The effect of primary motor cortex stimulation on the timing of motor responses in a
timed‐response task
James E. Stewart, BSc. (Hons)
School of Psychology
2015
THIS THESIS IS PRESENTED FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
AND PARTIAL FULFILMENT OF THE
MASTER OF PSYCHOLOGY (CLINICAL NEUROPSYCHOLOGY)
OF
THE UNIVERSITY OF WESTERN AUSTRALIA
iii
Abstract
The generation of a motor action requires both the preparation and execution of
a motor plan that specifies the necessary motor commands. Previous research has
demonstrated that transcranial magnetic stimulation (TMS) over the primary motor
cortex (M1) can advance the onset of a motor response in a reaction time (RT) task when
delivered early in the response latency (Pascual‐Leone, Valls‐Solé, et al., 1992; Sawaki,
Okita, Fujiwara, & Mizuno, 1999). It has been hypothesized that this advancement
reflects the facilitation of preparatory motor processes necessary for the generation of
the response (Pascual‐Leone, Valls‐Solé, et al., 1992; Sawaki et al., 1999; Soto, Valls‐Solé,
& Kumru, 2010), although the precise mechanisms for this effect remain unclear. The
interpretation of these findings is complicated by the occurrence of stimulus recognition,
motor preparation, and motor execution processes in close proximity to each other,
which makes it difficult to disentangle the effects of TMS on different perceptual and
motor processes (Miller, 1982; Sawaki et al., 1999).
The experiments reported in this thesis investigated the effect of TMS on the
timing of motor responses in a timed‐response task. The task required the onset of a
pinch to be synchronized with the last tone in a sequence of four evenly spaced tones,
which were presented at an interstimulus interval of 1000 ms. This timed‐response task
permits the advanced preparation of a motor response (Carlsen & MacKinnon, 2010;
Hening, Favilla, & Ghez, 1988; Steglich, Heuer, Spijkers, & Kleinsorge, 1999), which
temporally separates preparation and execution‐related processes and may help
disentangle the effects of TMS on different stages of motor processing. M1 TMS
advanced both ipsilateral and contralateral pinches by a constant amount, without
affecting the kinematics of the response, when administered over a wide range of
intervals preceding the target response time. Left M1 TMS was found to advance pinch
onsets more than right M1 TMS, consistent with the hypothesis that the left M1 has more
influence than the right M1 over the control of the limbs ipsilateral and contralateral to
each M1 (Haaland, 2006). TMS similarly advanced unimanual and bimanual pinches,
suggesting that the each hemisphere makes similar contributions to the control of the
timing of unimanual and bimanual responses. Similar levels of corticomotor excitability
were also observed prior to the execution of unimanual and bimanual pinches,
iv Abstract
suggesting that interhemispheric interactions involved in the control of bimanual
pinches do not affect corticomotor excitability during motor preparation.
The specificity of M1 stimulation to the advancement of pinches, produced by
TMS, was investigated by comparing the effects of M1 and occipital TMS on the timing
of these responses. M1 and occipital TMS were both found to advance responses to a
similar extent, indicating that non‐specific mechanisms, such as a startle‐like response,
could mediate this effect. However, occipital TMS was also found to increase the force
of the response, indicating that occipital TMS might not be an appropriate control for
non‐specific effects of M1 TMS. In the final study reported in this thesis, TMS was found
to advance the onset of responses that required muscle contractions but not responses
which required the relaxation of a sustained contraction. These findings suggest that
TMS does not facilitate preparatory processes that are shared between responses that
require a muscle contraction and those that require a muscle relaxation.
The findings of this thesis suggest that TMS advances the execution of muscle
contractions by increasing M1 excitability, thereby abbreviating a period of rising M1
excitability that precedes the execution of a response. The results also suggest that M1
can make small modifications to the timing of a motor response by altering the time
taken to execute the prepared motor plan. Overall, the results of this thesis demonstrate
the importance of neural processes separable from the motor plan in cued sensorimotor
tasks.
v
Contents
Abstract ................................................................................................................................. iii
Contents ................................................................................................................................. v
Acknowledgements ............................................................................................................ vii
Abbreviations ....................................................................................................................... ix
Chapter 1. General introduction ............................................................................................. 1
The neural control of motor actions ........................................................................... 2
The control of bimanual movements ......................................................................... 3
Left hemisphere dominance in motor control .......................................................... 5
Perturbing cortical activity with transcranial magnetic stimulation ..................... 7
Current thesis .............................................................................................................. 11
Chapter 2. General methods .................................................................................................. 15
Subjects ......................................................................................................................... 15
Materials and procedures .......................................................................................... 15
Data analysis ................................................................................................................ 19
Chapter 3. Single‐pulse transcranial magnetic stimulation over the left M1 advances
responses in a timed‐response task across a wide range of latencies prior to the
response ................................................................................................................................ 21
Methods ........................................................................................................................ 22
Results ........................................................................................................................... 23
Discussion .................................................................................................................... 27
Chapter 4. The effect of single‐pulse transcranial magnetic stimulation over the left or
right M1 on the timing of unimanual and bimanual pinches ...................................... 33
Methods ........................................................................................................................ 35
Results ........................................................................................................................... 36
Discussion .................................................................................................................... 39
vi Contents
Chapter 5. Corticomotor excitability during the preparation of bimanual forces of
equal and unequal magnitude ........................................................................................... 45
Methods ........................................................................................................................ 46
Results ........................................................................................................................... 47
Discussion ..................................................................................................................... 50
Chapter 6. Specific and non‐specific mechanisms of transcranial magnetic stimulation
induced response facilitation ............................................................................................. 55
Methods ........................................................................................................................ 57
Results ........................................................................................................................... 58
Discussion ..................................................................................................................... 61
Chapter 7. Mechanisms of transcranial magnetic stimulation induced changes in the
timing of a voluntary motor response .............................................................................. 65
Methods ........................................................................................................................ 66
Results ........................................................................................................................... 70
Discussion ..................................................................................................................... 75
Chapter 8. General discussion ............................................................................................... 81
Overview of research .................................................................................................. 81
Comparison of the effects of transcranial magnetic stimulation in timed‐response
and reaction time tasks .......................................................................................... 83
Specificity of effects of M1 stimulation..................................................................... 85
Conclusions .................................................................................................................. 90
References ............................................................................................................................. 91
Appendix 1. Supplementary statistics for Experiment 1 ............................................ 121
Appendix 2. Supplementary statistics for Experiment 2 ............................................ 123
Appendix 3. Supplementary statistics for Experiment 3 ............................................ 125
vii
Acknowledgements
First and foremost, I would like to thank my supervisors, Geoff Hammond, Gary
Thickbroom and Allison Fox, for their invaluable feedback, support and academic
guidance. Special thanks must go to my primary supervisor, Geoff, who has supervised
me since Honors and has continued to generously provide time for me, even in his
retirement. Geoff has always provided extensive, helpful feedback on all of my work,
which has been critical to the development of my academic writing. Thank you Geoff for
continuing to provide advice on what sometimes seemed like an endless number of
drafts and revisions to the thesis.
