing
of primary afferent input” (Pandyan et al., 2005). Spasticity can affect as many as 80% of
patients with iSCI (Elbasiouny et al., 2010). Treatment strategies include invasive surgical
procedures, non-invasive physical therapy as well as pharmaceutical solutions to reduce the
neural and biomechanical symptoms of spasticity The key circuit investigated in the study of
spasticity is that of the disynaptic reciprocal Ia-inhibitory pathway (Nielsen et al., 2007).
The reciprocal inhibition ensures that relaxation of antagonist muscles occurs during
movement (Nielsen et al., 2007). Reductions in reciprocal inhibition disinhibit the target
muscle’s motor neurons, and contribute to the hyperexcitability which produces spasticity
(Nielsen et al., 2007). The reciprocal inhibition Ia-pathway has been consistently shown to be
disrupted in patients with spasticity; however, the nature of changes and the role of this circuit in
the pathophysiology of spasticity is unclear (Elbasiouny et al., 2010). Studies of reciprocal
inhibition in individuals with spasticity following SCI have reported decreases in reciprocal
inhibition (Boorman, Lee, Becker, & Windhorst, 1996) as well as reciprocal facilitation (C.
Crone, Johnsen, Biering-Sørensen, & Nielsen, 2003). However, reciprocal inhibition has been
used to predict functional recovery in the bilateral soleus muscles of patients with SCI (Yasuyuki
Okuma, Mizuno, & Lee, 2002). Addressing the methodological limitations of studying reciprocal
inhibition assessment in resting humans is one of the aims of the project.
2.7 Recurrent Inhibition
Recurrent inhibition describes a circuit originally postulated by Birdsey Renshaw
following the observation that antidromic motor activation resulted in increased interneuron
firing and spinal motor neuron inhibition (Renshaw, 1941) . This inhibition was characterized as
19
having a short latency but long duration (~40ms) (Eccles, Fatt, & Koketsu, 1954). Eccles
examined this circuit in the cat following transection of the dorsal ganglia and identified the
inhibitory interneurons and labeled them Renshaw cells (Eccles et al., 1954). Renshaw cells
inhibit motor neuron firing through recurrent collaterals to provide a means of variable gain
control of the motor system, and improve resolution in the control of motor output (Figure 7)
(Hultborn, Lindström, & Wigström, 1979). Towards this end, it has been observed that changes
in recurrent inhibition are important for the physiological control of standing (PierrotDeseilligny, Morin, Katz, & Bussel, 1977). It has also been observed that this circuit adapts to
demands of high intensity or endurance training (Earles, Dierking, Robertson, & Koceja, 2002).
These insights are relevant to the clinical assessment of recurrent inhibition and the application
of strategies that target this pathway for the rehabilitation of patients with neurological
impairments.
Figure 7 Recurrent inhibition circuit in the soleus muscle.
20
2.8 Clinical Evaluations of Recurrent Inhibition
It has been observed in both patients after stroke and those with iSCI that recurrent
inhibition is increased (Chaco, Blank, Ferber, & Gonnen, 1984). Recurrent inhibition cannot be
observed using the paired H-Reflex technique in the affected side of 53% of patients with stroke
or in 72% of patients with iSCI (Chaco et al., 1984). It is believed that recurrent inhibition is
tonically inhibited by the cortex in healthy individuals which explains the increased inhibition
observed in patients with neurological impairments (Mazzocchio & Rossi, 1997). The observed
changes in recurrent inhibition of the agonist are opposite to those that would contribute directly
to symptoms of spasticity (Elbasiouny et al., 2010). Notwithstanding the direct involvement of
the recurrent inhibitory circuit on symptoms of spasticity, this circuit modulates the activity of
important circuits, namely the reciprocal Ia-inhibitory pathway, and may play a role in the
functional disability of patients (Elbasiouny et al., 2010).
2.9 Testing Recurrent Inhibition
The recurrent inhibition circuit was original described in the cat following transection of
the dorsal root ganglion (Eccles et al., 1954). Absence of afferent activation is critical to the
study of recurrent inhibition (Katz & Pierrot-Deseilligny, 1999). Two methods have been
described to test recurrent inhibition in humans:
1.
The selective antidromic activation of motor nerves using short duration conditioning
stimuli (Veale & Rees, 1973).
2. The paired H-Reflex technique, which uses two stimuli delivered through the same
electrode and the collision of antidromic motor and orthodromic sensory signals to
21
measure recurrent inhibition (Pierrot-Deseilligny, Bussel, Held, & Katz, 1976) (PierrotDeseilligny et al., 1977).
It has been noted that use of a selective antidromic motor nerve firing must be used carefully
in humans with intact dorsal root ganglia due to the orthodromic group I volley, and the complex
afferent discharge which follows the conditioning motor twitch. Thus the two circuits
investigated in the project, reciprocal Ia inhibition and recurrent inhibition of the soleus H-reflex
are summarized in the (Figure 8).
Figure 8 Schematic including the two circuits described in the studies, Ia Reciprocal
Inhibition and Recurrent Inhibition of the Soleus H-Reflex. EMG traces including the Mwave, H-reflex, and F-wave.
22
Chapter 3
3 Research Objectives
3.1 Hypotheses
We hypothesized that, based on the specific location of neuromuscular junctions and the
distribution of muscle spindles, PNS and MPS would differ in their activation of sensory and
motor axons. That is, MPS activates predominately motor pathways while PNS would activate
both motor and sensory pathways. Additionally, it was hypothesized that MPS will produce
strong antidromic activation.
