The convergence of
descending motor volleys
ont0 human spinal motoneurons
BY
Woei-Nan Bair
A thesis submitted to the School of Rehabilitation Therapy
in conformity with the requirements
for the degree of Master of Science
Queen's University
Kingston, Ontario
Septem ber, 1997
Copyright Q Woei-Nan Bair, 1997
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A bstract
This study examined the recovery profiles of the motor evoked potentials
(MEPs) generated in the relaxed or tonically active Flexor Carpi Radialis (FCR)
muscle following paired transcranial magnetic stimulation (TMS). A
conditioning-test paradigm was used in which suprathreshold stimuli were
applied over the contralateral skull at interstimulus intervals (ISIS) ranging from
20 to 4000
msec. H-reflex recovery profiles were also constructed at the same
ISIs in order to determine the segmental contribution to the characteristics of the
MEP recovery profiles. A control group of 15 healthy subjects demonstrated that
the test MEP response was facilitatecl at ISIs ranging from 20 to 80 msec when
the FCR was relaxed. With contraction, the test response was attenuated at ISIS
ranging from 20 to 100 msec, with 100 msec correspondhg to the termination of
the silent period following TMS. The characteristics of the MEP recovery profiles
can not be attributed to segmentai mechanisms alone since the H-reflex and
MEP recovery profiles differed significantly both in terms of direction (inhibition,
facilitation) and time course. It is proposed that intracortical mechanisms
contribute to these discrepancies. Five subjects with incomplete cervical lesions
were also tested in a similar manner. While the mean MEP recovery profile was
not different from the control group when FCR was relaxed, significant
differences were observed under contracteci conditions (pc0.0001). This may in
part be explained by an increase in alpha MN excitability as revealed by the
facilitation of the test H-reflex at ISIS of 20 and 30 msec. Additionally, temporal
dispersion of descending volleys associated with delays in central conduction
may have increased the likelihood of bringing MNs to threshold following the
i
test stimulus by raising the membrane potential over a prolonged penod of tirne.
The preliminary f indings suggest that intracortical inhibitory mechanisms were
not likely altered in subjects with spinal corci injury since the characteristics of
the silent period were similar in control subjects although further study is
needed.
Acknowledgements
I would like to thank all the volunteers for participating in this project.
Sincere thanks al= go to Dr. Karen Smith for her referral of subjects with
SC!and Dr. Terry Smith and Queen's STATLAB for suggestions relating to the
data analysis.
The help from Dr. Brenda Brouwer through the period of conducting the
project was enormous. The guidance from her was muttidimensional ranging
from the technical details to the perspectives of the science of neurophysiology.
A final but not last "thank yau" goes to my husband who is always
supporüng and always there for me.
This project was funded by the American Paralysis Association (BA1 -
9601).
Table of contents
Page
Abstract .....................................................................................................................
i
Acknowledgements ..............................................................................................
iii
Table of Contents ..................................................................................................
iv
List of Abbreviations .............................................................................................vi
Listof Figures ............................................................................................................ vii
Listof Tables ..........................................................................................................viii
I. Introduction ....................................................................................................... 1
II. Literaturereview ................................................................................................ 4
Direct motor cortical stimulation in humans
Transcranial electrical stimulation
.........................................
.........................................................
...........................
Transcranial magnetic stimulation ...................... .
.
.
Convergence of descending volleys ont0 spinal MNs
.......................
Effects of increased TMS intensity and voluntary contraction
..........
Silentpend .............................................................................................
TMS in spinal cord injury .........................................................................
Paired motor cortical stimulation ............................................................
Statementof purpose ...............................................................................
II I . Methodology .....................................................................................................
Objectives ...................................................................................................
Subjects ......................................................................................................
Neurologicalassessrnent .........................................................................
€MG recording .......................
......
.......................................................
iv
Transcranial Magneticstimulation .........................................................
20
PerÎpheralelectrical stimulation ............................................................. 21
Testprotocol ...............................................................................................
22
Data analysis ..........................
.
.
......................................................... 23
IV.Results ...............................................................................................................26
Subjeds ...................................................................................................... 26
MEP recovery in control subjects ...........................................................
H-reflex recovery in control subjects ......................................................
MEP recovery in subjects with SC1 ........................................................
H-reflex recovery in subjects with SC! ....................................................
Between group cornparisons ..................................................................
Temporal parameters ...............................................................................
V . Discussion .........................................................................................................
MEP recovery profiles in control subjectç
.............................................
The silent period and its relationship with MEP recovery
..................
Are the MEP recovery profiles altered in subjects with SCI ?
...........
Limitationsof the study ........................................................................
VI . Conclusionsand Future Research ...............................................................
Reference ...............................................................................................................
Appendix 1 .............................................................................................................
Appendix2 ............................................................................................................
82
Appendix3 .............................................................................................................85
Curriculum V i e ....................................................................................................
90
List of abbreviations
ANOVA
Analysis of variance
CMCT
Central motor conduction tirne
EMG
Electromyography
FCR
Flexor Carpi Radialis muscle
lnterstimulus interval
Motor evoked potential
Mmax
Maximal M wave amplitude
Motoneuron
MVC
Maximal voluntary contraction
SC1
Spinal cord injury
SP
Silent period
TES
Transcranial electrical stimulation
TMS
Transcranial magnetic stimulation
List of Figures
Page
Figure 1: Measurement of the ivlEP latency,
duration and amplitude and the duration of the silent period
.......
Figure 2: The MEP recovery profiles
with the target muscle relaxed in mntrol subjects ..........................
Figure 3: The MEP recovery profiles
with the target muscle relaxed in control subjects .......................
Figure 4: The rnean (I 1SEM) MEP recovery profile for the control group
under the relaxed and contracted conditions ...........................
Figure 5: The mean (I 1SEM) H-reflex recovery profile for the control group
under the relaxed and contracted conditions ...........................
Figure 6: A cornpanson of the mean MEP and H-reflex recovery profiles
for the control group .....................................................................
Figure 7: The MEP recovery profiles
with the target muscle relaxed in subjects with SC1 ...................
Figure 8: The MEP recovery profiles
with the target muscle contracted in subjects with SCI ..............
Figure 9: The mean (I ISEM) MEP recovery profile for the SC1 group
under the relaxed and contracted conditions ............................
Figure 10: The mean (I 1SEM) H-reflex recovery profile for the SC1 group
under the relaxed and contracted conditions ...........................
Figure 11: A cornparison of the mean MEP and H-reflex remvery profiles
for the SC1group ....................................... .................................
Figure 12: A between group cornparison of the MEP and the H-reflex recovery
44
profiles under relaxed and contracted conditions .....................
List of tables
Page
Table 1: Subject characteristics ......................................................................
27
Table 2: Summary of individual MEP recovery data for subjects with SC1 .... 46
1. Introduction
Transcranial magnetic stimulation (TMS) is a technique used to noninvasively assess the integrity of the central motor pathways (Barker et al, 1985;
Cadwell, 1991). TMS most readily activates cortical cells projecting to contralateral upper extremity distal muscles (Chiappa et al. 1991b; Hess et al. 1987) and
at higher intensity, lower extremity distal muscles are recruited bilaterally
(Brouwer & Ashby, 1990; Hess et al, 1987). These cortical motor neurons are
activated both directly and transynaptically via cortico-cortical afferents
(Boniface et al. 1991; Day et al, 1%Va, l989a; Hess et al, 1987; Mills, 1988;
Rothwell et al. 1991a) and converge onto spinal alpha motoneurons (MNs) to
evoke a phasic muscle contraction or a motor evoked potential (MEP) (Brouwer,
1990; Priori et al, 1993). The latency of the earliest MEP is consistent with conduction via the rapidly conducting corticospinal tract (Berardelli et al. 1991;
Brouwer & Ashby, 1990; Day et al. 1987b).
When TMS is applied while the target muscle is activated, the amplitude
of the MEP is enhanced as additional MNs are recruited (Mills et al. 1987b;
Rothwell et al, 1987; Valls-Solé et al, 1992). The MEP is then followed by a period of electromyographic inactivity referred to as a silent period (Marsden et al,
1983;Calancie et al, 1987; Amassian et al. 1990; Holmgren et al. 1990). The
silent period may in part reflect refractoriness of MNs (Boniface et al. 1991; Fuhr
et al, 1991 ; Triggs et al, 1993; Uncini et al. 1993), but since it can appear in the
absence of a prior MEP (Kukowski & Haug, 1992; Triggs et al, 1993; Uncini et
al, 1993). inhibitory rnechanisms are likely involved as well (Brasil-Neto et al,
1995; lnghilleri et al, 1993; Kukowski & Haug, 1992; Triggs et al, 1993). TMS
therefore is an effective means of activating both facilitatory and inhibitory pathways (Cracco et al, 1990) and as such has assisted researchers in better understanding descending motor control in normal (Barker, 1986; Caramia & Rossini,
1989; Day et al, 1989b) and pathological states (Berardelli et al. 1987 & 1988;
Boniface, 1991 & 1994; Cracco, 1987; Mills & Murray, 1987a).
In human spinal cord injury (SCI) the pathology includes selective
demyelination or dysmyelination of large calibre axons (Bunge et al, 1993;
Kakulas, 1985). The integrity of axonal conduction through or surrounding the
lesion site is variably cornpromised (Brouwer et al, 1992; Dimitrijevi'c et al,
1988; Gianutosus et al, 1987; Segura et al, 1992; Thompson et al,
1987aI1987b) depending on the severity of the damage and the time course
after injury (acute or chronic) (Ashby et al, 1974; Clarke et al, 1994; Fehlings et
al, 1987; Levy et al, 1987; Simpson et al, 1987; Macdonell & Donnan, 1995;
Wang et al, 1993). lmpaired central conduction has been reported in SC1
patients as reflected by delayed MEP onset following TMS (Brouwer et al, 1992;
Hayes et al, 1991). Additionally, muscles innervated from spinal levels just rostral to the lesion in cornplete and caudal to the lesion in incomplete SC1 are less
responsive to TMS than healthy control subjects (Hayes et al, 1991). The MEP
amplitude is decreased, and both the latency and duration are increased
(Hayes et al, 1991). These alterations in central motor conduction likely contribute to the decreased force producing capabilities of the affected muscles
(Boniface et al, 1991; Mills et al, 1991; Segura et al. 1992). If conduction is cornpromised, then the ability to spatially and temporally recruit motoneurons must,
by extension, also be affected (Boniface et al, 1991; Mills et al, l99l).