I would like to thank my partner, Zenobia, who also went through the PhD
program with me, and has not only supported me throughout all these years, but has
endured constant discussions about my research and has even provided comments on
some of my writing. Thanks also to all my peers within the School of Psychology for all
the support that you have given me, and for making my time in the PhD program
enjoyable, or at least bearable. I’m not sure I would have got to the end of this degree
without the community that I have found here.
I would like to thank my former (now finished) lab‐mates, Ann‐Maree, Li‐Ann
and Michelle, along with all those in my adopted EEG and Doppler lab‐group, for their
support, advice and encouragement. I would also like to thank all those who have taken
time out of their busy schedules to participate in my studies and those who helped me
pilot test my experiments. This thesis could not have been completed without your
contribution to this work.
This research has been supported by Australian Postgraduate Awards and
University of Western Australia Safety Net Top‐Up scholarships. The School of
Psychology and the Graduate Research School have also provided travel, equipment and
other funding which have helped support this research. As such, thanks must go to these
organizations and funding bodies for making this work possible.
ix
Abbreviations
ADM Abductor digiti minimi
APB Abductor pollicis brevis
CME Corticomotor excitability
CSP Cortical silent period
EMG Electromyography
FDI First dorsal interosseous
ISI Inter‐stimulus interval
M Mean
M1 Primary motor cortex
MEP Motor evoked potential
MVC Maximum voluntary contraction
RMS Root mean square
rMT Resting motor threshold
RT Reaction time
SD Standard deviation
SEM Standard error of the mean
SMA Supplementary motor area
TMS Transcranial magnetic stimulation
1
Chapter 1.
General introduction
The generation of a motor response, such as hitting a tennis ball with a racquet,
is preceded by a cascade of neural events. The generation of a motor response requires,
first, the recognition of a cue that signals the required response, such as the ball being
hit by an opposing player. After this cue has been recognized, the appropriate motor
response must be selected from a list of possible alternatives, such as list of tennis shots.
Then, the commands for the response must be programmed into a motor plan and,
finally, the response itself must be executed (Schmidt & Lee, 2011). The completion of
each of these stages requires a certain amount of time to complete the necessary
processing, which all contribute to the total reaction time (RT) for the response. An
examination of the timing of a motor response can therefore give insight into the
processing required to prepare and execute the response and how this processing is
affected by different neural and behavioral factors.
The existence of a motor plan, which is prepared prior to the execution of a motor
response, has been well supported over years of research (Schmidt, 2003). Its existence
has been supported by findings that more complex movements require more
preparation time, consistent with greater complexity of the corresponding motor plan
(Henry & Rogers, 1960). Movements requiring the coordination of multiple limbs
(Sternberg, Monsell, Knoll, & Wright, 1978) and movement sequences (Franks,
Nagelkerke, Ketelaars, & Van Donkelaar, 1998; Klapp & Zelaznik, 1996) have also been
found to require more preparation time, consistent with the greater complexity of these
actions. More direct evidence for the existence of a motor plan has been demonstrated
by findings that the removal of critical information immediately prior to the execution
of a response does not substantially affect the initial execution of the response,
suggesting that these actions were planned in advance. Subsequent components of the
response may be influenced by feedback, however, suggesting that an error‐correction
process monitors and corrects errors in the preparation or execution of the motor plan
(Cheng, Luis, & Tremblay, 2008; Elliott & Allard, 1985; Keele & Posner, 1968; Paulignan,
2 Chapter 1
Jeannerod, MacKenzie, & Marteniuk, 1991; Pélisson, Prablanc, Goodale, & Jeannerod,
1986; Zelaznik, Hawkins, & Kisselburgh, 1983).
The neural control of motor actions
Multiple cortical areas are involved in the preparation and execution of a motor
response. Early stages of motor preparation appear to primarily involve anterior motor
areas, including the dorsal premotor cortex and supplementary motor area (Koch et al.,
2006; O’Shea, Sebastian, Boorman, Johansen‐Berg, & Rushworth, 2007; Rushworth,
Johansen‐Berg, Göbel, & Devlin, 2003; Schluter, Krams, Rushworth, & Passingham,
2001). Associative areas in the parietal cortex also appear to assist in transforming
relevant perceptual information into the motor response (Rushworth et al., 2003). The
primary motor cortex (M1) is particularly important to the generation of motor actions
as both an area that contributes to the preparation of the motor plan and the largest
origin of pyramidal neurons through which these motor plans are executed (Davidoff,
1990; Holmes & May, 1909; Schieber, 2001). M1 appears to become more involved in later
stages of motor preparation, whereas the contribution of the premotor cortex decreases
closer to the onset of the response (Schluter, Rushworth, Passingham, & Mills, 1998; J. L.
Taylor, Wagener, & Colebatch, 1995).
The execution of a motor response requires the buildup of excitability within the
cortico‐motor system, including M1. Corticomotor excitability (CME), as measured by
transcranial magnetic stimulation (TMS) has consistently been found to increase prior to
the onset of a motor action (R. Chen & Hallett, 1999; R. Chen, Yaseen, Cohen, & Hallett,
1998; Hoshiyama et al., 1996; Leocani, Cohen, Wassermann, Ikoma, & Hallett, 2000;
Pascual‐Leone, Valls‐Solé, et al., 1992; Starr, Caramia, Zarola, & Rossini, 1988). This
increase in CME is accompanied by an increase in the firing rate of neurons in M1, which
is observed shortly prior to the onset a voluntary movement and continues until a
threshold is reached for discharging motor neurons (Evarts, 1966). Spinal motor neurons
also show increased excitability prior to movement onset (Schieppati, Nardone, &
Musazzi, 1985). These changes in excitability appear to be distinct from changes in motor
activity related to the preparation of a motor response, which does not require any
increase in CME (Kaufman, Churchland, Ryu, & Shenoy, 2014).
The control of a motor response is influenced by circuits of interneurons which
excite or inhibit pyramidal neurons in M1. Multiple different circuits of interneurons
General introduction 3
have been identified that either raise or lower the excitability of M1 cells (Ferbert et al.,
1992; Kujirai et al., 1993; Nakamura, Kitagawa, Kawaguchi, & Tsuji, 1997; Valls‐Solé,
Pascual‐Leone, Wassermann, & Hallett, 1992). Inhibitory processes within M1 and in
higher cortical areas are important for the prevention of premature responding and the
inhibition of competing, but inappropriate, responses (Duque, Lew, Mazzocchio,
Olivier, & Ivry, 2010; Jahfari, Stinear, Claffey, Verbruggen, & Aron, 2010; Mostofsky &
Simmonds, 2008; Stinear, Coxon, & Byblow, 2009; Tandonnet, Garry, & Summers, 2011).