3.2 Objective 1
To investigate the Ia-sensory activation by MPS and PNS. It is known that both MPS
and PNS activate motor pathways. That is, the presence of the electrophysiological trace, i.e., the
M-wave, in both modalities confirm that they both act on motor pathways. However, it is not
clearly revealed whether both of MPS and PNS activate the Ia-afferent similarly. As mentioned
above, H-reflex can be evoked by PNS while it is absent in MPS (Bergquist et al., 2012),
suggesting that there is discrepancy in the activation pattern between MPS and PNS. In this
thesis, we investigated the Ia-sensory activation of MPS directly using recruitment curves, which
confirms the abovementioned previous finding (Study 1) and indirectly through the activation of
the disynaptic reciprocal inhibition Ia-pathway (Study 2).
3.3 Objective 2
To investigate antidromic activation of MPS by testing recurrent inhibition. It is
known that PNS generates antidromic activation on motor nerve, while no investigation has been
done for MPS. As abovementioned, the antidromic activation is a condition for PASspinal and
23
FES therapy. Thus, in this thesis, we investigated whether MPS induced the antidromic
activation on motor nerve by testing recurrent inhibition. The activation of the Renshaw cell is
proportional to the strength of the antidromic volley and the induced recurrent inhibition. Thus
recurrent inhibition provides a measure of the strength of the volley which reaches the cell body
(Katz & Pierrot-Deseilligny, 1999).
24
Chapter 4
4 Methodology
Four studies are included in the thesis. In Study 1 I compared the M-H recruitment curves
between MPS and PNS of SOL. In Study 2 I tested reciprocal inhibition of SOL using MPS and
PNS of TA. In Study 3 and 4, recurrent inhibition of the SOL H-Reflex was assessed using
varying timings (Study 3) and intensities (Study 4) of MPS respectively. All measurements were
made on the right leg.
4.1 Participants
Ten able-bodied participants (4 females and 6 males; mean age 25.7 ± 5.7 years) with no
known signs of neurological or musculoskeletal impairments participated (Table 1).
Experiments were conducted in accordance with the Declaration of Helsinki and were approved
by the Research Ethics Board of the University Health Network in Toronto, Canada. All
participants gave written informed consent to participate in the study after receiving a detailed
explanation about the purposes, benefits, and risks associated with participation in the study.
25
Table 1 Demographic information of the 10 participants. The group mean ± standard
deviation (SD) were described at the bottom.
Participant
Age
Sex
Height (cm)
Weight (kg)
1
2
3
4
5
6
25
33
19
34
26
34
M
M
F
M
F
M
183
183
160
178
164
179
92
81
59
75
68
77
7
21
F
162
55
22
21
22
25.7 ± 5.6
F
M
M
175
182
174
174± 8
78
79
73
73.7± 10.2
8
9
10
Mean ± SD
4.2 Apparatus
4.2.1 Digitimer Stimulator
A general purpose single channel constant current electrical stimulator (DS7A, Digitimer,
Welwyn Garden City, UK) (referred to as a Digitimer stimulator afterward) was used to apply
electrical pulses to the posterior tibial nerve to induce H-Reflexes (Figure 9). The stimulator had
a single cathode and anode output that could be connected to stimulation electrodes. The
stimulator was triggered via TTL pulses programmed using a custom script.
26
Figure 9 Digitimer stimulator DS7A
A second stimulator (ISO-Flex and Master-8, A.M.P.I, Jerusalem, Israel) was used to
produce pair-wise stimulation in conjunction with the digitimer stimulator (referred to as a
Master-8 stimulator afterward)(Figure 10).
Figure 10 Master 8 Stimulator (left) an Iso-Flex stimulator (right).
27
4.2.3 Stimulation Electrodes
Self-adhesive surface electrodes (Axelgaard, Fallbrook, USA) were used to deliver
electrical stimulation. A square, 5X5 cm, electrode was used as the anode for conditioning
stimulation, while a circular electrode, 3.2cm round, was used as the cathode for conditioning
stimulation to elicit the H-reflex. MPS was delivered using 3.2cm round electrodes.
4.2.4 Electromyography
EMG was used to measure the muscle activity from the soleus (SOL), tibialis anterior
(TA) and peroneus (PER) muscles using adhesive foam electrodes (1.89 cm, Covidien,
Mansfield, MA, US) in a bipolar configuration. The electrodes were placed parallel to the
predicted path of the muscle fibers with a ~1-cm interelectrode distance. The common reference
electrode was placed on the lateral malleolus of the right ankle.
EMG signals were amplified 500 times and band-pass filtered at 10-1,000 Hz using an
EMG amplifier (AMT-8 System, A-Tech Instruments, Toronto, Canada) (Figure 11).
Figure 11 AMT-8 recording EMG system
28
4.2.5 Data Acquisition System
A 16 channel data acquisition system (PowerLab /30 Series, ADInstruments, Colorado
Springs, USA) was used to collect and store all analog signals with appropriate software on a
laptop computer (Figure 12).
Figure 12 Powerlab-30 data acquisition system
4.2.6 Joint Dynamometer
An electrical dynamometer (Biodex System 3, Biodex Medical Systems, Shirley, NY,
USA) was used to adjust subjects’ position and joint angles and hold the leg and foot in place
(Figure 13). Only the right knee extension attachment and footplate were used for this
experiment.
29
Figure 13 Biodex-System 3 dynamometer
4.3 Protocol
The four studies were performed over two sessions (Figure 14). One session lasted no
longer than two hours. The experiment was conducted over two sessions that were separated by a
minimum of 48 hours. Session 1 involved Study 1 (recruitment curve recordings) and Study 2
(reciprocal inhibition recordings), while Session 2 involved Study 3 (conditioning H-Reflex with
different timings) and Study 4 (conditioning H-Reflex with different intensities). The orders of
Study 1 and 2 in Session 1, Study 3 and 4 in Session 2, and Session 1 and 2 were counterbalanced among participants. The participant was instructed not to perform vigorous physical
30
activity the day prior to the first session or in the intervening days between experimental
sessions.