One way to examine the spatial and temporal summation ont0 spinal
alpha MNs is by using paired TMS (Berardelli et al, 1996; Claus et al. 1992;
Inghilleri, 1990; Jennum et al. 1996). The first stimulus (conditioning stimulus)
serves to activate a portion of the alpha MN pool while the second stimulus (test
stimulus) introduced at specific interstimulus intervals examines the extent to
which the response to the subsequent descendhg volleys is enhanced or attenuated (Inghilleri, 1990; Rothwell,l991). The nature of the test response is
dependent upon the interstimulus interval (Inghilleri, 1990; Jennum et al, 1996;
Rothwell, 1991; Valls-Solé et al. 1992), the stimulus intensity (Claus et al, 1992;
Valls-Solé et al. 1992). the state of the muscle (relaxed or contracted) (Claus et
al, 1992; Jennum et al. 1996; Valls-Solé et al, 1992) and the integrity of the
neural pathways. In order to gain insight into the neural pathways mediating the
response pattern, the normal effects under controlled stimulation conditions
must first be docurnented.
This study examined the recovery profile of MEPs produced in relaxed
and contracted target muscles under controlled experimental conditions. Additionally, a small group of subjects with chronic incomplete SC1 underwent the
same protocol in order to observe any alterations in the characteristics of the
recovery profile.
II. Literature review
Direct motor cortical stimulation in humans
Electrical stimulation of the exposed motor cortex results in a series of
descending volleys which can be recorded from the contralateral epidural
space of the human spinal cord (Katayama et
al, 1988). The latency of these
multiple descending volleys and their persistence under high frequency stimulation have pravided convincing evidence that they are in fact analogous to the
direct wave (D wave) and indirect waves (1 waves) recorded from animal spinal
cords following microstimulation of motor cortical cells (Amassian et al, 1987;
Jankowska et al, 1976). The latency of the first (D) wave recorded between the
2nd and 5th cervical levels suggests a conduction velocity of approximately 50 -
75 m/sec (Katayama et al, 1988) which is consistent with direct corticospinal
tract conduction in experimental animais (Amassian et al, 1987, 1989, 1991;
Kernell & Wu, 1967). The I waves yield successive delayç of 1
-
2 msec
(Katayama et al, 1988) which correspond to those observed in monkeys when
corticomotoneurons are activated via cortical afferents (Amassian et al, 1989).
The lack of temporal dispersion of the D and I waves recorded at various spinal
leveis indicates that both types of waves conduct through axons of similar
calibre (Katayama et al, 1988).
Although direct stimulation of the human motor cortex provides an effective means of examining the fast conducting motor pathways, the invasive
nature of the technique precludes its use clinically (Cracco et al, 1990).
Transcranial electrlcal stimulation (TES)
Transcranial electrical stimulation (TES) was first described by Merton
and Morton in 1980 who dernonstrated that intense anodal stimulation through
the intact scalp could evoke phasic muscle contractions contralaterally (Merton
& Morton. 1980). Since then TES has been shown to activate contralateral dis-
ta1 muscles of the upper extremity most readily (Marsden et al, 1983: Rossini,
1985, 1990; Rothwell, 1987) and from sites consistent with the known representation of the limbs in the motor cortex (Cohen & Hallett, 1988; Rossini, 1990;
Rothwell et al, 1987; Wassermann et al, 1992).
The response pattern (distal muscles having lower thresholds than proximal muscles and upper limb muscles having lower thresholds than lower limb
muscles; Rothwell et al, 1987; Wassermann et al, 1992) and the latency of the
MEPs (Boyd et al, 1987; Day et al, 1987b; Rothwell et
al. 1987) are consistent
with the activation of the fast corticospinal tract in a manner not unlike that attrk
butable to stimulation of the exposed motor cortex (Berardelli et al, 1991; Day et
al, 1987a, 1989a). As with direct cortical stimulation, TES also activates a series
of descending volleys (Boyd et al, 1987; Day et al, 1989a) which have been
recorded from the contralateral epidural space of the human spinal cord during
surgery (Boyd et al, 1987; lnghilleri et al, 1989; Levy et al, 1988; Pelosi et al,
1988; Rothwell et al, 1989). lntroducing a single supramaximal electrical stimulus of the peripheral nerve so as to initiate an antidromic volley in motor axons
abolishes the initial D wave elicited by TES although the MEP is still evident
due to the arriva1 of subsequent I waves at the spinal MNs (Berardelli et ai,
1987; Day et al, 1987a; Rothwell et al, 1987). Single motor unit studies which
have recorded the discharge times of rhythmically active units in relation to
repeated TES have noted changes in firing probability at times consistent with
D and I wave latencies (Day et al, 1989a). In combination, these findings
strongly support the view that direct noninvasive stimulation of corticornotoneurons is possible.
TES is an effective means of activating motor cortical cells although it has
not met with widespread acceptance. The high resistance of the skull necessitates the use of high voltages to ensure adequate current flow which makes stimulation quiet painful (Cracco, 1987; Mills et al, 1987b). The discomfort and
pain associated with TES has limited its applicability. particularly in studies
involving patient populations.
Transcranial magnetic stimulation (TMS)
In the mid 1 9 8 0 ' ~transcranial
~
magnetic stimulation (TMS) was introduced by Barker et al who reported that currents induced by a rapidly varied
magnetic field could cause contractions in contralateral muscles. TMS is painless because magnetic fields readily penetrate soft tissues and bone with minimal attenuation thus there is no current build-up at the skull (Cadwell, 1991;
Chiappa et al, 199 1a). Studies which have contrasted the responses observed
following TES and TMS have concluded that TMS is a valuable technique for
examining the integrity of the corticospinal tracts (Day et al, 1989a1Hess et al,
1987).
TMS, like TES, evokes large amplitude muscle twitches in the contralat-
eral dista! upper limb muscles (Chiappa et al, 1991; Hess et al. 1987). With
increased stimulus intensity, more proximal muscles and lower limb muscles
may be recruited bilaterally (Brouwer & Ashby. 1990; Hess et al, 1987). The
latencies of the MEPs are short and the response durations are consistent with
the descending axons having similar conduction velocities (Berardelli et al,
1991; Day et al, 1987b). There are, however, some distinct differences between
the two stimulation techniques.
Following TMS, the latency of the MEP is about 1
- 2 m e c longer than
that observed following TES suggesting that the neural structures activated may
differ between the two stimulation techniques (Berardelli et al, 1991; Day et al,
1987a; Hess et al, 1986; Mills et al, 1987b). Applying the stimulation mil in a
standard way (tangential to the scalp) likely excites cortico-cortical afferent
fibers from premotor and postcentral cortices or the deep tangential plexus in
the gray matter whose neurons synapse onto motor cortical cells (Boniface et al,
1991; Day et al, 1987a, 1989a; Mills, 1988). This transynaptic activation of
motor cortical cells would account for delays of 1 - 2 msec (Berardelli et al,
1991) which have also been noted in single motor unit studies (Day et al,
1987a, 1989a). Another notable difference between MEPs evoked by TES and
TMS is that the amplitude of MEPs are more variable following threshold TMS
(Rossini, 1990; Rothwell, 1991). The reliance on having to bring the presynaptic
cortical afferent cells to threshold may account for this discrepancy. The coupling between the site of stimulation and the spinal motoneurons would not be as
tight as in the situation where corticomotoneurons are activated directly as
occurs with the use of TES (Day et al, 1987b, 1989a). This difference rnay have
particular relevance when higher frequency stimulation is used.
Convergence of descending volleys ont0 spinal MNs
Despite the similarities in the response patterns following direct (TES)
and indirect (TMS) methods of motor cortical stimulation. the latter provides less
focal stimulation (Cracco et al, 1990). With TMS, the relative area of cortical
excitation is large (Day et al, 1989a) giving rise to motor responses that reflect
the composite of the output of extensive cortical neuronal activation. A portion of
the descending volley projecting to alpha MNs is likely rnonosynaptic as suggested by the consistent latencies of repeated single motor unit discharges following TMS (Boniface et al, 1991; Brouwer & Ashby, 1989; Priori et al, 1993).
however. oligosynaptic connections are also abundant (Amassian et al, 1989).
It is the net effect of the corticospinal volley spatially and ternporally summating
ont0 alpha MNs which determines the firing level of spinal MNs (Claus et al,
1991). In addition, sequential volleys may produce progressive augmentation of
the excitability of MNs (Amassian et al, 1987) occurring in a nonlinear manner
(Mills, 1988).A small change in corticospinal discharge therefore can determine
whether a muscle is activated or not.
It should be recognized that whether or not a given alpha MN fires in
response to descending volleys is a function of the intrinsic properties of that
MN (status of polarization, timing after spontaneous discharge) (Boniface et al,
1991; Calancie et al. 1987; Day et ai, 1989a; Mills et al. 1988, 1991). The excitability of MNs may be altered by descending tonic controls (Thompson et al,
1991; York. 1987) and segmental influences including the convergence of peripheral la volleys (Baldissera & Cavallari, 1993; Claus et al. 1988) and cutaneous inputs (Hayes et al, l99I. 1992; Kasai et al, 1992; Wolfe et al, 1995). It fol-
lows that the characteristics of the MEPs reflecting the discharge of a group of
alpha MNs are also influenced by a previous stimulus if the neural effects of the
original stimulus remain.
Effects of increased TMS intensity and voluntary contraction
The characteristics of a MEP are determined not only by the excitability of
the MN pool but also the stimulus intensity and the state of the muscle (relaxed
or contracted). As such, cornparisons of MEP responses should be made under
similar conditions.
lncreasing the intensity of stimulation to well above threshold raises the
probability of evoking a MEP (Valls-Solé et al, 1992),decreases the MEP onset
latency (Berardelli et al, 1991; Day et al, 1989a; Hess et al, 1987; Rothwell et al,
1987), increases its amplitude (Berardelli et al, 1991; Day et al, 1989a; Hess et
al. 1987; Rothwell et ai, 1987) and duration (Caramia and Rossini, 1989; Day et
al, l989a; Hess et al, 1987; Rothwell et al, l987), as well as increasing the complexity of the waveform (Day et al, 1989a). These alterations reflect changes in
the number of cortical and spinal motoneurons activated and the recruitrnent of
higher threshold neurons (Day et al, 1989a). The decrease in MEP latency, for
example, may be explained in part by the recruitment of larger, hence faster
conducting MNs (Calancie et al, 1987; Brouwer and Ashby, 1990).
Voluntary contraction of the target muscle by as little as 5
-
10% of the
maximal isometric voluntary contraction (MVC) can decrease the intensity of stimulation required to elicit a MEP (Rothwell et al, 1987; Valls-Solé et al, 1992),
increase its persistence (Rothwell et al, 1987; Valls-Solé et al, 1992). decrease
its latency (Mills et al, 1987b;Rothwell et al, 1987; Valls-Solé et al, 1992).
increase its amplitude (Millç et al, 1987b; Rothwell et al, 1987; Valls-Sole et al,
1992) and duration (Rothwell et al, 1987; Ugawa et al, 1995). These phenomena result from both an increase in the excitability of cortical MNs (Berardelli,
1991; Hess et al, 1987) and spinal MNs (Brouwer et al, 1989; Day et al, l98ïa)
causing larger post-synaptic potentials in spinal MNs and bringing more spinal
MNs to threshold, respectively. Slight contraction of the target muscle also
decreases the amplitude variability of successive MEPs (Kiers et al, 1993; Nielsen, 1994, 1996; Rossini, 1990) likely due to the facilitation of a larger proportion of the MN pool via more intense excitatory drive. Furthermore, the multiple
descending volleys can activate spinal MNs in a desynchronized pattern contributing to the polyphasic nature of the MEP (Rothwell et al, 1987).