Different circuits of interneurons appear to mediate different inhibitory processes such
as the inhibition of a specific competing response and the global inhibition of any
response (Criaud, Wardak, Ballanger, & Boulinguez, 2012; Duque, Labruna, Verset,
Olivier, & Ivry, 2012; Duque et al., 2010; Jaffard et al., 2008). The activity of inhibitory
circuits appears to be adaptively modified in response to task demands, both in reaction
to and in advance of a cue to inhibit a response (Boulinguez, Ballanger, Granjon, &
Benraiss, 2009; Criaud et al., 2012; Wardak, Ramanoël, Guipponi, Boulinguez, & Ben
Hamed, 2012). Motor responses appear to be inhibited by default by the motor system
(Criaud et al., 2012), meaning that the execution of a motor response requires the
withdrawal of inhibition. Consistent with this, a reduction in intracortical inhibition has
been found to precede changes in CME related to the execution of a motor response and
is sustained into the execution of the response (C. Reynolds & Ashby, 1999; Ridding,
Taylor, & Rothwell, 1995; Zoghi, Pearce, & Nordstrom, 2003). Preparation to respond to
an upcoming signal is also associated with a reduction in intracortical inhibition, along
with an increase in intracortical facilitation (Sinclair & Hammond, 2009, 2009; Tandonnet
et al., 2012; Tandonnet, Garry, & Summers, 2010), further supporting the role of changes
in excitability in the initiation of motor actions.
The control of bimanual movements
The control of bimanual actions appears to involve neural interactions between
the two hemispheres. These interactions are reflected in associations between the
movements produced by each limb, including a tendency towards the production of
symmetrical, synchronous actions, referred to as bimanual coupling (Swinnen, 2002).
Two aspects of bimanual coupling are spatial coupling and temporal coupling. Spatial
coupling, the tendency towards symmetrical actions, has been observed in drawing
tasks which require different shapes to be simultaneously drawn with each hand. The
4 Chapter 1
shapes produced in this task commonly take on characteristics of the shape drawn with
the other hand (Franz, 1997; Franz, Zelaznik, & McCabe, 1991). Spatial coupling has also
been observed in bimanual reaching tasks. When reaching to targets at different
distances, people typically overshoot the closer target while undershooting the further
target, such that the movements for both hands converge (Sherwood, 2006; Sherwood &
Nishimura, 1992). Similar effects are also observed in force production tasks
(Diedrichsen, Hazeltine, Nurss, & Ivry, 2003; Rinkenauer, Ulrich, & Wing, 2001).
Temporal coupling, the tendency towards synchronous actions, is observed
during naturalistic, goal oriented movements such as opening a drawer and retrieving
an object (Kazennikov et al., 1994; Perrig, Kazennikov, & Wiesendanger, 1999) or
pouring liquid into a glass (Weiss & Jeannerod, 1998). During reaching movements, the
initiation and termination of the movements produced by each hand occurs almost
simultaneously even when reaching to targets at different distances (Kelso, Southard, &
Goodman, 1979b). During force production, the times taken by each hand to reach peak
force from the onset of each response are also closely associated (Diedrichsen et al., 2003;
Rinkenauer et al., 2001; Steglich et al., 1999) and this association is preserved even when
subjects are instructed to increase the forces produced by each hand over different time
periods (Rinkenauer et al., 2001).
The neural mechanisms mediating bimanual coupling appear to differ between
spatial and temporal coupling. Spatial coupling appears to depend on the transfer of
pre‐motor and motor information via the corpus callosum. This hypothesis has been
supported by several ablation studies (Eliassen, Baynes, & Gazzaniga, 1999, 2000; Franz,
Eliassen, Ivry, & Gazzaniga, 1996). Individuals with a surgical section or agenesis of the
corpus callosum are impaired on tasks requiring coordinated bimanual movements
(Eliassen et al., 2000; Preilowski, 1972) but appear to have an advantage in decoupling
spatial aspects of movements, as they are able to produce two different shapes with little
interference between the hands (Franz et al., 1996; Ivry & Hazeltine, 1999; Tuller & Kelso,
1989). Similarly, force coupling between the limbs is lower in individuals with a surgical
section or agenesis of the corpus callosum than it is in normal controls (Diedrichsen et
al., 2003).
In contrast to spatial coupling, temporal coupling appears to be mediated by
either callosal or subcortical and cerebellar interactions, depending on the action being
performed (Ivry & Richardson, 2002; Kennerley, Diedrichsen, Hazeltine, Semjen, & Ivry,
General introduction 5
2002). The temporal coupling of continuous movements, such as those in a continuous
circle drawing task, appears to depend on connections through the corpus callosum
since people with a callosotomy show reduced coupling on these tasks (Kennerley et al.,
2002; Serrien, Nirkko, & Wiesendanger, 2001). Similarly, associations between the
temporal characteristics of a movement, such as the time taken by each hand to reach
the peak force of a pinch, are reduced in individuals with a callosotomy. However, these
associations are not completely eliminated in either individuals with a callosotomy or
callosal agenesis, suggesting that other connections, such as subcortical connections, also
contribute to these associations (Diedrichsen et al., 2003). Unlike continuous movements,
the coupling between movement onsets in a discrete tapping task persist in callosotomy
patients, suggesting that these associations are not primarily mediated by the corpus
callosum (Kennerley et al., 2002). Temporal coupling is similarly preserved (Franz et al.,
1996; Ivry & Hazeltine, 1999) or even enhanced (Tuller & Kelso, 1989) in other tasks with
discrete components such as opening a drawer with one hand and retrieving an object
inside with the other (Serrien et al., 2001). The associations between the actions produced
by each hand in these tasks could be mediated by subcortical or spinal interactions, as
well as shared contributions from cerebellar structures (Ivry & Richardson, 2002).
Left hemisphere dominance in motor control
Each limb appears to be primarily controlled by the contralateral hemisphere
(Brinkman & Kuypers, 1973). However, in right‐handed individuals, the left hemisphere
appears to be dominant and to contribute to the control of both limbs. Left‐handed
individuals also exhibit hemispheric dominance, although dominance tends to be more
variable within this group (Hammond, 2002). Early studies showed that lesions to either
hemisphere impaired movements performed by the contralateral upper limb but only
left‐hemisphere lesions impaired movements performed by the ipsilateral limb
(Liepman, 1908, 1920, as cited in Goble & Brown, 2008; Wyke, 1968, 1971). Left but not
right‐hemisphere lesions have been found to impair multiple aspects of motor control
including impairments in the control of bimanual motor sequences (Haaland &
Harrington, 1994), motor preparation (Haaland & Harrington, 1989) and complex goal‐
directed behavior (Haaland, Harrington, & Knight, 2000). Imaging data have also
supported the role of the left M1 in the control of both limbs. Greater activation has been
found in the premotor and motor areas of the left hemisphere than the right hemisphere
6 Chapter 1
during the performance of bimanual sequential finger‐thumb movements (Jäncke et al.,
1998) and ellipse drawing (Viviani, Perani, Grassi, Bettinardi, & Fazio, 1998). Increased
left M1 activation has been observed during the preparation of complex movements for
either hand (Haaland, Elsinger, Mayer, Durgerian, & Rao, 2004; Singh et al., 1998),
further supporting the role of the left M1 in the control of both limbs.