Figure 14 Study protocol design for each participant. Four studies were divided evenly
between two sessions. In each session, studies were separated by 10 minutes and sessions
were separated by a minimum of two days. Note that the order of Session 1 and 2 were
counter-balanced among participants, so this figure indicates the case when Session 1 was
first.
4.4 General Set Up
The participant was seated in the Biodex, with the right leg semi-flexed at the hip (110°),
at the knee (120°), and plantar flexed at the ankle (110°) (Figure 15). The right foot was
strapped to a foot plate.
31
Figure 15 General set up for all tasks, all assessments were made on the right leg.
For each session, the participant’s right lower limb was cleaned with isopropyl alcohol
wipes and allowed to dry. All tasks required EMG recording of SOL. The recording electrodes
for SOL were placed on the muscle belly at a distance of one third of that from the lateral
malleolus of the right ankle to the head of the fibula (Figure 16). The electrodes were carefully
placed over SOL and positioned to avoid overlap with the gastrocnemius muscle. Recordings
from SOL were taken from the medial and lateral sides of SOL, however, due to the similarity in
data recorded from these two sites and to avoid excessive repetition only the data from the lateral
side of SOL are included in the results.
In Session 1 (Study 1 and 2), when testing reciprocal inhibition, EMG from TA was
recorded from the muscle belly at a point 6-10cm distal and ventral to the head of the fibula.
32
EMG from PER was recorded over the muscle belly at a point 6-10cm distal from the head of the
fibula.
In all cases of SOL, TA and PER EMGs, the reference electrode was located at the lateral
malleolus of the right ankle.
Figure 16 Stimulation (MPS) (square electrodes) and recording electrodes (circular
electrodes) for Soleus (A), Stimulating electrodes for TA and SOL (B) Recording electrodes
for TA and PER (C).
4.5 Study 1: Recruitment Curves
Stimulation Paradigm. PNS was delivered to SOL either over the posterior tibial nerve
(PTN) while MPS was delivered over the motor point on SOL (Figure 16). In both cases, 1-ms
rectangular wave pulses from the constant current stimulator was used. Stimulation over the PTN
was delivered through two adhesive gel electrodes arranged in a monopolar configuration. The
anode was placed on the anterior aspect of the thigh above of the patella and the cathode was
placed over the PTN in the popliteal fossa at a location where PNS evoked a motor response with
the lowest threshold of stimulation intensity. MPS was delivered using adhesive gel electrodes
with the cathode on the motor point and the anode on the mirrored location on the opposite head
33
of the SOL across the tibial axis (Figure 16Error! Reference source not found.A). The motor
point was identified using a probe electrode as the location where the soleus muscle was
activated with the lowest motor threshold (MT) (Gobbo, Maffiuletti, Orizio, & Minetto, 2014b).
The recruitment curves of M-wave and H-reflex were recorded separately for PNS and
MPS of SOL. To construct the recruitment curves, 5 electrical pulses (width, 1msec) were
delivered at 0.1 Hz. Stimulation intensity was initially set at a sub-motor threshold level and was
gradually increased in ~2mA increments up to 1.2 times the minimum intensity required to elicit
the maximal M-wave (M-max). The exerted torque was also measured at each stimulation.
Statistical analyses. The main measurements from the recruitment curve were the
maximal H-reflex (Hmax) and M-waves (Mmax). Each of Hmax and Mmax was compared
between MPS and PNS using a paired t-test. Further, the percentage of Hmax to Mmax (Hmax in
%Mmax) was also compared similarly. The exerted torque was compared between MPS and PNS
using one-way ANOVA. The significance level was set at P < 0.05.
4.6 Study 2: Reciprocal Inhibition
Test stimulation. The soleus H-reflex and M-wave were induced by stimulating the PTN.
The test stimulation intensity was set to evoke a SOL H-reflex equal to 5% of M-max to the
method proposed by Meinck (Meinck, 1980). Throughout the trials, the M-wave was carefully
monitored to assess changes in baseline excitability. The stimulation intensities were set
according to the values collected in the recruitment curves from Study 1.
Conditioning stimulation. To test reciprocal inhibition, the SOL H-reflex was conditioned
by a stimulation of TA with PNS or MPS. PNS of TA was delivered to the deep peroneal nerve.
The cathode was placed distally and ventrally to the head of the fibula and the anode was placed
34
~ 2 cm proximally and ventrally to the head of the fibula (Perez et al., 2003). Great care was
taken to select the optimal stimulation site which minimized activation of PER with maximal TA
activation. The absence of PER activity was confirmed by visual inspection and EMG of PER.
MPS of TA was delivered by stimulating the motor point of TA, which was identified by probing
the TA muscle with a pen electrode to determine the points with the lowest motor threshold. For
TA MPS, the cathode was placed over the motor point and the anode was placed parallel to the
muscle fiber direction with an interelectrode distance of ~1cm. For both MPS and PNS the
conditioning stimulation intensity was set to 1.0 times MT, which produced the smallest
perceivable muscle twitch, confirmed by visual inspection, as well as palpation of the TA tendon
(Kubota et al., 2013). For both MPS and PNS conditioning stimulation was comprised of single
rectangular pulses with a 1 msec duration (Perez et al., 2003).
Testing paradigm. A SOL H-reflex conditioning test paradigm was used to test reciprocal
inhibition with MPS or PNS of TA as the conditioning stimulation (Crone et. Al. 1990).