Silent period (SP)
Following the cortically evoked MEP in a contracting muscle is a period
of electrical inactivity termed the silent period (SP) (Marsden et al, 1983; Calancie et al, 1987; Amassian et al, 1990; Holmgren et al. 1990). The duration of the
SP is proportional to the stimulus intensity (Kukowski & Haug, 1992; lnghilleri
et al, 1993; Triggs, 1993; Wilson et al, 1993; Uncini et al, 1993), although it is
independent of the magnitude of the MEP (Inghilleri et al, 1993; Rossini, 1990;
Triggs et al, 1993). In fact, the threshold for eliciting a SP is lower than that
required to evoke a MEP as evidenced by the existence of a SP without a preceding MEP (Classen, 1995; Kukowski & Haug, 1992; Triggs et al, 1993; Uncini
et al, 1993).
The underlying neurophysiological mechanisms of the SP remain somewhat elusive. The early part of SP has been attributed to the refractoriness of
spinal MNs (Boniface et al, 1991; Fuhr et al. 1991; Mills, 1988; Triggs et al,
1993; Ziemann et al, 1993) although this explanation is clearly not complete
since, as indicated above, these MNs need not necesarily discharge in a previous MEP. It is, however, acknowledged that asynchronous discharge of alpha
MNs is responsible for maintaining the tonic contraction, therefore it is plausible
that çorne MNs rnay well be refractory.
One way of exarnining the excitability of alpha MNs is by introducing a
second stimulus following TMS. Fuhr et al (1991) activated low threshold group
I afferents via electrical stimulation of
the peripheral nerve known to make
monosynaptic connections with alpha MNs (Hugon. 1973). He found that the
resultant H-reflex was attenuated in the 50 msec period following TMS. Others
have reported that the H-reflex recovers fully if evoked 100 msec after TMS
(Triggs et al, 1993; Uncini et al, 1993). One may argue that the use of the Hreflex in examining the excitability of alpha MNs is questionable since the same
MNs may not be activated by both stimuli. Small MNs, however, are likety to be
activated by both modaiities acwrding to the size principle of MN recruitment
(Bawa & Lemon, 1993; Boniface et al, 1991; Jones et al, 1996) therefore it is
reasonable to assume that there would be some degree of overlap in the MNs
activated by TMS and group I volleys.
Single motor unit studies support the conclusions drawn from the Hreflex studies. Boniface et al (1991) showed that TMS applied within 30 msec of
a spontaneous motor unit action potential was unlikely to activate the spinal
MN. The probability of discharge increased to 20% when TMS was applied 40
msec after spontaneous motor unit firing. Increasing the relative time interval
further increased the probability of TMS associated discharge suggesting an
early period of absolute followed by relative refractoriness of the spinal MNs.
Such a mechanisrn would contribute to the early portion of the silent period
(Boniface et al, 1991; Mills, 1988; Rossini, 1990; Ziemann et al, 1993).
Reported SP durations range from 110 msec to 160 msec for the Flexor
Carpi Radialis (FCR) muscle following TMS (Fuhr et al, 1991; Uncini et al, 1993)
with several different mechanisms proposed to explain the later portion (>1 O0
mec) of the SP (Brasil-Neto et al, 1995; Calancie et al, 1987; Haug et al, 1992;
lnghilieri et al, 1993, 1996; Priori et al, 1994). It is proposed that the inhibition is
secondary to contraction induced segmental inhibitory mechanisms. These
include the activation of the Renshaw cells by the highly synchronized discharge of the spinal MNs (Day et al, 1987a) and Ib afferent influences sternrning
from the Golgi tendon organs (Calancie et al, 1987). The positive relationship
between the force level of the tonic contraction and duration of the SP
(Stetkarova et al, 1994; Wilson et al, 1993) supports the involvement of the Ib
aff erents. Others, however, have failed to detect any signif icant association
between these variables (Haug et al, 1992; Kukowski & Haug, 1992; Inghilleri,
1993).
An alternative explanation is that intracortical inhibitory mechanisms are
responsible for the later part of the SP (Brasil-Neto et al, 1995; Haug et al, 1992;
lnghilleri et al, 1993, 1996; Priori et al, 1994; Roick et al, 1993). This conclusion
is based on a combination of findings including the following. The duration of
the SP is related to the site and localization of the stimulus. Electrical stimulation of the brainstem (Brasil-Neto et a1,1995) produces a SP with a duration of
25 msec which increases to 70 msec when the stimulus is applied to the scalp
overlying the motor cortex (Brasil-Neto et al, 1995; Uncini et al, 1993). TMS is
associated with longer duration SPs (130 msec) which can be decreased with a
more focal application (Amassian et al, 1990; Wassermann et al, 1993) or
applying the stimulus over the cervicomedullary junction (Inghilleri et al, 1993).
Applying TMS at different cortical sites also produced SPs of different durations
in the same muscle (Kukowski & Haug, 1992). The implication from these findings is that cortical mechanisms are likely contributory to the SP duration. It is
therefore not surprising that the SP has been found to be altered following
neurological trauma or disease (Kukowski & Haug, 1992, 1993; Priori et al,
1994; Triggs et al, 1992).
T M S in spinal cord injury (SCI)
Following human SCI there is selective demyelination or dysmyelination
of large axons depending on the nature and severity of the lesion (Bunge et al,
1993; Kakulas, 1985). Furthermore, the integrity of axonal conduction through
and surrounding the lesion site may be variably compromised (Brouwer et al,
1992; Dimitrijevi'c et al. 1988; Gianutosus et al, 1987; Segura et al, 1992;
Thompson et al, 1987a, 1987b) depending on the severrty of the darnage and
the tirne course after injury (acute or chronic) (Ashby et al, 1974; Clarke et al,
1994; Fehlings et al, 1987; Levy et al, 1987; Simpson et al, 1987; Macdonell &
Donnan, 1995; Wang et al, 1993). Hayes et al (1991) revealed that typically,
muscles innervated from roots below the level of lesion respond to TMS with
MEPs which are prolonged in latency, low in amplitude. high in threshold, or are
absent. The rnarked delays in central conduction may be attributed to segmental demyelination (Brouwer et al, 1992) or slower conducting descending
axons (Hayes et al, 1991). The delayed MEP onset has been associated with
prolonged MEP duration which may reflect an increase in temporal dispersion
of the descending volleys ont0 the spinal MNs (Kukowski, 1993). Estimates of
the rise time of the postsynaptic potential in alpha MNs determined from peristimulus time histograms of the discharge times of single motor units is compatible
with this view (Brouwer et al, 1992). The projection pattern of corticospinal
axons onto alpha MNs, however, is not altered in chronic SC1 suggesting an
absence of detectable corticospinal reorganization (Brouwer et al, 1992;
Brouwer and Hopkins-Rosseel, 1997).
Although the temporal abnormalities of the MEPs (latency and duration)
after TMS are well documented in SCI, little is known about how this might influence the ability to rnaintain motoneuronal firing. The association between
delayed central conduction and deficits in the force producing capabilities of the
affected muscles has been proposed but not examined (Boniface et al, 1991;
Mills et al, 1991; Segura et al, 1992). One way to determine the effects of multiple descending volleys onto spinal MNs is by using paired motor cortical stimulation and varying the interstimulus interval (Berardelli et al, 1996; Claus et al,
1992; Inghilleri, 1990; Jennum et al, 1996).
Paired motor cortical stimulation
In a paired stimulus paradigm, the first stimulus (the conditioning stimu-
lus) serves to depolarize a portion of the alpha MN pool. In response to the
complex series of facilitatory and inhibitory inputs spatially and temporally converging ont0 these alpha MNs, the excitability of the MN pool will be altered.
lntroducing a second stimulus (the test stimulus) at a predetermined time provides insight into the relative state of the MN pool. Varying the interstimulus
interval (ISI) can be used to profile the test response characteristics (Inghilleri.
1990; Jennum et al, 1996; Rothwell. 1991; Valls-Solé et al. 1992). The ampli-
tude of the test response expressed as a percentage of the conditioned
response amplitude indicates the relative excitability of the neural structures
involved.
The characteristics of the recovery profile are dependent on the state of
the muscle (relaxed or contracted) (Claus et al, 1992; Jennum et al. 1996; Valls-
Solé et al, 1992). the intensity of the cunditioning stimulus (Jennum et al, 1996),
and the intrinsic properties of the MNs. It is therefore important to control the stimulus pararneters if conclusions are to be drawn concerning neuropathology.
In a relaxed target muscle, the test response is larger than the conditioned response at short (10 msec - 30 m e c ) ISIS when suprathreshold stimulus intensities are used (Claus et al, 1992; Triggs et al, 1992; Valls-Solé et al,
1992). This is attributed to cortical facilitation since paired peripheral la volleys
of similar ISIS result in the attenuation of the amplitude of the test response
(Claus et al, 1992).
Interestingly, if the TMS intensity is reduced to subthreshold levels, then
the test response is attenuated at ISIS less than 30 msec when compared to a
control MEP amplitude (Valls-Solé et al. 1992).The mechanism for these differential effects related to stimulus intensity is not clear although it is suggested
that modulation stems from changes of cortical and subcortical excitability
(Valls-Solé et al, 1 992).
When the target muscle is contracted, the test response is attenuated at
short (10 - 100 msec) ISIS with the use of suprathreshold stimulation (Inghilleri
et al, 1990; Triggs et al 1992). At ISIS exceeding 200 msec the test response
recovers. This period is compatible with the termination of the SP (Claus et al,
1992).
Under both the relaxed and contracted conditions there is an inverse
relationship of the amplitude of the conditioned response with that of the test
response at short ISIS (Claus et al, 1992;lnghilleri et al, IWO).This effect likely
occurs because different M N s from the MN pool are activated in response to
each of the conditioning and test stimuli rather than the same MNs responding
to both (Claus et al, 1992;lnghilleri et al, 1990).This has been confirmed in single motor unit studies which demonstrated that individual MNs are unable to
respond to both stimuli of a pair if the 1S1 is short (c70 m e c ) (Mills, 1988; Rossini, 1990). By extension, if a large portion of the MN pool is activated in response
to the conditioning stimulus then only a small portion remains capable of
responding to the test stimulus (Inghilleri et al, 1990).