The left hemisphere appears to be more involved in the control of complex
movements than simple movements. Greater activation has been consistently found in
the motor areas of the left than right hemisphere during the performance of complex
movements with the ipsilateral hand (Callaert et al., 2011; Haaland, 2006; Haaland et al.,
2000; Koeneke, Lutz, Wüstenberg, & Jäncke, 2004; Serrien, Ivry, & Swinnen, 2006;
Swinnen et al., 2010). In contrast, similar levels of activation have been found in the
motor areas of the left and right hemisphere during the production of simple movements
with the ipsilateral hand (Jäncke et al., 1998; Volkmann, Schnitzler, Witte, & Freund,
1998) and during simple bimanual tapping movements (Pollok, Muller, Aschersleben,
Schnitzler, & Prinz, 2004). Greater left hemisphere activation has also been found during
the performance of a choice RT task than during a simple RT task with the ipsilateral
hand, which could be due to the greater complexity of the choice RT task (Schluter et al.,
2001).
TMS studies have supported the dominant role of the left M1 in the performance
of complex tasks. Greater increases in CME have been observed during the performance
of a complex task than a simple task with the ipsilateral hand (Tinazzi & Zanette, 1998;
van den Berg, Swinnen, & Wenderoth, 2011; Ziemann & Hallett, 2001). The increase in
CME during the performance of a complex task was also greater in the left than right M1
(van den Berg et al., 2011; Ziemann & Hallett, 2001). In contrast, similar increases in CME
have been observed in the left and right M1 during the performance of a simple
unimanual contraction with the ipsilateral hand (Stinear, Walker, & Byblow, 2001).
Furthermore, another study found that repetitive TMS over either M1 disrupted the
performance of a simple tapping task, performed with the ipsilateral hand, but only
repetitive TMS over the left M1 disrupted the performance of a more complex reach‐to‐
grasp task, performed with the same hand (Dafotakis, Grefkes, Wang, Fink, & Nowak,
2008). These data further support the dominant role of the left M1 in the control of
complex motor tasks.
General introduction 7
The left M1 also appears to be particularly important in the control of the timing
of motor responses. Increased left M1 activation has been observed during the
production of force responses with precise durations with either hand. This activation
was not observed when the task was modified to require precise forces, suggesting that
it did not result from increased task complexity but is specific to the control of the
temporal aspects of the response (Macar, Anton, Bonnet, & Vidal, 2004). Further support
for the role of the left M1 in the control of movement timing comes from an rTMS study
which found that rTMS to the left M1 could advance or delay the onset of muscle
recruitment in the ipsilateral hand, depending on the time at which this stimulation was
administered, relative to the expected onset of the response (Davare, Duque,
Vandermeeren, Thonnard, & Olivier, 2007). Another study found that disrupting M1
with rTMS can induce timing errors in the execution of metronome‐paced movement
sequences performed with the ipsilateral hand. These errors were produced by both left
and right M1 stimulation although the effects were stronger and outlasted the
stimulation period when rTMS was applied to the left M1 (R. Chen, Gerloff, Hallett, &
Cohen, 1997), further supporting the role of the left M1 in the control of the timing of
motor actions.
Perturbing cortical activity with transcranial magnetic stimulation
It has been proposed that TMS may be used to investigate the involvement of a
stimulated region in a function or behavior of interest (Paus, 2005). TMS can be used to
perturb or facilitate ongoing neural activity (Bohning et al., 2000; Silvanto, Cattaneo,
Battelli, & Pascual‐Leone, 2008), which may disrupt or improve the performance of a
behavior being investigated. If TMS disrupts the performance of a behavior, it may be
concluded that the regions activated by TMS are required, but not necessarily sufficient,
for the performance of this behavior (Chouinard & Paus, 2010). Similarly, if TMS
improves performance, this demonstrates that modulating the activity of the stimulated
region alters the control of this behavior, and that this region must therefore contribute
to the control of this action. This approach has been used in a number of studies,
discussed below, which investigated the effect of TMS on the timing of a motor response
in RT tasks.
8 Chapter 1
Reaction time responses delayed by transcranial magnetic stimulation
Suprathreshold TMS over M1 has been shown to delay RT in the contralateral
hand by up to 150 ms when administered within approximately 120 ms prior to
movement onset (Burle, Bonnet, Vidal, Possamaï, & Hasbroucq, 2002; Day et al., 1989;
Hashimoto, Inaba, Matsumura, & Naito, 2004; McMillan, Nougier, & Byblow, 2004;
Romaiguère, Possamaı̈, & Hasbroucq, 1997; Schluter et al., 1998; Schluter, Rushworth,
Mills, & Passingham, 1999; Ziemann, Tergau, Netz, & Hömberg, 1997). TMS has been
found to only delay responses when delivered at suprathreshold intensities (Burle et al.,
2002; Day et al., 1989; Hashimoto et al., 2004; McMillan et al., 2004; Meyer & Voss, 2000;
Romaiguère et al., 1997; Schluter et al., 1998, 1999; Ziemann et al., 1997). Suprathreshold
TMS has been found to delay responses in both the contralateral and ipsilateral hand.
However, delays in ipsilateral responses are only observed at high stimulus intensities
(approximately twice the resting motor threshold intensity) (Foltys et al., 2001; Meyer &
Voss, 2000) and are typically shorter (40 ms) than those observed in the contralateral
hand (Day et al., 1989; Meyer & Voss, 2000). Delays in contralateral responses are longer
at higher stimulus intensities (J. L. Taylor et al., 1995; Ziemann et al., 1997) and when
TMS is applied closer to the expected movement onset time (Day et al., 1989). Motor
responses executed following these delays appear to be intact, as they exhibit the
triphasic pattern of electromyographic (EMG) activity characteristic of a ballistic
voluntary motor response, consisting of sequential agonist‐antagonist‐agonist muscle
activation. This finding that TMS does not disrupt the structure of the response suggests
that the motor plan is not disrupted by TMS, which has led to the hypothesis that TMS
delays responses by temporarily blocking the transfer of the motor program to the
circuitry responsible for executing the response (Day et al., 1989).