Conditioned and unconditioned H-reflexes were randomly presented. The interstimulus intervals
(ISIs) for the conditioned reflexes ranged from -1 to 3ms, where TA stimulation came first. For
each condition and each ISI, 12 reflexes were evoked that was averaged to represent the
participant’s value. For each participant the value of the conditioned H-reflexes were normalized
to the unconditioned value.
Statistical analyses. One sample t-tests, with Bonferonni correction were used to compare
how the conditioned H-reflexes for PNS and MPS differed from 1, which is equivalent to the
normalized unconditioned value. To test the maximal amount reciprocal inhibition evoked by
PNS and MPS, the ISI that produced the largest inhibition for each participant was aggregated
and compared to 1 using a one sample t-test. The significance level was set at P < 0.05.
35
4.7 Study 3: Conditioning H-Reflex with different timings of MPS.
To study recurrent inhibition, MPS of SOL was used to condition the SOL H-reflexes in a
pair-wise fashion. Prior to the experiment MPS and PNS, MH-Recruitment curves were
constructed using the same method as in Study 1 to obtain the maximal values for the H-Reflex
and M-waves so as to appropriately set the intensity of stimulation in testing. The H-Reflex
amplitude for the test stimulation was set to 80% of H-max, the intensity of MPS for the
condition stimulation was set to 80% of SOL M-max. These values were selected to allow for a
sufficiently strong conditioning stimulus to produce recurrent inhibition as well as a sufficient
test reflex to reveal large changes in inhibition. Both stimulations were comprised of single
rectangular pulses with 1 msec duration. The ISI of the paired pulses increased from 0 to 500
msec with a 50msec pitch, with MPS first. This ISI was set based on the established duration of
recurrent inhibition in humans, which typically lasts ~40ms (Eccles et al., 1954) Five test
reflexes were recorded at each ISI. These reflexes were stored offline using the data acquisition
system with a sampling frequency of 40 KHz, and analyzed using a custom script on a
computational software (Matlab ver. 2015a, Mathworks, Natick, MA, US).
Statistical Analyses. The conditioned SOL H-reflexes were normalized relative to the
unconditioned H-Reflexes. One sample t-tests with Bonferroni correction were used to test
whether the normalized H-reflex amplitudes were equivalent to 1 or not, at each latency (0 to
500ms), with an adjusted alpha level of 0.0045 (0.05/11).
36
4.8 Study 4: Conditioning the H-Reflex with different intensities of MPS.
To measure the amount of recurrent inhibition that could be evoked by MPS, the SOL HReflex was conditioned using different intensities of conditioning MPS. The same stimulation
locations were used as in Study 3. The ISI between conditioning stimulation (SOL MPS) and the
testing stimulation (H-Reflex) was maintained at 50msec, with MPS first. The intensity of
conditioning MPS stimulation was increased from 10 to 100mA with a pitch of 10mA. Five
responses were recorded at each intensity.
Statistical Analyses. The conditioned SOL H-reflexes were normalized to the amplitude
of the unconditioned H-reflexes. One sample t-tests with Bonferonni correction were used to test
whether the normalized H-reflex amplitudes were equivalent to 1 or not, at each intensity (10100 mA) with an adjusted alpha level of 0.005(0.05/10).
37
Chapter 5
5 Results
5.1 Study 1: Recruitment Curves
Figure 17 shows the M-H recruitment curves for PNS (left) and MPS (middle) for a
representative participant as well as the Group data for the MPS recruitment curves (right.). Note
that similar group data for the PNS recruitment curve could not be produced due to high
heterogeneity in the threshold for H-reflex activation across participants. As seen in this figure,
robust H-reflexes were evoked during PNS, which was seen in all participants. However, Hreflexes during MPS were small and rarely present during stimulation, i.e., with MPS, only 4
subjects showed consistently measurable waveforms at the period of H-reflex. The Mmax was
about similar between the PNS and MPS ones.
Table 2 summarizes the Mmax, Hmax and Hmax in %Mmax . There was not a significant
difference in Mmax between PNS and MPS (p = 0.818). There was a significant difference in
Hmax (p=0.000435). Hmax in %Mmax was significantly larger (p =0.00007109) for PNS compared
to MPS.
The exerted torque at each stimulation intensity for each of PNS and MPS is shown in
Figure 18. In both of the representative data (left) and the group data (right), it is shown that
both of PNS and MPS generated similar joint torque. There was no statistical difference between
PNS and MPS in the exerted torque (F = 0.987, p = 0.325).
38
Figure 17 Typical examples of recruitment curves by PNS (left) and MPS (middle) from a
representative individual, and MPS group data (right) Data normalized to PNS M-max
value .
Table 2 Summary of differences between MPS and PNS recruitment curves between Mwaves and H-reflexes . All traces normalized toe the size of the PNS evoked Mmax * denotes
significant difference (p<0.05).
PNS
MPS
1. 00 ±0.253
0.963 ±0.401
0.477*± 0.231
0.0428*±0.0402
100
90
80
70
60
100
90
60
50
40
30
20
10
80
MPS
0
50
PNS
30
4
20
6
70
Torque [nM]
8
2
Group
8
7
6
5
4
3
2
1
0
40
Single Participant
10
Mmax
(mV)
Hmax
(mV)
Stimulation Intensity [mA]
Figure 18 The exerted torque data during PNS and MPS for a single participant (left) and
the group (right).
39
5.2 Study 2: Reciprocal Inhibition
The average intensity of conditioning stimulation for PNS was 6.9mA ± 3.6, for MPS it
was 6.8mA ± 3.3 (Table 3). A paired t-test revealed that there was no difference in the
conditioning stimulation intensities between MPS and PNS (p = 0.964).