Examination of the MEP recovery profile during muscle contraction provides a means of examining the intracortical inhibitory mechanisms in view of
the influence of the SP (Inghilleri. 1990;Rothwell, 1991 ). It is known that the SP
characteristics are sensitive to neurological impairment involving the central
nervous system (Haug et al, 1992; Kukowski & Haug, 1992; Priori et al, 1994;
Triggs et al, 1993). For exampie, in SC1 the silent period is reported to be
abnormally long (Haug, 1994) which may reflect alterations in the balance
between facilitatory and inhibitory mechanisms (Kukowski & Haug, 1992; Priori
et al, 1994; Triggs et al, 1993).The impact of aiterations in SP duration on the
MEP recovery profile is not known. Before mis issue can be addressed, how-
ever, the normal MEP recovery profile for a specific muscle under contralled stimulus conditions needs to be confirmed-
Statement of purpose
This study characterized the recovery profile of the MEPs evoked in the
relaxed and contracted Flexor Carpi Radialis (FCR) muscle in response to
paired suprathreshold TMS. Additionally, the protocol was repeated in a srnall
group of subjects with chronic incomplete SC1 in whom the FCR was abnormally weak. In this manner, preliminary observations could be made regarding
the existence of any abnorrnalities in the recovery of corticospinal neurons in an
effort to better understand the nature of the impairment associated with chronic
SCI.
III. Methodology
Objectives
The objectives of this study were :
1. to characterize the recovery profile of cortically evoked MEPs in the relaxed
and contracted FCR in healthy control subjects using suprathreshold paired
TMS.
2. to make preliminary obsewations about the nature of the MEP recovery pro-
file in subjects with incomplete cervical SC1 and contrast the characteristics with
those observed in healthy controls.
Su bjects
Healthy volunteers were recruited from the Queen's University community by word of mouth and from posted advertisement. subjects with incomplete
SC1 at the ceMcal level of at least 6 months duration were recruited through the
Department of Rehabilitation Medicine at the Kingston General Hospital. All
subjects were screened to ensure they had no self reported history or family history of epilepsy, had no cardiac pacemaker, and no cochlear or metal implants
(al1 contraindications of magnetic stimulation) (Pascual-Leone et al. 1993).
Healthy subjects had no history of neurological trauma or disease (self reported) and al1 were pretested to ensure that an H-reflex could be recorded from
the FCR muscle. Subjects with SC1 were considered if they were classified as a
C5 to C7 level quadriplegic.
Subjects gave their informed consent to participate in the study
(Appendix 1) and al! protocols had been approved by the Research Ethics
Board at Queen's University.
Neurological assessrnent
All subjects with SC1 were assessed using the American Spinal lnjury
Association (ASIA) standard neurological and functional classification system
(ASIA, 1992; Appendix 2). This system categorises function on the basis of the
degree of motor and sensory sparing. Neurological level was defined as the
lowest neurological segment with normal sensory function (al1 modalities) and a
muscle grade of at least 3. Any evidence of motor and sensory function of the
sacral segments S 4 - 5 defined an incomplete lesion (Marino, 1995).
Met hod
EMG recording
Disposable surface silver-silver chloride electrodes (Meditrace) with a
recording surface area of 1 square cm were used to record the electrical activity
from the FCR muscle. The active electrode was placed overlying the belly of the
FCR approximately one third the distance from the medial epicondyle to the
radial styloid. The reference electrode was placed 3 cm distal to the active electrode in line with the muscle fiber orientation. A ground electrode was placed
over the lateral epicondyle (Jabre, 1981).
The EMG signal was bandpass filtered at 10-2000 Hz, amplified 1,000
times, and digitally sampled by a laboratory computer at 5 KHz. The EMG signal
was also viewed on a oscilloscope to monitor background activation. Data were
stored on disk and analyzed off-line using commercial software (DataWave
Technologies)
.
Zranscranial Magnetic stimulation
A Cadwell rapid-rate magnetic stimulator was used to activate cortical
neurons transcranially. This device has a peak magnetic flux of 1.6 Tesla and
introduces a bidirectional current (50 psec rise tirne) through a circular coi1
(external diameter of 9.4 cm) applied over the scalp to induce currents in underlying conductive tissue. The stimulating coi1 was placed tangentially on the
scalp with its center placed midway between the vertex and C3 (International
10-20 system of electrode placement; Jasper, 1958). From this position the coi1
was systernatically moved anterio-posteriorly and rnedio-laterally in approximately 1 cm intervals in order to determine the optimal stimulus site. This was
determined as the site which evoked an MEP in the target muscle at the lowest
stimulus intensity. The point was marked on the scalp and served as the site of
stimulation throughout the protocol.
Stimulation threshold. defined as the lowest stimulus intensity required to
evoke an MEP in at least 6 out of 10 repetitions (Valls-Solé et al, 1992) was
determined with the target muscle at rest and with a low level contraction (10%
MVC). The intensity, expressed as a percentage of the maximum stirnulator out-
put. was then adjusted to correspond to 120% of the threshold intensity in order
to increase the probability of evoking a muscle response (Valls-Solé et al,
1992).
Peripheral electrical stimulation
Electrical stimulation of the rnedian newe was used to evoke an H-reflex
in the FCR muscle as a rneans of monitoring the excitability of the spinal MN
pool. In this manner segmentai rnechanisrns could be accounted for when interpreting the findings associated with TMS. Subjects reclined in a chair with their
forearm supported on a table such that the angle between the elbow and upper
arm was about 150 degrees and the forearm was supinated. A Grass 44 stimulator coupled with a constant current isolation unit provided rectangular pulses
of 0.5 msec duration (Hugon, 1973) through a bipolar stimulating electrode. Stimulation was applied overlying the median nerve at the elbow level (Jabre,
1981) or 10 cm above the cubital fossa between the Biceps Brachialis and Bra-
chialis muscles (Sabbahi. 1990). The cathode was 2 cm proximal to the anode
and the stimulating electrode was held in position with a velcro strap.
The intensity of stimulation was determined by progressive increments
until an H-reflex was clearly evident with or without an accompanying M wave.
The maximum amplitude H-reflex was found and the intensity of stimulation
reduced to evoke an H-reflex of an amplitude equivalent to approximately 5
0
°
'
of the maximum amplitude H-reflex. This intensity was determined under both
relaxed and contracted conditions and was used throughout the protocol.
Test pro toc01
Each subject received both transcranial magnetic and peripheral nerve
stimulation in turn with the order determined randomly. Stimuli were applied first
with the target muscle (FCR) relaxed and then wntracted to 10% of the subject's maximal voluntary isometric contraction force. The maximum isometric
voluntary contraction was determined by having subjects exert a maximal force
against a load cell positioned at the metacarpal heads. The average of two trials
was used to calculate the 10% MVC force value. A target line reflecting this
force value was displayed on an oscilloscope and the subject was instructed to
superimpose the transducer output on the target line and to maintain the contraction while stimuli were applied. Subjects with SCI who did not have antigravity FCR strength were instructed to try to contract their wrist flexors to the
best of their ability. In ail cases frequent rest breaks were introduced to avoid
fatigue.
The stimulation procedure was as follows. Ten single stimuli (TMS or
peripheral nerve stimulation), 5 seconds apart provided baseline data of the
evoked response. Next, 5 sets of 12 paired stimuli with ISIS of 20, 30, 40, 50, 80,
100, 200, 300, 500, 1000, 2000, and 4000 msec were introduced. The ISISwere
randomized within each set and 5-10 seconds were allotted between wnsecutive pairs of stimuli to avoid the influence of transient changes in MN excitability.
Following this an additional set of baseline data (10 single stimuli) were gathered as described above to ensure the consistency of stimulation conditions
over t h e . After al1 the data were collected, supramaximal electrical stimulation
was applied over the median nerve to activate al1 the alpha MN axons project-
ing to the FCR muscle in order to generate the maximal M wave (Mmax).
Data analysis
All data were analyzed off-line. The peak-to-peak amplitude of the MEPs
and H-reflexes were measured from the individual EMG traces. Baseline data
gathered before and after the paired stimuli were averaged over the 10 trials,
respectively. If these two rnean values varied by less than IO%, the conditions
were viewed as stable and the subject's data were included for analysis.
For recordings associated with paired stimuli, the amplitude of the test
response was expressed as a percentage of the conditioned response then
averaged over the 5 repetitions at a given ISI. The average value for each ISI
for al1 control subjects and subjects with SCI, respectively, were pooled to
obtain group averages and variances.
The temporal parameters analyzed included the MEP onset latency,
duration, and duration of the SP. The latter was measured under the contracted
conditions only and was defined as the period from the stimulus artifact to the
return of baseline EMG activity which was at least 50 pV peak to peak amplitude
(Triggs et al, 1993). Figure 1 illustrates the measurement of the various MEP
characteristics and the SP duration.
Additionally, central motor conduction time (CMCT) was estimated from
the shortest latency MEP and the H reflex latency as follows :
CMCT (msec) = MEP latency - [( H reflex latency + M wave latency )R + 1 rnsec];
MEP latency
SP duration
v
n
MEP duration
MEP amplitude
Fiqure 1: Measurernent of the motor evoked potential (MEP) latency, duration and
amplitude and the duration of the silent period (SP).
where 1 msec corresponds to the synaptic delay (Brouwer et al. 1992). The M
wave latency was added to the H-reflex latency to equalize to relative distances
to and from the spinal cord. The H-reflex latency reflects the peripheral la conduction time from the stimulus site to the alpha MNs and the efferent conduction
time to the FCR muscle.
Two-way analyses of variance (ANOVA) were used to compare the
recovety profiles of the FCR muscle. The factors included each of the following:
conditions (relaxed, contracted), groups (control, SCI) and stimulus modality
(TMS, peripheral nerve stimulation) and the second was in al1 case interstirnu-
lus interval. If significant main effects were found, post-hoc analyses were carried out using the Turkey's multiple cornparison test. Between group compari-
sons were made using unpaired t-tests of the temporal parameters and also of
the recovery profile characteristics at specific ISIS. Such analysis permitted
inferences to be drawn from the prelirninary data. The significance level was set
in al1 cases at 0.05.
IV. Results
Su bjects
A total of 20 healthy control subjects were recruited and 5 were excluded
from participating because H-reflexes could not be elicited from the FCR muscle. The remaining 15 subjects were between the ages of 19 and 46 years
(mean 30 years). Six subjects with SC1 were recruited, but one was excluded
due to an absence of an FCR MEP under both the relaxed and contracted conditions despite using maximal intensity stimulation. H-reflexes could not be elicited from 2 other subjects with SCI, however, they remained in the study since
the objective was to obtain preliminary data pertaining to the recovery of the
MEP responses. Additionally, one subject from each group was not tested with
the target muscle contracted due to time limitations. One control subject's data
were excluded on the basis of excessive (>IO%) variability in baseline EMG
responses.