Reaction time responses advanced by transcranial magnetic stimulation
Single‐pulse TMS has been found to advance responses in both the hands
contralateral and ipsilateral to TMS when administered during the response latency of
an RT task (Foltys et al., 2001; Hallett, Cohen, & Bierner, 1991; Leocani et al., 2000;
Molinuevo, Valls‐Solé, & Valldeoriola, 2000; Pascual‐Leone, Valls‐Solé, et al., 1992;
Pascual‐Leone, Brasil‐Neto, Valls‐Solé, Cohen, & Hallett, 1992; Pascual‐Leone, Valls‐
Solé, Brasil‐Neto, Cohen, & Hallett, 1994; Soto et al., 2010). TMS has been found to
advance contralateral responses more at lower, subthreshold intensities (Hashimoto et
General introduction 9
al., 2004; Pascual‐Leone, Valls‐Solé, et al., 1992), whereas it advances ipsilateral
responses more at higher, suprathreshold intensities (Hashimoto et al., 2004; Pascual‐
Leone, Valls‐Solé, et al., 1992). However, TMS has been found to advance contralateral
responses at both subthreshold (Brasil‐Neto, Pascual‐Leone, Valls‐Solé, Cohen, &
Hallett, 1992; Pascual‐Leone et al., 1994; Sawaki et al., 1999) and suprathreshold
intensities (Burle et al., 2002; Foltys et al., 2001; Leocani et al., 2000; Pascual‐Leone, Valls‐
Solé, et al., 1992; Romaiguère et al., 1997; Soto et al., 2010) when administered early in
the response latency. Later in the response latency, shortly before the expected onset of
the response, TMS has been shown to advance contralateral responses at subthreshold
intensities but to delay them at suprathreshold intensities (Hashimoto et al., 2004). The
effector of the response does not appear to moderate the extent to which TMS advances
a responses (Pascual‐Leone, Valls‐Solé, et al., 1992), nor is this effected by whether the
response is executed unimanually or bimanually (Foltys et al., 2001). Responses
advanced by TMS have been found to exhibit the same pattern of EMG activity as those
in conditions in which TMS was not administered, suggesting that TMS does not disrupt
the integrity of the response (Hashimoto et al., 2004).
Non‐specific mechanisms
The advancement of RT responses by TMS might be due to both non‐specific
mechanisms and mechanisms specific to the stimulation of M1, which will be discussed
in turn. Previous studies have produced mixed findings concerning whether non‐
specific factors, such as the sound or tactile stimulation produced by TMS, contribute to
the advancement of responses produced in RT tasks. Some studies have found that off‐
scalp stimulation or the stimulation of non‐motor areas can advance responses to a
similar extent to M1 TMS (Romaiguère et al., 1997; Terao et al., 1997). However, other
studies have found that TMS produces greater reductions in RT when delivered over M1
than when delivered off‐scalp or over non‐motor areas (Burle et al., 2002; Pascual‐Leone,
Valls‐Solé, et al., 1992; Ziemann et al., 1997). It has been suggested that differences in
these findings may be due to differences in the TMS intensity used between studies
(Hashimoto et al., 2004) or the use of different control stimulation conditions (off‐scalp
or non‐motor TMS) (Burle et al., 2002). However, it appears that both non‐specific and
specific effects contribute to the advancement of RT responses produced by TMS in most
10 Chapter 1
studies (Burle et al., 2002; Foltys et al., 2001; Hashimoto et al., 2004; Pascual‐Leone, Valls‐
Solé, et al., 1992; Sawaki et al., 1999).
It has been suggested that TMS could produce non‐specific effects through
intersensory facilitation (Terao et al., 1997), a reduction in RT to an imperative stimulus,
produced by the presentation of an accessory stimulus (Nickerson, 1973). The imperative
stimulus is the stimulus which is used to cue the response (the ‘go’ signal), whereas the
accessory stimulus is an additional stimulus that is not necessary to perform the task.
The sound and tactile stimulation produced by TMS could act as accessory stimuli to
produce intersensory facilitation. Intersensory facilitation may be mediated by the faster
detection of the imperative stimulus (Mordkoff & Yantis, 1991; Otto & Mamassian, 2012)
or temporal preparation, preparing to respond at a certain time (Los, Hoorn, Grin, & Van
der Burg, 2013).
A loud acoustic stimulus, such as the one associated with TMS (Counter & Borg,
1992; Nikouline, Ruohonen, & Ilmoniemi, 1999), could also elicit a startle response, a
pattern of bilateral muscle activity including include eye closure, facial grimacing and
neck flexion in response to an intense stimulus with a sudden onset (short rise time),
which could advance responses by involuntarily triggering the early execution of a
prepared motor plan (Blumenthal, 1988; Blumenthal et al., 2005; Carlsen, Maslovat, Lam,
Chua, & Franks, 2011; Valls‐Solé, Kumru, & Kofler, 2008). The startle response is more
reliably triggered at high auditory stimulus intensities (>100 dB) but components of the
startle response can be triggered at stimulus intensities as low as 50 to 70 dB (Blumenthal
et al., 2005; Blumenthal & Goode, 1991; Blumenthal & Keith Berg, 1986; Hoffman & Ison,
1980). These sound levels are exceeded by that produced by TMS, which is often in
excess of 100 dB, even at low stimulation intensities, and can exceed 130 dB at maximum
stimulator output (Counter & Borg, 1992; Gilbert et al., 2004; Nikouline et al., 1999). TMS
also produces tactile stimulation which may contribute separately to a startle response
(Nikouline et al., 1999; B. K. Taylor, Casto, & Printz, 1991; Yeomans, Li, Scott, &
Frankland, 2002). Although the startle response habituates rapidly when a loud acoustic
stimulus is presented at rest (Abel, Waikar, Pedro, Hemsley, & Geyer, 1998; Brown et al.,
1991; M. Davis & Heninger, 1972; Leaton, Cassella, & Borszcz, 1985), the habituation of
this response greatly diminished when a loud acoustic stimulus is presented during the
preparation of a motor response (Carlsen, Chua, Inglis, Sanderson, & Franks, 2003;
Siegmund, Inglis, & Sanderson, 2001; Valls‐Solé, Valldeoriola, Tolosa, & Nobbe, 1997).
General introduction 11
As such, a startle response may be present throughout a prolonged motor task (Carlsen
et al., 2003). A loud (startling) acoustic stimulus has been shown to advance responses
in RT tasks (see Valls‐Solé et al., 2008 for a review), and it has been suggested that this
phenomenon may contribute some of the advancement of responses produced by TMS
(Leocani et al., 2000).
M1‐stimulation specific mechanisms
TMS could advance RT responses by reducing the duration of motor processes
required to prepare or execute the response. TMS has been argued to advance responses
by reducing the duration of late motor processes, particularly the transfer of the motor
program from higher motor areas (e.g. premotor cortex) to the output circuitry in M1
(Pascual‐Leone, Brasil‐Neto, et al., 1992; Sawaki et al., 1999). TMS has been found to
produce the greatest advancement of the response when administered approximately
120 ms before the onset of EMG activity, approximately 30 ms before the onset of the
lateralized movement related potential (Sawaki et al., 1999). As the lateralized
movement related potential has been argued to reflect M1 activation, coincident with the
transfer of the motor program to the output circuitry, these findings indicate that TMS
produces its strongest effects on the timing of responses when administered
immediately prior to this event (Sawaki et al., 1999). While this finding could indicate
that the effects of TMS are mediated by the facilitation of the transfer of the motor
program to the output circuitry, TMS could also abbreviate subsequent motor processes
required for the execution of the response, such as the development of a sufficient level
of M1 excitability for response execution, by increasing M1 or subcortical excitability
(Molinuevo et al., 2000; Pascual‐Leone et al., 1994).