Table 3 Intensity of the conditioning stimulation for reciprocal inhibition of the Sol HReflex using MPS and PNS
Participant
Intensity of MPS (milliIntensity of PNS (milliAmp)
Amp)
1
7.5
11.8
2
4.0
2.0
3
3.5
3.4
4
3.7
3.5
5
7.0
6.7
6
11.9
7.9
7
14.0
11.4
8
7.8
8.7
9
2.5
3.8
10
7.0
9.0
Average
6.9 ± 3.6
6.8 ± 3.3
Figure 19 shows the result of the Soleus H-Reflex amplitude conditioned by TA stimulation
delivered through PNS or MPS. The one sample t-tests revealed significant inhibition with
conditioning stimulation delivered by PNS at the 0ms ISI (p = 0.0079) when compared to 1,
indicating reciprocal inhibition. No significant differences at any of the ISIs tested were
observed for MPS.
To further examine the differences in reciprocal inhibition induced by PNS and MPS the
ISI which produced the maximal inhibition were analyzed and compared to 1 using a one sample
t-test. At the point of maximal inhibition, the H-reflex was significantly depressed to 71.6% ±
29.6% (p < 0.0001) of the unconditioned value and with MPS it was not significantly inhibited to
94.5% ± 40% (p = 0.285) of the unconditioned value (Figure 20).
40
Figure 19 Group data for the Soleus H-Reflex by conditioning TA stimulation delivered
through PNS or MPS.
Figure 20 The maximal reciprocal inhibition of Sol H-reflex induced by TA activation by
MPS and PNS.
41
5.3 Study 3: Recurrent Inhibition with different timings of MPS
Figure 21 Time course of the conditioned Sol H-reflex with different latencies of Sol MPS,
pitch 50ms, MPS first.
shows the timecourse of the conditioned the Sol H-reflex with different latencies of Sol MPS.
Depending on the ISI, it is shown that the H-reflex amplitude was modified.
In Figure 21 Normalized H-reflex amplitude from a representative participant for each ISI
(left), and group data for the M-wave (middle) and H-reflex (right) amplitudes. The
conditioning intensity of stimulation was 0.8X the intensity required to evoke Mmax and
the corresponding M-wave was normalized to this value. The intensity of test H-reflex
stimulation was set to 0.8X the intensity required to evoke H-max and the corresponding
H-reflex was normalized to this value. * denotes significant difference from the
unconditioned value (p<0.05).
, the left panel shows the normalized H-reflex amplitude from a representative participant for
each ISI. It is shown that a strong inhibition occurred for ISIs of 0ms – 100ms, while maintaining
a constant M-wave size. In Figure 21 Normalized H-reflex amplitude from a representative
participant for each ISI (left), and group data for the M-wave (middle) and H-reflex (right)
amplitudes. The conditioning intensity of stimulation was 0.8X the intensity required to
evoke Mmax and the corresponding M-wave was normalized to this value. The intensity of
test H-reflex stimulation was set to 0.8X the intensity required to evoke H-max and the
corresponding H-reflex was normalized to this value. * denotes significant difference from
the unconditioned value (p<0.05).
, the middle and right panels show the group data for the M-wave and H-reflex
amplitudes, respectively. The t-tests revealed that the H-reflex was smaller than 1 at the 0ms (p <
0.0001), 50ms (p < 0.00001) , 100ms (p = 0.008), 350ms (p = 0.006), 400ms (p = 0.003), 450ms
(p = 0.004), and 500ms (p = 0.006). There was no significant difference at 150ms (p =0.561),
200ms (p = 0.797), or 250ms (p = 0.507) or 300ms (p=0.04), timepoints.
42
ISI =
0 ms
100 ms
200 ms
300 ms
400 ms
500 ms
M Wave induced by MPS
Conditioned H-wave induced by
PNS
Figure 21 Time course of the conditioned Sol H-reflex with different latencies of Sol MPS,
pitch 50ms, MPS first.
Figure 21 Normalized H-reflex amplitude from a representative participant for each ISI
(left), and group data for the M-wave (middle) and H-reflex (right) amplitudes. The
conditioning intensity of stimulation was 0.8X the intensity required to evoke Mmax and
the corresponding M-wave was normalized to this value. The intensity of test H-reflex
stimulation was set to 0.8X the intensity required to evoke H-max and the corresponding
H-reflex was normalized to this value. * denotes significant difference from the
unconditioned value (p<0.05).
43
5.4 Study 4: Recurrent inhibition with different intensities of MPS
Figure 23 shows a typical timecourse of the Sol H-reflex conditioned with different
intensities of MPS. Depending on the MPS intensities, it is shown that the H-reflex amplitude
was modified.
In Figure 24, the left panel shows the normalized H-reflex amplitude from a representative
representative participant for each conditioning MPS intensity. M-wave induced by MPS
increased along the MPS intensity, while H-reflex amplitude decreased along the MPS intensity.
In Figure 23 Testing Recurrent inhibition by conditioning the Sol H-reflex with different
intensities of MPS
44
, the middle and right panels show the group data for the M-wave induced by MPS and
H-reflex amplitudes, respectively. The t-tests revealed that the M-wave was smaller than 1 at
10mA (p < 0.000001), 20mA (p < 0.00001 ) , 30mA (p < 0.00001) 40mA (p = 0.003) and no
significant difference was observed at 50mA (p = 0.0278), 60 mA (p = 0.0645) , 70mA
(p=0.101), 80mA (p=0.438) , 90mA (p=0.580) or 100 (p = 0.890). Also it was revealed that the
H-reflex was smaller than 1 at 30mA (p = 0.003), 40mA (p = 0.003), 50mA (p = 0.001), 60mA
(p = 0.001), 70mA (p < 0.001 ), 80mA (p < 0.0001), 90mA (p < 0.0001), and 100mA (p <
0.0001
Figure 22 Time course of the conditioned SOL H-reflex with different intensities of MPS,
pitch 10 mA, MPS first.