The five subjects with SC1 al1 had incomplete cervical lesions. The mean
duration after SC1 ranged from 3 to 20 years with an average of 12 years. They
were between the ages of 18 and 61 years (rnean 35 years). The subject characteristics are summarized in Table 1. The control and SC1 groupç were similar
in age (p=0.4) and height (control: 1 7 h 9 cm; SCI: 173k9 cm; p=0.58).
The entire protocol took approximately 2.5 to 3 hours. All subjects tolerated the protocol well and no untoward effects were reported.
Table 1 Subject characteristics
- -
-
- -
-
-
Age
Gender Height
(cm)
Lesion A S l A
level
-
-
Time
post
injury
(years)
Ctll
Cti2
Ct13
Ctl4
C t 15
C t 16
Ct17
Ct18
Cti9
Ctll O
Ctll 1
Ct112
Ctl13
Ctl14
Ct 1 15
-Mean
- -SD
- -SC101 R
SC101 L
SC102
SC103
SC104
-
-
-
_.
-
_ -
FCR
Wrist flexor
Strength
tone
--
---- -- . --
-.
-
.
-
3
3
13
20
18
13
wosMean
S D --
_
9
Good
Poor
Trace
Good
Fair
Good
Normal
Normal
Normal
Severe spastic
Mild spastic
Normal
---
60th sides of one subject with SCI (SCIOI ) were tested, R = right, L = left.
FCR: Flexor Carpi Radialis muscle
MEP recovery in control subjects
Threshold stimulation intensity was 696% of the stimulator output with
the target muscle relaxed, and was significantly lower 5511 1% with contraction
(pcO.001). The relative amplitude of the baseline MEP (expressed as a percent-
age of the maximal M wave) was 6*4% with the target muscle relaxed, and was
significantly higher 35121 % when the target muscle was contracted (p4.001).
With the target muscle relaxed, the test response amplitude was
enhanced at ISIS ranging from 20 msec to 80 msec (Figure 2A). This was consistent across repeated trials for the same subject (Figure 28).At longer ISIS
(2100 msec), the magnitude of the test response was similar to that of the condi-
tioned MEP. These f indings were consistent across al1 control subjects (Figure
2C) although MEPs could not be elicited in 3 subjects.
The nature of the MEP recovery profile differed depending on the condi-
tion (relaxed, contracted) of the target muscle. With the target muscle contracted, the test response amplitude was attenuated at ISISslO0 msec (Figure 3A).
Note that the full recovery of the test MEP amplitude is consistent with the second stimulus being applied at the end of the SP (approximately 100 mec; see
Figure 3A). The attenuation of the test response was consistent across repeated
trials for the same subject (Figure 38) as well as for the control subjects as a
group (Figure 3C).
e 7. The MEP recovery characteristics following
suprathreshold cortical stimulation with the target muscle relaxed.
Raw EMG traces illustrate the MEP responses in the relaxed FCR
following paired TMS (A). The interstimulus interval (ISI) is
indicated above each trace and the stimulus artifacts are noted by
the dots. The average ratio of the test 1 conditioned response
(expressed in percentage) of 5 trials at each ISI is presentated for
the same subject (B). The mean recovery profile for the control
group (n=12) is also shown (C). Error bars reflect 1 SEM.
m e 3: The MEP recovery characteristics following
suprathreshold cortical stimulation with the target muscle
contracted. Raw €MG traces illustrate the MEP responses in the
contracted FCR following paired TMS (A). The interstimulus interval
(ISI) is indicated above each trace and the stimulus artifacts are
noted by the dots. The average ratio of the test I conditioned
response (expressed in percentage) of 5 trials at each ISI is
presentated for the same subject (B). The mean recovery profile for
the control group (n=14)is also show (C). Error bars reflect 1
SEM.
Figure 4 illustrates the mean MEP recovery profile for the control subjects
under relaxed and contracted conditions with the test response being more
excessive under the relaxed condition at short ISIS. A WO way ANOVA revealed
that there was an interaction effect between the activation state of the muscle
and ISI (F=7.62, pcû.0001) as well as significant main effects of the activation
state (F=36.82, p4.0001) and ISI (F=2.67, p=0.003). Additional analysis of the
data corresponding to ISIS5100 msec revealed a significant effect of the state of
muscle activation (F=5.88, p=0.01) but not 1S1 (F4.13, p=0.99) or an interaction
effect of these two variables (F=0.86, pd.69). Paired t tests confirmed that the
test MEP was facilitated to a greater extent at ISIs of 20, 30, 40,50 and 80 m e c
(p=0.03, ~0.001,CO. 001, 0.002 and 0.5, respectively) when the target muscle
was relaxed. The ANOVA summary tables are presented in Appendix 3.
H-reflex recovery in control subjects
In order to determine the extent to which the MEP recovery profiles reflect
the excitability of the alpha MNs, the H-reflex recovery profiles were determined
under similar test conditions. Figure 5 shows an attenuation of the test reflex at
short ISIS, with recovery being more rapid when the target muscle was contracted. A two way ANOVA indicates an interaction effect between muscle activation
state and ISI (F=5.05, pc0.0001). Signifiant main effects of muscle activation
state (F=92.62, p<0.0001) and ISI
were also detected (F=l6.7I1pcû.0001).
Paired t tests indicated that the test reflex recovery was more robust at ISIs of
50, 80, 100, 200, 300, 500 and 1O00 msec. (p=0.04, 4.0001,cû.0001, 0.05,
0.003, 0.002, and 0.001, respectively) when the target muscle was contracted.
--*-Relaxation (n=l2)
+Contraction
(n=14)
EQWP 4: The mean (i1 SEM) MEP r e c m r y profile for the control group under
relaxed and contracted conditions. The ordinate reflecfs the ratio of the
testlconditioned MEP amplitude expresçed as a percentage.
' = significant difference betwen the
See text for details.
states of muscle activation.
--+Rehtion
(n= 15)
+- Contraction (n= 14)
150-
*
s
h 100-
8
>
O
O
g
so01
1
I
I
1
I
1
b
1
20
30
40
50
80
IO0
200
300
500
1
1
i
1000 2000 4000
ISI (msec)
E@ue 5: The mean (f ISEM) Kreflex recovery profile for contrd group under
relaxed and contracted conditions. The ordinate reflects the ratio of the
testiconditioned Kreflex anplitude expressed as a percentage.
= significantdifference behirRen the hm states of muscle activation.
See text for details.
When comparing the MEP and the H-reflex recovery profiles it was evident that they were markedly different when the target muscle was relaxed
(Figure 6A). and to a lesser extent when the FCR was contracted (Figure 68).In
relaxation (Figure 6A), the stimulus modality (TMS, nerve stimulation) and ISI
interacted to a significant degree (E8.67, p4.0001). Main effects of stimulus
rnodality (F=112.?0, pcû.0001) and ISI (F=3.26, p4.0001) were also detected.
Paired t tests showed enhanced MEP recovery at ISIS of 20, 30,40,50 and 80
msec (pc0.001, CO.001, cû.001, 4.001 and 0.01, respedvely) as compared to
the recovery of the H-reflex.
When the target muscle was contracted (Figure 6B). there was no differ-
ence in the recovery profiles attributable to the stimulus modality (Fd.24,
p=0.62), however, ISI exerteû a significant effect (F=11.08, pcû.0001). and there
was an interaction effect between these two variables (F3.51. p=0.0001). At
ISIS of 80 msec and 100 msec the test response was nearly fully recovered fol-
lowing peripheral nerve stimulation, but not TMS (p=0.0002). At shorter and
longer ISIS, aie H-reflex and MEP responses recovered to similar extents.
MEP
Kreflex
+
-4-
t
l
I
I
I
I
I
I
20
30
40
50
80
100
200
300
I
I
i
1
500 1000 2000 4000
ISI (msec)
MEP
2oo~
+
I
1
I
I
t
I
I
I
I
20
30
40
50
80
100
200
300
500
1
I
1
1000 2000 4000
ISI (rnsec)
Eigw~B
A cornparison of the mean MEP and H-reflex recovery profiles for the
control group generated with the target muscle relaxed (A) and contraded (B).
Error bars reflect 1 SEM. * indicates signifiant differences (pc0.01).
MEP recovery in subjects with SCI
Threshold stimulation intensity was 7 4 ~ 7 %with the target muscle
relaxed, and was not significantly different 64*14% with contraction (p0.20).
The relative amplitude of the baseline MEP responses (expressed as a percent-
age of maximal M wave) was similar for both relaxed (17I22%) and contracted
(2&14%) target muscle conditions (pa.68).
Unlike control subjects, relaxation of the FCR as evidenced by electrical
silence in the €MG signal was rarely observed despite an absence of quantifiable force production (Figure 7A). Providing no measurable force was evident,
the muscle was considered to be relaxed. In this condition, the test response
was markedly facilitated at ISIS ranging from 20 msec to 80 msec (Figures 7 A
and B). Although there was some variability across trials for the same subject
(Figure 7B), the pattern was maintained. At longer ISIS(2100msec), the magnitude of the test response relative to the conditioned response fluctuated, but
approached full recovery (1OC)%). The mean MEP recovery profile for al1 subjects with SC1 is illustrateci in Figure 7C.
With the target muscle contracted, the test response was facilitated by the
conditioning stimulus in one subject with SC1 whose FCR strength was poor
(Figures 8A and 6). A similar pattern was evident when the data were pooled
and averaged for ail subjects with SC1 (Figure 8C).
muce
7: The MEP recovery characteristics following
suprathreshold cortical stimulation with the target muscle relaxed.
Raw €MG traces illustrate the MEP responses in the relaxed FCR
following paired TMS (A). The interstimulus interval (ISI) is
indicated above each trace and the stimulus artifacts are noted by
the dots. The average ratio of the test I wnditioned response
(expressed in percentage) of 5 trials at each ISI is presentated for
the same subject (B). The mean recovery profile for the SC1 group
(n=5) is also shown (C). Error bars refiect 1 SEM.
Eigure 8: The MEP recavery characteristics following
suprathreshold cortical stimulation with the target muscle
contracted. Raw EMG traces illustrate the MEP responses in the
contraded FCR followi-ng paired TMS (A). The interstirnulus interval
(ISI) is indicated above each trace and the stimulus artifacts are
noted by the dots. The average ratio of the test / conditioned
response (expressed in percentage) of 5 trials at each ISI is
presentated for the sarne subject (B). The mean recovery profile for
the SC! group (n=5) is also show (C). Error bars reflect 1 SEM.
Recovery %
Recovery %
O
N
Ui
O
E
Figure 9 illustrates the mean MEP recovery profiles of the SC1 group
accentuating their similarity under both relaxed and contracted conditions
(F=1.73, p=0.19). Only a main effect of ISI was found (F=2.33, p=0.01) and post-
hoc analysis indicated facilitation of the test response at ISISof 40 and 50 msec.