Current thesis
As outlined above, TMS could advance responses in RT tasks through several
different mechanisms. Different perceptual and motor processes occur in close proximity
and may even overlap in RT tasks, which makes it difficult for experiments using these
tasks to delineate the effects of TMS on different motor and perceptual processes (Miller,
1982; Romaiguère et al., 1997; Sawaki et al., 1999). Therefore, the experiments in this
thesis used a timed‐response task which permits advanced preparation of a motor
response to examine the effect of TMS on motor processing (Carlsen & MacKinnon, 2010;
12 Chapter 1
Hening, Favilla, et al., 1988; Hening, Vicario, & Ghez, 1988; Steglich et al., 1999). This
task required the synchronized execution of a pinch response with the last of four tones,
presented at an interstimulus interval (ISI) of 1000 ms. The use of this task allows
potential effects of TMS on stimulus recognition and response selection processes to be
excluded as these processes can be completed well in advance of the administration of
TMS. Tasks that require the anticipation of a motor response such as timed‐response
tasks have also been argued to be more ecologically relevant than RT tasks as most
everyday motor actions involve predictable stimuli that can be reliably anticipated,
rather than a rapid execution of a response to an unexpected event (Schmidt & Lee, 2011).
Thesis outline
This thesis assessed the contribution of M1 to the control of the timing of motor
responses by perturbing M1 with single‐pulse TMS during the performance of a timed‐
response task. The details of this task and general methods for all of the experiments in
this thesis are presented in Chapter 2.
Chapter 3 presents a study which investigated the effect of TMS on the timing of
a response, when administered at various times prior to the expected onset of the
response. TMS was found to advance responses made with either hand over a wide
range of TMS‐response intervals. Chapter 4 describes an experiment which compared
the effects of TMS over the left and right M1 during the performance of a timed‐response
task which required either unimanual or bimanual pinches. Left and right M1 TMS were
both found to advance responses in the hands contralateral and ipsilateral to TMS,
regardless of the required response. TMS produced stronger effects on the timing of both
ipsilateral and contralateral responses when administered over the left M1 than when
administered over the right M1. Both bimanual and unimanual pinches were similarly
advanced by TMS. Chapter 5 presents findings indicating that CME does not differ
between the preparation of these unimanual and bimanual pinches.
Chapter 6 presents findings from an experiment which aimed to quantify the
contribution of non‐specific effects to the advancement of response onsets produced by
TMS, by comparing the effects of left M1 and left occipital TMS. TMS over the occipital
cortex was found to advance responses to a similar extent to TMS over the left M1. This
finding could suggest that non‐specific mechanisms, such as a startle‐like response,
mediate this effect. However, occipital TMS was also found to increase the force of the
General introduction 13
response, which may indicate that occipital TMS was an inappropriate control for non‐
specific effects of TMS over M1.
The experiment presented in Chapter 7 examined whether TMS facilitated
processes involved in the preparation or execution of a motor response. This was
accomplished by examining the effect of TMS on the timing of responses that required a
muscle contraction or the relaxation of a sustained contraction. These responses are
hypothesized to involve shared preparatory processes but opposing changes in CME,
related to the execution of the response. TMS was observed to advance contraction but
not relaxation responses suggesting that TMS advances responses by facilitating
processes required for the execution of a muscle contraction.
Chapter 8 integrates the findings from the thesis and discusses the potential
implications of these findings.
15
Chapter 2.
General methods
All experiments in this thesis used a timed‐response task which required the
synchronized execution of a unimanual or bimanual pinch with the fourth tone in a
sequence of equally spaced tones. Experiment 1–3 (Chapter 3–6) required brief pinch
responses whereas Experiment 4 (Chapter 3) required either the application or release
of a sustained contraction in separate conditions. In each experiment, the required force
and hand of the response were specified with a pair of force targets which represented
the left and right hand and were presented on corresponding sides of a computer
monitor. Practice trials familiarized subjects with the task in each session of every
experiment. TMS was administered during the experimental trials of each experiment to
quantify CME and to examine the effect of TMS on the timing of pinch onsets.
Subjects
Right‐handed subjects were recruited separately for each experiment using an
online notice board. Handedness was determined via self‐report. Subjects were either
awarded course credit or provided with a small remuneration for their time and travel
expenses. All subjects gave written informed consent and were screened for medical
conditions which might make them unsuitable for testing with TMS such as a history of
brain surgery, epilepsy, episodes of faintness, or the current use of psycho‐active
medication. All experimental protocols were accordance with the Declaration of
Helsinki and were approved by a local research ethics committee.
Materials and procedures
Pinch response
Subjects sat with their forearms supported on a table with the index finger and
thumb of each hand lightly touching either side of a Loadstar LAD‐050‐025‐S force
transducer or a pair of back‐to‐back force transducers. In Experiment 2, fingertip pinches
were made by pressing the tips of the index finger and thumb against opposite sides of
16 Chapter 2
a pair of back‐to‐back force transducers In Experiment 1, 3 and 4, lateral (key) pinch
responses were made by pressing the radial side of the index finger and thumb against
opposite sides of a force transducer. The lateral pinch response was used in these later
experiments to ensure that the first dorsal interosseous (FDI) muscle, to which all
magnetic stimulation was calibrated, was the prime mover for the response1. Subjects
were instructed to keep their hands relaxed between trials in each experiment.
Maximum voluntary contraction determination
Maximum voluntary contraction (MVC) forces were determined as the largest
peak force amplitude from five successive bimanual pinches, with each bimanual pinch
separated by 6 s. Pinches were recorded separately for each hand. The pinch onset times
for each hand were required to be separated by less than 150 ms and pinches were
required to be less than 1 s in duration. Visual feedback was given on these criteria and
trials were discarded and repeated if these criteria were not met.
Task
The task used in Experiment 1–3 is described below. This task was modified in
Experiment 4. The details of these modifications are presented in Chapter 7.
At the start of each trial, subjects fixated on a cross displayed in the center of a
monitor. Four tones, each 60 ms in duration, were presented at an inter‐stimulus interval
of 1000 ms. Subjects were required to synchronize the onset of their responses with the
last of these four tones. In Experiment 2–4, the force targets were presented 600 ms before
the onset of the final tone. These targets were presented 800 ms before the final tone in
Experiment 1 to compensate for the administration of TMS at earlier intervals in this
experiment. The force targets were contained within two vertical bars, which
represented the left and right hand, and were displayed on corresponding sides of a
computer monitor (see Fig. 1). These bars displayed force on a linear scale, from 0% MVC
at the bottom to 100% MVC at the top. The target force was indicated with three
horizontal lines that spanned the width of the bar corresponding to the relevant hand.
1 Experiments are labelled in their order of presentation in this thesis, rather than
chronologically. Experiment 2 was completed prior to Experiment 1 and all other experiments.
General methods 17
The center horizontal line represented the target force (10% or 30% MVC) and the upper
and lower lines indicated the range of forces that were considered correct (±30% of the
target force).