45
Figure 23 Testing Recurrent inhibition by conditioning the Sol H-reflex with different
intensities of MPS
46
Chapter 6
6 Discussion
6.1 Study 1: Comparing recruitment curves by MPS and PNS
The comparison of recruitment curves by PNS and MPS demonstrated similar levels of
muscle contraction, as evidenced by the amplitude of the M-wave (Error! Reference source not
found.) as well as the exerted torque Error! Reference source not found.. This indicates that
the activated muscle fibres by PNS and MPS were about equivalent. The H-reflex shows a clear
recruitment pattern when elicited by PNS as expected. However, the H-reflex induced by MPS
was quite different from the one by PNS (Error! Reference source not found.). That is, the Hreflex induced by MPS is significantly smaller than that evoked by PNS and is at maximal
amplitude with a large M-wave (Figure 24 Example of SOLl EMG during MPS
). The H-reflex is the electrical analog of the muscle spindle stretch reflex and is the direct
electrophysiological manifestation of Ia-afferent activation (Knikou, 2008). Its magnitude can be
used to quantify the proportion of Ia afferent activation of the mixed peripheral nerve, and as
such its absence during MPS can indicate an absence of Ia-afferent activation.
The pattern of activation by MPS is not indicative of an H-Reflex but rather an F-wave.
That is, the small amplitude of the wave, its persistence at high intensities of stimulation, unlike
the H-reflex elicited by PNS (Mayer & Feldman, 1967). For example, when stimulated by PNS
the H-max value was approximately 40%Mmax compared to 4% when elicited by MPS. This is
consistent with the amplitude of the F-wave which in able bodied subjects rarely exceeds 5% of
the maximal M-wave (Eisen & Odusote, 1979); the amplitude of the F-wave amplitude was
larger at higher stimulation intensities; a defining feature of F-waves when elicited by PNS
(Congiu et al., 2017). .
47
The findings clearly demonstrate that an H-reflex is not evoked by MPS and that the
waveform that is generated is more likely to in fact be an F-wave (Figure 24 Example of SOLl
EMG during MPS
). This absence of an H-reflex suggests that MPS does not activate the Ia-afferent which are
responsible for the reflex when stimulated by PNS to a meaningful degree. The findings suggest
a model in which PNS strongly stimulates the Ia afferents due to the stimulation of the nerve
branch while MPS stimulates predominately the motor efferents at the motor point (Figure 25
MPS is able to stimulate the motor efferents orthodromically and generate an antidromic
pulse which can produce an F-wave (top) PNS stimulates the entire nerve branch leading to
stimulation of the Ia afferents which at low stimulation intensities can generate the Hreflex.
).
Figure 24 Example of SOLl EMG during MPS
Figure 25 MPS is able to stimulate the motor efferents orthodromically and generate an
antidromic pulse which can produce an F-wave (top) PNS stimulates the entire nerve
branch leading to stimulation of the Ia afferents which at low stimulation intensities can
generate the H-reflex.
48
6.2 Study 2: Reciprocal Inhibition with MPS or PNS
The reciprocal inhibition was induced by PNS at an ISI of 0 ms, while not by MPS
(Figure 19). That is, at the point of maximal inhibition, PNS was able to significantly inhibit the
H-reflex to 71% of the unconditioned value, while MPS had no significant change on the Hreflex (
Figure 20). The conditioning stimulation for both modalities was set to motor threshold with a
barely perceptible M-wave or presence of a perceived twitch by palpation of the TA tendon.
This absence of reciprocal inhibition with MPS lends further support to the
predominately motor activation pattern with this mode of electrical stimulation. In the reciprocal
Ia inhibitory pathway, the afferent stimulation of the TA leads to the activation of the Iainhibitory interneuron and subsequent depression of the SOL H-reflex (Figure 6). The presence
and amount of this inhibition is indicative of Ia-afferent activation. MPS was unable to induce
reciprocal inhibition presumably due to an absence or insufficient threshold of afferent
stimulation to depolarize the RI Ia inhibitory interneurons at motor threshold of stimulation.
A notable finding from the study was that maximal inhibition was observed at 0ms for
the group data. This finding differs from other studies of the TA to SOL reciprocal inhibition in
that other groups report maximal inhibition occurring at 2-3ms (Crone et al., 1987)(Perez et al.,
49
2003). The inhibition observed at this latency can be attributed to the amplitude of the H-reflex
used in testing (5%) and the low stimulation intensity used to condition the test reflex 1.0XMT
conditioning TA stimulation. The low intensity of stimulation preferentially activates the highest
diameter sensory fibers and therefore can account for the conduction velocities resulting in the
difference in ISI being less in the current study at 0ms than has been seen in other research.
6.3 Study 3: Recurrent Inhibition of the Soleus H-Reflex with different
timings of MPS
Study 1 showed that the MPS induces F-wave, indicating that the MPS induces
antidromic motor nerve firing. In Study 2, the antidromic motor nerve firing was further
investigated by measuring recurrent inhibition at different interstimulus intervals of MPS and the
SOL H-reflex evoked by PNS. Antidromic firing of the motor nerve activates Renshaw cells, a
class of inhibitory interneurons, which provide feedback control of the firing motor neuron
(Figure 7). Recurrent inhibition occurs at a later latency and results in long lasting inhibition
(Renshaw, 1941). We sought to assess the ability of MPS to induce recurrent inhibition of the
SOL H-Reflex via the antidromic motor nerve firing by MPS.