H-reflex recovery in subjects with SC1
The H-reflex recovery profiles were similar when the FCR was relaxed
and contracted (Figure 10). The test H-reflex was attenuated at ISIS ranging
from 40 msec to 80 msec with the FCR contracted and extended to an ISI of 30
msec when FCR was relaxed. Comparing the MEP and the H-reflex recovery
profiles revealed markedly different curves for both relaxed (Figure 11A) and
contracted (Figure 11B) conditions depending on the stimulus modality. Generally, the test MEP was facilitated at short ISISwhereas the test H-reflex was attenuated. Statistical analyses were not conducted due to the small nurnber of
subjects in whom cornplete data sets were available.
-4R e i a d (n=5)
-+ Contracted (n= 5)
S 300-
L
aa
g 200O
P 1000I
I
1
b
1
1
1
1
1
20
30
40
50
80
100
200
300
500
1
1
I
Io00 2000 4000
EÏgure9:The mean (I 1 SEM) MEP recovery profile for the SC1 group under
reiax?d and contracted conditions. The ordinate reflects the ratio of the
testkonditioned MEP ampiitude expressed as a percentage.
* Significant difference from other ISIS, pc0.05
Relaxation (n=3)
++Contraction (n=2)
--O--
T
Eigure 1O: The mean (i1SEM) Kreflex recovery profile for SC1 group under relax4
and contracted conditions. The ordinate reflects the ratio of the test/condiioned
Wreflex ampitude expressed as a percentage.
300-
-
S
-
2 2009O
-c- MEP
H-reflex
--+-
O
3 1000-
E i g u A~cornparison of the mean MEP and H-reflex recovery profiles for the
SC1 group generated with the target muscle relaxed (A) and contracted (B).
Error bars reflect 1 SEM.
Between group comparisons
TMS thresholds were not different between control and SCl subjects
when the target muscle was either relaxed (p=0.25) or contracted (p=0.18).
TMS activated a similar proportion of the alpha MN pool in both groups of sub-
jects as evidenced by similarities in the MEP to maximal M wave ratios during
relaxation (p=0.10) and contraction (pdl.22).
The MEP recovery profiles generated while the target muscle was
relaxed were not different between groups (F=0.20, pd.66; Figure 12A). This
was not the case when the target muscle was contracted (F=4.81, pc0.0001;
Figure 12C). Unlike the control group, the test MEPs arnorig suujecis wiiii SSi
were markedly facilitated at ISIS from 40 msec to 80 msec (pcû.01). The significance of these group effects were evident despite highly variable data, particularly within the SC1 group. A range in functional abilities may have contributed
to the variability and as such, it was felt that it would be valuable to examine the
data individuaily. Table 2 summarizes the individual ME? recovery data revealiriy that subjects with poor or trace FCR strength (SC101L and SC102 respect-
ively) demonstrate extremes of the group pattern at short ISIS (40msec). For
example, marked facilitation of the test MEP was evident in the more involved
side of SClOl (left) and in SC102 when the FCR was contracteci.
---.-Control
SC1
T
1
I
1
I
I
1
I
I
1
20
30
40
50
80
100
200
300
500
1
r
1
1000 2000 4000
t
1
I
I
l
20
30
40
50
80
1
100
1
I
200
300
1
1
1
I
500 1000 2000 4000
ISI (rnsec)
ISI (m-)
t
I
I
1
I
I
I
1
I
20
30
40
SO
80
100
200
300
500
ISl (msec)
1
1
1
1000 2000 4000
I
20
I
I
1
1
1
I
1
1
30
40
50
80
100
200
300
500
1
1
1
1000 2000 4000
BI (msec)
E@Jre 22: A between group cornparison of the MEP (A, C)and the H-reflex (B. D) recovery profiles under relaxed (top)
and contracted conditions (bottom). Error bars refled 1 SEM. * indicates significant difference.
The H-reflex recovery profiles were not statistically analysed due to the
srnall number of SC1 subjects in whom reflexes were observed. The profiles,
however, appeared similar between control and SC1 groups onder both relaxed
(Figure 128) and contracted conditions (Figure 12D). There was a tendency for
the test H-reflex to be attenuated at very short ISIS(20 - 30 msec) among control
subjects in the contracted condition. but not so in subjects with SCI.
Temporal parameters
In control subjects. the mean MEP latency was 17.6I2.2msec with the
target muscle relaxed. With contraction, the onset latency decreased signifie
antly to 15.411.8 m e c (p=0.007). This shift was not significant in subjects with
SC1 (30.3k24.5 msec, relaxed; 19.114.5 m e c , contracted; p=0.34). Between
group differences in MEP latency were not detected with the target muscle
relaxed (p=0.08), although significant delay was evident in subjects with SC1
when the target muscle was contracted (p=0.02). Using the H-reflex data to estimate central conduction time revealed a significant decline from 6.2d-3 msec
with the target muscle relaxed to 4.411.1 msec with target muscle contracted
(pc0.001) in control subjects. In subjects with SCI, central conduction time
ranged from 4.0 to 14.1 mec.
The duration of the MEPs visibly increased when the target muscle was
contracted versus being in a relaxed state. It was not possible, however, to measure the change as the polyphasic nature of the MEP waveform under contraction (compare Figure 7A with 8A) precluded accurate measurement of duration.
This was most problematic in subjects with SCI. In relaxation the mean MEP
Table 2: Summary of individual MEP recovery data for subjects with SCI. The numbers reflect the mean
ratio of the tesVconditioned response amplitude expressed as percent.
ISIS (msec)
Fi: Relaxed, C: Contracted.
Numbers in parentheses represent 1 SD.
N/A, data no! available (test response latency exceeded the recording time).
duration was significantly longer in the SC1 group (control: l3.2I4.Ornsec; SCI:
35.5123.0
msec; p=0.004). The difference was not attributable to between
group differences in MEP amplitude which is known to be directly associated
with MEP duration.
Similarly, the SP duration following TMS tended to be longer in subjects
with SC1 (control: 106I20 msec; SCI: 120I23 msec). Although this was not
borne out statistically (p=0.25).Following peripheral nerve stimulation, the SP
durations seemed less than occurred after TMS (control: 9911 1 m e c ; SCI,
1 1 M . 2 msec), but again, significant differences were not detected (pS.22).
V. Discussion
MEP recovery profiles in control subjects
The characteristics of the MEP recovery profiles revealed by this study
are comparable to reports by others under similar testing conditions
(suprathreshold stimulus intensity, target muscle relaxed or contracted). With
the target muscle relaxed, faciiitation of the test response at short ISIS (20 - 80
msec) was consistent with the findings of the study by Valls-Solé (1992; 20-50
msec). When the target muscle was contracted, the amplitude of the test MEPs
averaged approximately 32% to 43% of the conditioned MEP at ISIs of 20 - 100
msec. Claus (1992) reported similar attenuation of the test MEPs, but not to the
same extent (47% - 65%). In the latter study, the relative proportion of the alpha
MN pool activated by the conditioning stimulus (as a percentage of the max-
imum M wave) was lower (35%) than in the present study (42%) which left a
greater proportion available to be recruited by the test stimulus. The inverse
relationship between the conditioned and test MEP amplitudes has been well
documented when ISIs are short (cl00m e c ; Claus et al, 1992; lnghilleri et al,
1990; Valls-Solé et al, 1992) and has been largely attributed to refractoriness of
alpha MNs (Boniface et al, 1991; Fuhr et al, 1991; Mills, 1988; Triggs et al,
1993). With fewer alpha MNs responding to the conditioning stimulus, more
remain to be facilitated by the successive descending volleys (Claus et al,
1994) and they reach the firing threshold more readily by the test stimulus
(Claus, 1992). The refractoriness of MNs becomes increasingly apparent when
the target muscle is contracted as a result of the increased number of MNs activated (Ziemann et al, 1993).
Attenuation of the test response rnay be observed in the absence of target muscle contraction providing the conditioning stimulus is well above threshold (150%; Valls-Solé et al, 1992). Likewise, the test MEP may be facilitated
when the target muscle is contracted by reducing the intensity of the conditioning stimulus to subthreshold levels (Claus et al, 1992). It should be noted, however, that while the nature of the test MEP response can be modulated by the
intensity of stimulation, more robust effects are evidenced by altering the muscle's state of activation (Valls-Sole et al, 1992).
The mechanisms accounting for the differential MEP recovery profiles
when the target muscle was relaxed or contracted include, as mentioned above,
refractoriness of alpha MNs. If this were the sole mechanism, however, one
might expect the recovery profiles of the H-reflex to have a similar shape. This
was not the case (see Figure 6, p 33). During relaxation, the H-reflex recovery
profile showed an initial inhibition at ISISfrom 20 - 80 msec which is consistent
with the findings of Paniua et al (1990) for the FCR muscle. Using single motor
unit recordings from the soleus muscle, Mailis and Ashby (1990) suggested that
the attenuation of the test H-reflex was due to peripheral nenie refractoriness or
decreased synaptic efficiency. It is not possible to determine the extent to which
these mechanisrns contributed to the modulation of the test H-reflex since it
could not be determined from their data whether the same motor unit, hence
MN, fired in response to both conditioning and test stimuli. Although, given that
the cortically evoked MEP was markedly facilitated at the same ISIS (20 - 80
msec) suggests that the alpha MN pool was certainly accessible to the test stimulus thus inhibitory influences were not widespread.
When the target muscle was contracted, the H-reflex recovered ample-
tely at an
1st of
80 msec which is earlier than occurred when the FCR was
relaxed. The ability of H-reflex to recovery at shorter ISIS may reflect increased
synaptic efficiency resulting from active contraction (Paniua et al, 1990). Interestingly, the MEP recovery profile following TMS showed attenuation of the test
MEP at ISISas high as 100 msec.
The difference in the recovery curves following peripheral nerve stimulation and TMS cannot be due to refractoriness of cortical fleurons. Stimulation of
human motor cortical cells has indicated that these MNs can respond to high
frequency stimuli at a rate of 280 Hz to 500 Hz (Fujiki et al, 1996; Inghilleri et al,
1989). Furthemore, intraoperative recordings of spinal cord evoked potentials
following paired TMS have also shown persistent conduction of descending
volleys by the corticospinal axons at ISIS of 2 msec or 500 Hz (Nakamura et al,
1995).The shortest ISI in the present study was 20 msec or 50 Hz. Also when
the target muscle was relaxed, the test MEP was facilitated to a significant
degree indicating the capacity of the involved neural structures to respond at a
minimum frequency of 50 Hz.