Fig. 1 Screen shot of the display used for the experimental task, as seen immediately following
a correct response to a 30% MVC target for the left hand. The force target, maximum acceptable
force and minimum acceptable force are indicated by the three horizontal lines on the left hand
bar. The subject’s peak force is shown in blue and was displayed both during and after the
response. The LED‐style indicators shown at the top of the screen were displayed following the
response and were each lit (filled with green) when the relevant criterion was met.
Forces were digitized at 200 Hz from the onset of the third tone until 800 ms after
the onset of the final tone. The vertical bars and force targets remained on screen during
and immediately after the pinch response. The onset of the pinch response was taken as
the first time point at which force exceeded 5% of the maximum force exerted on that
trial. Feedback on the force of the response was displayed by filling the appropriate
vertical bar with color as force increased, similar to a thermometer. The bars remained
18 Chapter 2
filled up to the peak force recorded on that trial. The bars remained on screen for 2 s after
the response had been completed while additional feedback was displayed with a set of
LED‐style indicators (Fig. 1). Each of these indicators was labelled with a response
criterion, each of which had to be met for the response to be considered correct on that
trial. These criteria varied slightly between experiments and included restrictions on the
timing and duration of the response. The next trial commenced immediately after
feedback had been displayed.
Practice trials
During the practice trials, subjects produced unimanual pinches in response to
the force targets. The target force and response hand was randomly selected for each
trial. Practice continued until correct responses were recorded on seven out of ten
consecutive trials. A correct response was considered one in which all the criteria
specified by the LED‐style indicators were met and the peak force was within the force
range indicated by the target lines.
Stimulation and recording
TMS was delivered through a figure‐of‐eight coil, 90 mm in diameter, by a
Magstim 200 stimulator. TMS was delivered to M1 with the coil placed tangential to the
scalp with the handle posterior such that the induced current flows in the postero‐
anterior direction (Kammer, Beck, Thielscher, Laubis‐Herrmann, & Topka, 2001). Scalp
sites were marked on a tight fitting cap with a 1 cm spaced grid referenced to C3 and C4
on the international 10‐20 system for EEG recording. EMG activity was recorded with
Ag‐AgCl electrodes, placed in a belly‐tendon configuration. A ground electrode was
placed over the lateral posterior tubercle of the radius of the right forearm. The EMG
signal was digitized at 4 kHz, amplified (1,000×) and bandpass filtered (10–1,000 Hz).
Root‐mean‐square (RMS) EMG activity was recorded in the period 45–15 ms prior to
TMS stimulation as a measure of the post‐synaptic state of the spinal motoneurons.
MEPs were recorded as the peak‐to‐peak EMG amplitudes in the period 10–45 ms
following stimulation. Stimulation and data acquisition was controlled by locally written
software.
The optimal site for eliciting a motor evoked potential (MEP) in the FDI
contralateral to the stimulated M1 was determined as the site over which TMS elicited
General methods 19
the largest median MEP amplitude over five successive pulses. The TMS intensity
required to elicit an MEP of approximately 1 mV in the relaxed FDI was determined as
the TMS intensity which produced a median peak‐to‐peak MEP amplitude of 1 mV ±33%
over five successive pulses. In experiments with multiple sessions, these parameters
were determined separately for each session. For several subjects a reliable 1 mV ±33%
MEP could not be obtained, so the minimum TMS intensity that produced an MEP of at
least 1 mV was used instead. All test pulses for M1 were delivered at the optimal site for
eliciting an MEP in the FDI at the intensity which produced a 1 mV MEP in that muscle.
The resting motor threshold (rMT) was also determined in Experiment 1, 3, and 4 as the
minimum intensity required to elicit an MEP of at least 50 μV in five out of ten trials.
Data analysis
Kernel density estimates showing the distribution of response onset times were
fitted in each experiment using publicly available R software (Botev, Grotowski, &
Kroese, 2010). Kernel density estimation is a non‐parametric method of frequency
estimation that has been argued to provide a more accurate representation of the
underlying distribution than histogram methods (Wand, 1997; Wand & Jones, 1995).
Within‐subject medians were calculated for each dependent variable and
condition analyzed in each experiment. MEP data were normalized with the square root
transformation as Shapiro‐Wilk tests indicated that the normality assumption was
violated for these data in multiple experiments (p < 0.05). In experiments which
examined the relationship between behavioral or electrophysiological measures,
correlation coefficients were calculated using 20% percentage‐bend correlations. The
percentage‐bend correlation is a robust alternative to the Pearsonʹs correlation which is
less susceptible to distortion from outliers (Wilcox, 2012). Correlation coefficients were
normalized with the Fisher’s r‐to‐z transformation prior to subsequent analysis. All
transformed data have been back‐transformed for reporting in‐text and in the relevant
figures.
Behavioral and electrophysiological data were analyzed with repeated measures
ANOVAs. An alpha level of 0.05 was used for all inferential statistics. Greenhouse‐
Geisser corrections were used for all relevant analyses in which Mauchlyʹs test of
sphericity indicated that the sphericity assumption was violated. Significant effects in an
ANOVA were further investigated with Bonferroni‐Holm‐corrected post‐hoc pairwise
20 Chapter 2
comparisons. Partial eta‐squared was used as the effect size measure for the ANOVAs
and Hedges’ g was used for mean differences. For comparisons across factors comprised
of more than two groups, within‐subject Hedges’ g statistics were calculated using the
pooled error variance for the relevant factor, as calculated in the ANOVA. Within‐subject
confidence intervals were also determined from this variance estimate, using the
procedure described by Masson and Loftus (1994).
21
Chapter 3.
Single‐pulse transcranial magnetic stimulation over
the left M1 advances responses in a timed‐response
task across a wide range of latencies prior to the
response
Single‐pulse TMS has been found to advance the onset of responses in RT tasks
when delivered over M1 in synchrony with or closely following the presentation of an
imperative signal (Brasil‐Neto et al., 1992; Burle et al., 2002; Foltys et al., 2001; Leocani et
al., 2000; Pascual‐Leone, Valls‐Solé, et al., 1992; Pascual‐Leone et al., 1994; Sawaki et al.,
1999; Soto et al., 2010). TMS has also been found to delay responses when administered
at later intervals, close to the expected onset of the response (Burle et al., 2002; Day et al.,
1989; Hashimoto et al., 2004; McMillan et al., 2004; Meyer & Voss, 2000; Romaiguère et
al., 1997; Schluter et al., 1998, 1999; Ziemann et al., 1997). These delays appear to be
caused by an interruption of late motor processes that is induced by the TMS pulse (Day
et al., 1989; Ziemann et al., 1997).