A strong inhibitory effect was observed at ISIs less than 100ms, with complete inhibition
of the soleus H-Reflex at ISIs of 0ms and 50ms (Figure 21 Normalized H-reflex amplitude
from a representative participant for each ISI (left), and group data for the M-wave
(middle) and H-reflex (right) amplitudes. The conditioning intensity of stimulation was
0.8X the intensity required to evoke Mmax and the corresponding M-wave was normalized
to this value. The intensity of test H-reflex stimulation was set to 0.8X the intensity
required to evoke H-max and the corresponding H-reflex was normalized to this value. *
denotes significant difference from the unconditioned value (p<0.05).
). Recurrent inhibition lasts approximately 40ms, and therefore these results are consistent with
recurrent inhibition studied using the paired H-reflex technique (Katz & Pierrot-Deseilligny,
1999). The intensity of conditioning stimulation was high, being almost at the maximal motor
activation possible by MPS. This results in strong inhibition of the H-reflex to <9% of the
unconditioned value (Figure 21 Normalized H-reflex amplitude from a representative
50
participant for each ISI (left), and group data for the M-wave (middle) and H-reflex (right)
amplitudes. The conditioning intensity of stimulation was 0.8X the intensity required to
evoke Mmax and the corresponding M-wave was normalized to this value. The intensity of
test H-reflex stimulation was set to 0.8X the intensity required to evoke H-max and the
corresponding H-reflex was normalized to this value. * denotes significant difference from
the unconditioned value (p<0.05).
). The intensity of the conditioning stimulus also resulted in longer lasting inhibition with the Hreflex being inhibited up to 40% of the unconditioned value at the 100ms ISI (Figure 21
Normalized H-reflex amplitude from a representative participant for each ISI (left), and
group data for the M-wave (middle) and H-reflex (right) amplitudes. The conditioning
intensity of stimulation was 0.8X the intensity required to evoke Mmax and the
corresponding M-wave was normalized to this value. The intensity of test H-reflex
stimulation was set to 0.8X the intensity required to evoke H-max and the corresponding
H-reflex was normalized to this value. * denotes significant difference from the
unconditioned value (p<0.05).
). The H-reflex returned to normal at 150 ms and remained identical to the unconditioned value
at ISIs up to 250ms. Inhibition was observed at the later latencies from 250ms to 500ms. This
can be attributed to the sensory activation induced by the MPS generated soleus contraction.
Thus we have provided a further evidence that MPS induces antidromic motor firing,
which induced recurrent inhibition (Figure 21 Normalized H-reflex amplitude from a
representative participant for each ISI (left), and group data for the M-wave (middle) and
H-reflex (right) amplitudes. The conditioning intensity of stimulation was 0.8X the intensity
required to evoke Mmax and the corresponding M-wave was normalized to this value. The
intensity of test H-reflex stimulation was set to 0.8X the intensity required to evoke H-max
and the corresponding H-reflex was normalized to this value. * denotes significant
difference from the unconditioned value (p<0.05).
).
6.4 Study 4: Recurrent Inhibition with different intensities of MPS
In addition to Study 3, we further tested recurrent inhibition of the SOL H-reflex using
MPS delivered at a consistent ISI of 50ms (MPS first) while varying the intensity of stimulation.
51
To exclude the possibility of antidromic collision the conditioning ISI was set to 50ms.The
average H-reflex latency for the group data was 40± 4ms. The 50ms conditioning latency thus
ensured that collision of the test-reflex with the antidromic conditioning stimulus could not
account for any observed depression.
The amplitude of the test reflex decreased to 9.1% ± 11.1% of the unconditioned value,
as the amplitude of the M-wave for the conditioning MPS stimulation increased (Figure 23
Testing Recurrent inhibition by conditioning the Sol H-reflex with different intensities of
MPS
52
). Significant inhibition was first observed at 20mA and steadily increased with increasing
stimulation intensity up to 80mA, after which further increases in intensity of the conditioning
stimulation did not result in further inhibition of the H-reflex.
6.5 Potential Mechanism of FES therapy
The primary objectives of the thesis project were to compare the motor and sensory
activation patterns of PNS and MPS to elucidate the mechanisms by which these modes of
NMES can modify the nervous system in therapeutic applications. The overall model of
electrical stimulation by PNS and MPS obtained from this thesis project is presented in Figure
27. In this model it can be seen that by activating the entire nerve branch PNS stimulates the
motor nerve orthodromically and antidromically as well as the Ia sensory afferents which lead to
the sensorimotor cortex. This is in contrast with MPS which, due to the specific location of
motor points and the distribution of muscle spindles, preferentially stimulates the motor nerve
leading to antidromic motor activation which targets the alpha motor neuron in the spinal cord.
The patterns of activation are well understood for PNS. However, for MPS, commonly
found in FES orthotic and therapeutic devices, the activation patterns and potential for
modifications to neural circuitry are not well known. We aimed to investigate motor and sensory
and sensory circuits to determine targets for the development and refinement of therapeutic
applications of electrical stimulation.
Our findings suggest that motor point stimulation does not activate the afferent pathway
to a clinically meaningful degree. In Study 1 we observed that the pattern of M-wave growth was
similar for both PNS and MPS, however, the H-reflex was absent during MPS, or if present
negligible in amplitude as compared to the PNS evoked waveform. In fact, the character of the
wave at higher simulation intensities suggest the waveform evoked by MPS was an F-wave and
53
not an H-reflex, indicating that MPS induces the antidromic motor nerve firing. The findings
from Study 2 further support the suggestion that MPS does not activate Ia-afferent, in that MPS
was unable to induce reciprocal inhibition of the SOL h-reflex even when the conditioning
stimulation intensity was at a comparable intensity (Table 3). Additionally, the findings from
Study 3 and 4 support the suggestion that MPS induces the antidromic motor nerve firing, by its
ability to induce recurrent inhibition of the SOL H-reflex. Taken together the findings suggest
that MPS preferentially activates the motor nerve with minimal activation of Ia afferents.