The silent period and ifs relationship with MEP recovery
The wmplete recovery of the test MEP at an ISI of 100 msec when the
FCR was tonically active conesponded to the temination of the SP. The early
portion of the silent period (s50 msec) is reportedly due to refractoriness of
MNs (Boniface et al, 1991; Fuhr et al, 1991; Mills, 1988; Triggs et ai, 1993). Inhibitory postsynaptic potentials which are known to occur in the absence of a prior
facilitation (Brouwer and Qiao, 1995; Palmer and Ashby, 1992) are also likely
contributors. In addition to these largely segmental influences, it must be acknowledged that the SP duration is influenced by the focality of the cortical stimulus (Amassian et al, 1990; Wassermann et al, 1993), the muscle in question
(Roick et al, 1993), and the locus of stimulation, ie. longer SPs following cortical
stimulation versus cervicomedullary junction stimulation (Inghilleri et al, 1993).
Together, these findings suggest that both intracortical and segmental mechanisms are involved in modulating the MEP recovery profile. Evidence of the involvernent of intracortical inhibitory mechanisms in the latter part of the SP
(2 50
msec) is based largely on the continued attenuation of the test response in spite
of the recovery of the excitability of alpha MNs (Fuhr et al, 1991).
Are the MEP recovery profiles altered In subjects with SCI ?
With the target muscle relaxed, the MEP recovery profile in subjects with
SC1 showed marked facilitation at ISIS ranging from 20 to 80 m e c . The profile
was consistent with that obtained from control subjects implying that the spontaneous discharges obsewed in the baseline €MG did not modulate the MEP
recovery to any appreciable extent.
With contraction, the MEP recovery profile differed significantly in the SC1
group compared to control data. The profile closely resembied the curve generated when the target muscle was relaxed, ie: marked facilitdticin at 1%
between
20 to 80 msec. Unlike control subjects, the amplitude of the MEPs measured at
baseline during both relaxation and contraction were similar in subjects with
SCI. Normally. the estimated proportion of the MN pool activated by TMS
increases significantly when the muscle is contracted (Berardelli et al, 1991;
Day et al, l989a;Hess et al, 1987; Rothwell et al, 1987). Since this did not
occur in SCI, the relative number of MNs available to respond to the test stimu-
lus was similar in relaxation and contraction. Topka et al (1991) also noted that
contraction failed to enhance MEP amplitude in patients with long standing thoracic cord lesions. In combination these findings suggest that the activation of
spinal MNs is not necessarily accompanied by enhanced cortical excitability in
SCI, or that the descending pathways maintaining the tonic activation are not
accessible to TMS.
Examination of the segmental excitability in subjects with SC1 was lirnited
by few observations, however, some comment is warranted. The H-reflex recov-
ery profiles demonstrate that recovery is enhanced with contraction as occurred
in control subjects. Unique to those subjects with SCI was a slight facilitation of
the test reflex at ISIS of 20 and 30 msec when the FCR was contracted. Mailis
and Ashby (1990) have reporteci similar findings in their patients with spasticity
due to SCI. The abnormal increase of alpha MN excitability has been attributed
to increased synaptic transmission through oligosynaptic pathways from la
afferents ont0 MNs or sprouting of la afferent collaterals to form new synapses
onto remaining MNs (Mailis and Ashby, 1990).
The above noted mechanisms imply that abnormalities are primarily at
the segmental level. Their influence on cortical excitability changes appear
minimal as evidenced by the similarity in MEP amplitudes under both relaxed
and contracted conditions. Furthermore, the stimulus intensity required to produce a MEP was also sirnilar under both conditions of muscle activation. Normally, the threshold is significantly reduced in the presence of target muscle activation which has been attributed, in part, to an increase in cortical excitability
(Day et al, 1989a). Brouwer et al (1989) however. concluded that tonic levels of
activity may be sustained by pathways other than those activated by TMS. They
found that the estimated magnitude of the post-synaptic potential decreased
when a motor unit was voluntarily discharged at a higher frequency. It is reasonable that in SC1 the reliance on rapidly conducting corticospinal influences on
alpha MN discharge is reduced in MN pools caudal to an incomplete lesion.
The present study demonstrated prolonged delays in central conduction
in subjects with SCI, a finding consistent with previous reports by others
(Brouwer et al, 1992;Dimitrijevi'c et al. 1988; Hayes et al, 1991; Segura et al,
1992; Thompson et al. 1987a). This was not associated with the subjects with
SC1 being taller, as the average heights of control and SC1 groups were not dif-
ferent. Pathology studies have shown that continuity of central axons exists following incomplete SC1 surrounding the cyst, but there is breakdown of the myelin sheaths (demyelination) (Bunge et al, 1993; Kakulas, 1985). Alternatively,
there is diffuse axonal disruption. The damaged axons are mostly large calibre
(Bunge et al, 1993) which if markedly reduced in nurnber, rnay result in an
absence of MEPs or delayed MEPs mediated by srnaller calibre, slower conducting corticospinal tract axons (Cracco, 1987). It is unlikely that the MEPs
generated in the present study were mediated solely through slow corticospinal
axons since the delays would be expected to be approximately 50 msec
(Calancie et al, 1987). The delays observed which were as much as 10 m e c
would be consistent with focal demyelination near the lesion site (Brouwer et al,
1992) or from partial conduction block from dysmyelination of fast conducting
descending axons (Waxman, 1989; Katz et al, 1990). The resultant temporal
dispersion of the descending volleys due to nonhomogeneous conduction limits
the ability to bring alpha MNs to threshold following a single stimulus, but can
enhance the probability of raising the membrane potential sufficiently over a
prolonged period of time such that a second stimulus could discharge the MN
(Cracco, 1987). The marked facilitation of the test MEP at ISIS from 30 msec to
80 msec supports this view.
The increased complexity of the MEP wavefon observed in the subjects
with SC1 mirrors the temporal dispersion of descending volleys due to nonhornogeneous conduction caused by demyelination or dysmyelination (Day et al,
1989a). The prolonged duration over which multiple descending volleys sum-
mate ont0 alpha MNs may be so great that MNs are prevented from ever reach-
ing threshold leading to clinical weakness (Boniface et al, 19% ; Mills et al,
1991). The introduction of unnatural synchronous volleys via TMS rnay increase
the likelihood of generating composite excitatory postsynaptic potentials in the
alpha MNs, although this effect may not be possible voluntarily.
The silent period duration following TMS was not different between the
control group and subjects with SC1. This rnay be because the inhibitory and
excitatory mechanisms activated by TMS are mediated by distinct cortical elements which may have different susceptibilities to pathophysiological processes. In patients with upper motor neuron diseaçe elevated thresholds for gener-
ses. In patients with upper motor neuron disease elevated thresholds for gener-
ating MEPs or an absence of MEPs have been observed without alteration in
SP duration (Triggs et al, 1992, 1993). Patients with Parkinson's disease how-
ever show abnormally large MEP amplitudes with shortened SP durations
(Priori et al, 1994) following TMS. A prolonged SP has been associated with the
paretic side of patients with stroke and in subjects with multiple sclerosis (Haug
& Kukowski, 1994). In SCI, cortical reorganization following SC1 (Levy et al,
1990;Topka et al, 1991) might be expected to alter the relative balance of inhibitory and excitatory cortical mechanisms thus altering the SP duration. Others,
however. have failed to support this view of reorganization (Brouwer & HopkinsRosseel. 1997; Cohen et al 1991) which may be a precursor to changes in the
SP. The small sample size (5 in the SCI group) of the present study precludes
drawing conclusions on the basis of similarities of the SP duration with control
subjects, yet the marked differences in the MEP recovery profiles suggest a
need for further research.
Limitations of the study
Recording compound muscle action potentials in response to transcranial cortical stimulation cannot provide detailed information regarding the ways in which
the descending volleys affect the excitability and discharge of individual spinal
motoneuron. As such it was not possible to elucidate the specific mechanisms
underlying the alteration in the MEP recovery profiles observed under the two
conditions of muscle activation (relaxed , contracted) or between control subjects and those with chronic SCI. To do so would require the recording of single
motor units.
The small sample size of the SC1 group and the variability among these
subjects limit the conclusiveness of the findings. The consistency in observing
abnormalities in the data, particularly when the FCR was cuntracted, however,
provides the rationale for continued research in this area. lncreased numbers
irnprove the power of study and consequently the conclusiveness of the findings.
VI. Conclusions and future research
The present study revealed that in 15 healthy control subjects the test
MEP amplitude was enhanced when suprathreshold TMS was applied at ISIs
ranging from 20 to 80 msec with the target muscle relaxed. The nature of the
MEP recovery profiles differed significantly depending on the activation state of
the target muscle with the test MEP amplitude attenuated at ISIS slOO rnsec
when the target muscle was contracted.
The H-reflex and MEP recovery profiles differed at similar ISIS, with the
test H-reflex demonstrating earlier recovery when the FCR was contracted. At
rest the test H-reflex was attenuated at ISIS ranging from 20 to 80 msec while
the MEP was markedly facilitated at the sarne ISIS. These data suggest that
supraspinal mechanisms are likely involved in modulating the segmental
response to paired TMS.
In subjects with incomplete cewical SCI, the
MEP recovery profile was
similar to that of the control subjects when the target muscle was relaxed, however, the profiles differed significantly when the FCR was contracted. Unlike
control data, marked facilitation of the test MEP was evident at ISIS ranging frorn
20 to 80 msec, similar to the profile generated when the target muscle was
relaxed. This may be explained by the failure of contraction to enhance the conditioned MEP in SCI, therefore a relatively larger proportion of the MN pool
would be "available" to respond to the test stimulus. Alternatively, temporal dispersion of descending volleys associated with delays in central conduction
may have limited the ability to bring alpha MNs to threshold following a single
stimulus, but raised the membrane potential sufficiently over a prolonged period
of time to facilitate the test response.
This study reported the characteristics of the recovery of the MN pool
associated with FCR and presented preliminary findings suggesting abnormalities associated with SCI.With surface electromyography it was not possible to
elucidate the state of excitability of individual motoneurons which would provide
more conclusive evidence pertaining to their recruitment. Further studies using
single motor unit recordings would provide such detailed information. In addition, it would be of benefit to increase the sample size of the SC1 group and
examine the relationship between functional ability and the characteristics of
MEP recovery. This rnay provide a better understanding of the pathophysiology
associated with chronic SCI.
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Appendix 1
SCI~OOLOF REHABILITATIONTHWY
Queen's University
I;ACIILIY OF hIEL)ICINE:
Kingston, Canada
K7L 3 ~ 6
CONSENT FORM
A STUDY OF THE CONVERGENCE OF DESCENDING VOLLEYS ONT0
SPINAL MOTONEURONS - HOW DOES CENTRAL CONDUCTION
RELATE TO FUNCTION?
Principal Investigator: Brenda Brouwer, Ph-D. School of Rehabilitation Therapy. 545-6081
Co-Investigator: Karen Smith, MD, FRCPC; Kingston General Hospital. 548-3232
Student Investigator: Woie-Nan (Barbara) Bair. M.Sc. Candidate. School of Rehabilitation Therapy. 5456203)
Background Information
You are being asked to participate in a research project conducted by Dr. B. Brouwer of the School of
Rehabilitation Therapy at Queen's University and Dr. K. Smith of the Kingston general Hospital. The
objective of this project is to gather data relating to how reff exes and how the brain respond to certain inputs.
This information is important as it contributes to our undetstanding of whether muscles which have decreased
function as a result of an incornplete spinal cord lesion of the cervical spine can be made to contract given
two inputs in rapid succession.
Details of the stndy
Functionul hsessmenr A clinical neurological examination will be done in order to detemine the arnount of
motor and sensory sparing you have and to esîablish the spinal level of your incornplete cord lesion. The
impact that the spinal cord injury has on your ability to perform certain tasks or activities will also be
evaluated using a standard questionnaire designed to address function in people with quadriplegia.
Laborarory Arsessment: This study involves recording from a muscle in your forearm (flexor carpi radialis)
which flexes your wnst. Small disc electrodes will be filled with conductive gel and placed on your skin
overlying the muscle after first cleaning the area with an alcohol wipe. Another pair of electrodes will be
placed near your etbow (the inside surface) such that the electrodes overlie the nerve which activates the
muscle of interest. Through these electmdes brief electncal stimuli (0.5 millisecond duration) will be given in
pain (i.e. two stimuli, one after the other). The intensity of the stimulus will be hiph enough to cause a small
muscle contraction but it should not be painful. No more than 50 of these stimulus pairs will be given and the
response of your muscle will be recorded. The time between each of the stimuli of the pair will be varied such
that some will be very close together in time and others not so close. Following this the intensity of the
stimulus will be increased to the point where your muscle responds maximally. One stimulus will be given and
only one such recording is necessary. From experience. some people descnbe the higher intensity stimulation
is "uncornfortable", some Say it's painful and others find it not much different than the lower stimulus
intensities. It is, however, in ail cases very brief.
2
Another type of stimulation will also be introduced. This is called transcranial mapetic stimulation. A
circular shaped coi1 will be placed slightly to the left of the top of your head and you will hear a "click" as the
stimulator is discharged causing current to flow through the coil. The response to this is that your scalp
muscles will contract slightly (probably causinp you to blink) and you rnay notice that a muscle on your right
side might contract. This is because the cells in your brain which tell your muscles what to do have been
activated by the magnetic stimulator. This form of stimulation is not painful. The intensity of stimulation will
be that which is just able to evoke a response in the muscle of interest. If, because of your spinal cord injury a
response is not evident, you will be asked to gently contract the muscle of interest to enhance the likelihood
of observing a response. Once the intensity of stimulation required has been detennined, paired stimuli will be
introduced in a manner similar to that described above in relation to electricai stimulation. The stimulus pairs
will be delivered at -30 second intervals and about 40 pairs will be &en.
Testine
Al1 testing will take place in a laboratory in the Louise D. Acton Building on Queen's campus. You will be
asked to come in for one session only which will take approximately two and a half hours. During testing
you can rernain seated in your wheelchair.
Risks and exclusions
Both electrical and magnetic stimulation have been used for a decade or more without incident. Magnetic
stimulation of the brain has undergone rigorous safety testing and adverse affects or incidents have not been
reported. There are precautions which we have adopted even though the research indicates this f o m of
stimulation can be used safely with individuals who have any of the ailments included in the list below:
lndividuals who have any of the following mav not participate in this study:
- cardiac pacemaker
- cochlear implant
- a history or familial history of epilepsy
- metai implants in the nght forearm
- a history of neurologkal disorder other than spinal cord injury.
Benefits
There are no direct benefits to participating in this research snidy. The information is being gathered to better
understand whether signais from the brain can converge in the spinal cord to enhance the ability of a muscle
to contract. Such neurophysiological information wil1 be correlated with the measures of function and if an
association is found then this protocol may provide a means of monitoring recovery or response to specific
treatrnent strategies geared toward improving conduction through the motor pathways.
Volnntarv participation
Participation in this study is voluntary. Withdrawal rnay occur at any time for any reason without
consequence.
Pavment
Each volunteer will receive $u).ûû for their participation in the study. This will be paid following completion
of the data collection. In addition, if required, travel costs (gas or taxi) will be reimbursed to a maximum of
$20.00. Parking is available behind the Louise D.Acton Building.
3
Confiden tialitv
The information obtained dunng this study will remain coofdential. An alphanumeric code will be applied to
your data which is stored according to this code. The list rnatching your name to the coded data will be
shredded upon completion of the study. The information gathered may be used for publication and
presentation at scientific meetings wi th the understanding that your data cannot be linked to you. On1y the
investigators involved in this study will have access to your data which is stored and locked in a research
laboratory .
My signature below indicates that 1 am satisfied that the purpose of this study and its pmtocol have been
clearly explained to me by one of the investigators, my questions have been addressed, and 1 freely agree to
participate. I have none of the ailments described which would exclude me from participating. I know that 1
may ask further questions at any tirne during the experiment and may contact Dr. Brenda Brouwer at 5316087if 1 have any concerns or Dr. Malcolm Peat, the director of the School of Rehabilitation Therapy (5456104) . I will retain a copy of this consent fom for my own information.
I
volunteer to iake part in the study descri bed above.
Signature:
Date :
Wi tness:
Date:
$tatement of the investigator
I have carefully explained the nature of the study and 1 cedf'y to the best of my knowledge, the volunteer
understands the nature, demands and exclusion criteria of this study.
Appendix 2
STANDARD NEUROLOGICAL CLASSIFICATION OF SPINAL CORD INJURY
MOTOR
SENSORY
1'1 N
PRICK
R
L
KEY MUSCLES
R I,
( '2
( '-3
('4
('5
( -0
.
,
l
,
0
;
KEY SENSORY POINTS
.
I
1
l
I
/
.
, !
!
I I
;
I
,, i
I
1
!
1
, i i 1
('7
1
('8
'1' I
'1'2
'1'3
'1'4
i !
I
ii
:
i
!
;
I
'
i
1 '
'
'
1
/
'1'7
'1'8
l'9
'1' 1 O
-1. 1 1
8
1
1
'1.0
i
1
i !
1
'i.5
t
1
(
: /
;
i '
l
I
1
1
i
I I /
'
l
1
/
I l . i
i I I
'1' 1 2
' 1
! I
i
: i
1
j II
i
1
1.1
1.2
1.3
i 1;
1A
IS
s1
52
S3
SJ-.5
TOTALS
1 i+l I= M MOT OR SCORE
TOTALS
(hI~\SlhlllXI)
(X ~
NEUROLOGICAL
LEVEL
R L
11
I X I ~ I U I (%Y)
~ )
(50)
COMPLETE OR
INCOMPLETE ?
l'lie r n ~ mc.an.rnl s q t t i r ~ ~ r
I r t m t t i p / r t ~= l ~ r c w t ~ trt rj
w'ilh tronnnl firricviittt
tnotvr f11t11
,thtri hi
=
=
(Sb) (Sb)
O LIGHT TOUCH SCORE
(iiirilr
I ' ~ i r t i c i l l \ititrcri~cttrdsegrnrtrts
I I ~
I 17)
( i ~ u i r 1 I 2)
ZONE OF PARTIAL
R L
PRESERVATION SENSORY
1-
cm! wrtsc~rvttr
II~IVCW
.MITII/
W ~ I I ~
PIN PRICK SCORE
ASIA IMPAlRMENT SCALE
UA= Complete: No motor or sensory function is preserved in
the sacral segments S C S S .
a~= Incomplete: Sensory but not
-
motor function is preserved
below the neurological level
and extends through the sacral
segments S4-S5.
AC = Incomplete:
Motor function is
preserved below the neurological level, and the majority of
key muscles below the neurological level have a muscle
m d e less than 3.
b
ID= Incomplete:
Motor function is
preserved below the neurological level, and the majority
of key muscles below the neurological level have a muscle
grade greater than or equal to
3.
]E
= Normal: Motor and sensory
function is normal.
Appendix 3
3.1. ANOVA for MEP recovery profiles under relaxed and contracted
conditions of control group
Source
Muscle
activation
state
Sums of DF
Mean
Squares
Squares
190600
190600
1
F
ratio
P value
36.82
p<O.OOOl
DF = Degrees of freedom
3.2. ANOVA for MEP recovery profiles under relaxed and contracted
conditions a t ISIs~100msec of control group
Source
Sumsof
Squares
OF
Mean
Squares
F
ratio
P value
Interaction,
59800
5
11960
0.86
0.69
Muscle
activation
state
81750
1
81 750
5.88
0.01
8890
5
1778
0.13
0.99
ISI
DF = Degrees of freedom
86
3.3. ANOVA for H-reflex recovery profiles under relaxed and
contracted conditions of control group
1
1
Source
,Sums of DF
Mean
Squares
Squares
Muscle
activation
state
F
ratio
P value
92.62
p<0.0001
.
'
86380
1
86380
DF = Degrees of freedorn
3.4. ANOVA for test modalities under relaxed condition of control
WuP
I
Source
,
Test
i modality
Mean
Squares
F
ratio
P value
l
;
499900
1
158900
11
499900 112.7 p<0.0001
1
1
ISI
I
Sums of DF
Squares
'
DF = Degrees of freedorn
14450
3.26
~0.0001
3.5. ANOVA for test modalities under contracted condition of
control group
Source
Interaction
Sumsof
Squares
DF
57280
11
Mean
Squares
5207
F
ratio
3.51
P value
0.0001
Test
modality
DF = Degrees of freedom
3.6. ANOVA for MEP recovery profiles under relaxed and contracted
conditions of SC1 group
Source
Interaction
Sums of
Sauares
DF
Mean
Squares
F
ratio
41010
11
3728
0.47
0.92
13790
1
13790
1.73
0.1 9
P value
Muscle
activation
state
DF = Degrees of freedom
3.7. ANOVA for MEP recovery profiles between two groups under
relaxed condition
-
--
Source
Sumsof
Squares
DF
F
Squares r a t i o
Mean
P value
57280
11
5207
3.51
0.0001
355.9
1
355.9
0.24
0.62
180700
11
1 6420
1 1 .O8
p<O.OOOl
Interaction,
-
Test
rnodality
ISI
----
.
-
DF = Degrees of freedom
3.8. ANOVA for MEP recovery profiles between two groups under
contracted condition
Source
Sums of
Squares
DF
Mean
Squares
F
ratio
P value
4.80 p<O.0001
Interaction,
163900
11
14900
Group
52880
1
52880
17.04
yxO.0001
ISI
33770
11
3070
0.99
0.46