54
Figure 26 Overall model of electrical stimulation by PNS and MPS in relation to sensory
and motor contributions of NMES.
These findings cast doubt upon the explanation that it is afferent direct activation by
NMES that drive the neural adaptations of FES therapy (Barsi et al., 2008). This is especially
true for applications of FES that use MPS, which accounts for the majority of such applications.
Afferent stimulation is believed to drive cortical reorganization that results in the adaptive
benefits that follow FES therapy. If MPS does not activate this Ia afferent pathway significantly,
it is unlikely that benefits from therapy occur at cortical sites, and it does not explain why
therapeutic benefits observed can be superior to those seen with conventional therapy. The
results show that MPS activates predominately motor axons and that these signals travel
antidromically to the cell body located in the spinal cord. This antidromic firing is unique to
electrical stimulation and is consistent with a model of adaptation following FES-therapy in
which spinal circuits are the sites of adaptive modification. The data suggest that neuroplastic
changes in the alpha motor neuron, activated antidromically by electrical stimulation, may be
responsible for the lasting benefits seen with FES-therapy.
55
6.6 Limitations
The thesis project examined the motor and sensory activation patterns of PNS and MPS
in isolation with able bodied subjects with stimulation parameters that are used to investigate
neural circuits but not necessarily used to modify those circuits in therapy. MPS was delivered
using single pulses in the experiments in order to be matched with PNS and limit confounding
interpretation arising from activation due to large evoked contractions. MPS in therapy is
typically delivered at higher frequencies and in trains of stimulation in therapeutic applications
(Gobbo et al., 2014). The project aimed to identify neural targets that are modified by electrical
stimulation to lead to lasting improvements. The data suggest that the site of modification is the
spinal cord. It remains to be examined which specific circuits are being modified and how these
changes can be best adapted to rehabilitation of neurological impairment.
6.7 Future Recommendations
PNS and MPS are traditionally applied in different contexts in neurophysiological
research and therapy. PNS is more commonly used as a research tool to probe the nervous
system, while MPS is used in therapeutic applications to artificially evoke contractions. Here we
have shown that MPS predominately activates the motor neuron through antidromic activation of
the alpha motor neuron. PNS activates the alpha motor neuron and the sensory neuron. A
comparison of PNS and MPS in a therapeutic setting could further elucidate how changes in
excitability of the motor neuron can contribute to lasting rehabilitative effects. A majority fo the
research in to the therapeutic effects of FES has been demonstrated in the upper limbs where
56
both motor points and peripheral nerves are accessible. Development of FES therapy protocols
for lower limb muscles, such as quadriceps, whose nerves are frequently inaccessible are
warranted.
The findings of the thesis are consistent with a hypothesis put forth by Rushton which
implicates spinal synapses as the appropriate targets for neuromodulation using electrical
stimulation (Rushton, 2003). Paired associative stimulation (PAS) has been used as a successful
therapeutic tool for the rehabilitation of patients with incomplete SCI (Bunday & Perez, 2012).
This therapy inspired by the Rushton hypothesis, targets spinal circuits by timing TMS of the
motor cortex with PNS of muscles such that the signals meet at the spinal cord within a narrow
temporal window so as to strengthen the connection and thus increase the excitability of the
motor nerve to descending drive termed PASspinal . All of the work in this area has used PNS to
stimulate the target muscle (Shulga et al., 2016). This limits the viability of such a therapy to the
muscles with superficially accessible peripheral nerves. Here we have shown that antidromic
activation by MPS reaches the motor neuron and could thus be used in PAS applications to
specifically target the motor neuron without confounding afferent stimulation introduced by
PNS. Use of MPS in PASspinal therapy would expand the range of muscles accessible for therapy
and aid in the confirmation of its neural mechanism.
Here we have proposed a novel method for studying recurrent inhibition using MPS of
the target muscle to antidromically activate Renshaw Cells. We have stimulated the target
muscles up to intensities that are higher than those used in the traditional methods to study
recurrent inhibition. This method relies on orthodromic stimulation of the H-reflex to stimulate
Renshaw cells and uses submaximal stimulation to measure the difference between conditioning
and test H-reflexes to measure recurrent inhibition. The technique described in the thesis
57
provides the possibility to measure recurrent inhibition with higher stimulation intensity, requires
less equipment, and offers a practical method for studying recurrent inhibition for use in a
clinical setting. Validation of this technique using a combination of the paired H-reflex technique
with conditioning MPS would allow for the proliferation of this technique to investigate
recurrent inhibition in humans.
Chapter 7
7 Conclusions
We demonstrated that (1) PNS and MPS showed different patterns of motor and sensory
recruitment curves, (2) PNS and MPS differed in inducing the reciprocal inhibition, and (3) MPS
induces strong antidromic motor nerve firing sufficient to evoke a measurable spinal reflex.
These results suggest that distinct differences exist in the motor and sensory recruitment by PNS
and MPS, in that MPS preferentially activates motor axons while inducing antidromic motor
nerve firing. Therapeutic applications of NMES including FES-therapy and PAS-therapy can
benefit from the understanding of the site at which neural modifications are taking place to:
improve targeting of the specific circuits responsible for adaptations, and select of appropriate
stimulation protocols to maximize beneficial outcomes and the viability of therapeutic solutions.
The study demonstrated distinctions between MPS and PNS in reciprocal Inhibition from
TA to SOL. Further, it also demonstrated a novel method for studying the spinal neural circuits
using MPS. Thus, it has shown that MPS can be used as a unique tool to investigate neural
circuits.
58
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