TMS might advance responses by disrupting an inhibitory process, such as
proactive inhibition, which is engaged to prevent premature responding. Proactive
inhibition is a form of volitional inhibition that is applied proactively, prior to the
occurrence of any stimulus, to prevent the premature execution of a motor response
(Boulinguez et al., 2009; Criaud et al., 2012; Wardak et al., 2012). Proactive inhibition
appears to originate from prefrontal and parietal areas (Jaffard et al., 2008), and is
associated with a reduction in M1 excitability, which may mediate the inhibition of the
motor response (Claffey, Sheldon, Stinear, Verbruggen, & Aron, 2010; Criaud et al., 2012;
Duque & Ivry, 2009; Jaffard et al., 2008; Sinclair & Hammond, 2009; Stinear et al., 2009).
Longer RTs have been observed in tasks which are hypothesized to require the later
removal of proactive inhibition, such as those in which there is uncertainty about the
upcoming stimuli, suggesting that the time taken to release proactive inhibition
contributes to the latency of the response (Boulinguez et al., 2009; Boulinguez, Jaffard,
Granjon, & Benraiss, 2008; Criaud et al., 2012; Wardak et al., 2012). TMS might therefore
22 Chapter 3
advance the execution of a motor response by disrupting or counteracting changes in
M1 excitability that mediate the suppressive effects of proactive inhibition on the
response.
The current study examined the effect of TMS on the timing of response onsets
in a timed‐response task which required the synchronized execution of force responses
with a predictable auditory tone. This task permits the advanced preparation of a motor
response, which must be withheld until the appropriate time (Carlsen & MacKinnon,
2010; Hening, Favilla, et al., 1988; Steglich et al., 1999). It was hypothesized that TMS
would trigger the premature execution of the prepared voluntary response, consistent
with the disruption of an inhibitory process, such as proactive inhibition, which prevents
premature responding. Proactive inhibition appears to be engaged, and may be
vulnerable to disruption, from early stages of motor preparation (Boulinguez et al., 2009;
Criaud et al., 2012; Wardak et al., 2012). Thus, it was further hypothesized that TMS
would advance responses more when administered further before the target response
time, consistent with the expectation that this earlier stimulation would disrupt
proactive inhibition earlier, leading to the earlier initiation of the response. It was also
expected that TMS would delay responses when administered close to the expected
execution of the response, consistent with the hypothesis that TMS interrupts late motor
processes that are common to both timed‐response and RT tasks.
Methods
Subjects
Nineteen right‐handed first‐year psychology undergraduates (7 male, 12 female)
participated in the study. The subjectsʹ ages ranged from 17 to 26 years (median = 18).
Procedures
The timed‐response task required brief unimanual pinches to be executed in
response to 10% and 30% MVC force targets. Force targets were presented for both the
left and right hand. During the experimental trials, TMS was either withheld or
administered over the left M1 350 ms, 300 ms, 250 ms, 200 ms or 150 ms before the target
response time. EMG activity was recorded from the FDI, abductor pollicis brevis (APB)
and abductor digiti minimi (ADM) muscles of the right hand. Ten trials were completed
TMS advances responses across a wide range of TMS‐response latencies 23
for each of the 24 experimental conditions (6 TMS × 2 force × 2 hand), giving a total of
240 trials. An equal number of trials was completed for each condition. Trials were
arranged into blocks of 24 trials, each of which contained all possible combinations of
force, hand and TMS conditions. Condition order was randomized within each block.
Trials were discarded and repeated if responses were not made with correct hand
or if the duration between the onset and the peak force of the response (force rise time)
exceeded 300 ms. Feedback was given on both of these criteria using LED‐style
indicators. During the practice trials, subjects were also required to ensure that the onset
of their responses occurred within 150 ms of the target time and feedback was given on
this criterion. This feedback was withheld during the experimental trials to prevent
subjects from using this information to compensate for any potential effects of TMS on
the timing of their responses. Subjects were, however, requested to continue to attempt
to commence their responses as close as possible to the target time during the
experimental trials.
Data analysis
In addition to the analyses outlined in the general methods, a mixed‐effect model
was used to examine the effect of TMS administration time on pinch onset times. The
no‐TMS condition was excluded from this analysis. TMS, response hand and force
condition were entered into the model as fixed effects and subject was entered as a
random effect. TMS administration time was included as a second‐order polynomial to
examine both potential linear and quadratic effects of administration time on pinch onset
times. The model was fitted with random slopes and random intercepts for the effect of
TMS across subjects. Degrees of freedom for p value calculations were estimated using
the Satterthwaite approximation.
Results
Behavioral Data
Right hand MVCs were an average of 1.5% greater (SD = 17.5%) than left hand
MVCs, within subjects. Mean MVCs were 43.6 N for the left hand (SD = 17.0 N) and
43.3 N (SD = 15.8 N) for the right hand. During the experimental task, forces were
generally accurate, with mean forces falling within the target range in both the 10% MVC
24 Chapter 3
and 30% MVC conditions. Summary statistics showing the means and standard
deviations of peak forces in each condition are shown in Table 1. Peak forces, as a
percentage of MVC, did not significantly differ between the hands, F(1, 18) = 2.79,
p = 0.11, ηg2 = 0.01. Peak forces were less precise, as measured by the coefficient of
variation, in the 10% MVC condition (M = 0.28) than in the 30% MVC condition
(M = 0.22), F(1, 18) = 46.79, p < 0.001, ηg2 = 0.17. Force precision did not significantly differ
between the hands, F(1, 18) = 0.15, p = 0.70, ηg2 = 0.00.
Table 1 Means and standard deviations (in brackets) for peak forces in each condition,
expressed as a percentage of MVC. TMS was either withheld (none) or administered 350 ms,
300 ms, 250 ms, 200 ms, or 150 ms before the target pinch onset time.
TMS
(ms)
Left hand force (% MVC) Right hand force (% MVC)
10% MVC
target
30% MVC
target
10% MVC
target
30% MVC
target
None 11.5 (1.5) 26.9 (2.4) 11.3 (1.9) 27.8 (3.6)
350 11.9 (1.7) 28.5 (3.1) 11.1 (2.1) 27.3 (5.0)
300 11.9 (1.7) 27.9 (2.9) 11.1 (2.0) 27.8 (3.8)
250 11.7 (1.7) 28.0 (3.8) 11.6 (1.4) 26.7 (3.4)
200 11.6 (1.9) 27.9 (3.6) 11.2 (1.7) 27.7 (3.4)
150 11.6 (1.7) 28.5 (3.7) 11.5 (1.8) 27.5 (3.1)
Summary statistics showing the means and standard deviations of pinch onset
times in each condition are shown in Table 2. Supplementary statistics, which describe
other characteristics of the pinch response, are listed in Appendix 1. Pinch onset times
did not significantly differ between the hands, F(1, 18) = 0.50, p = 0.49, ηg2 = 0.00 or
between the production of 10% and 30% MVC forces, F(1, 18) = 0.32, p = 0.58, ηg2 = 0.00.
Mean force rise times (onset‐to‐peak durations) varied between 124 and 186 ms across
all experimental conditions. Force rise times were significantly longer, by 15 ms, in the
right than left hand, F(1, 18) = 31.74, p < 0.001, ηg2 = 0.12, and were longer for the
production of 30% MVC forces (M = 174 ms) than 10% MVC forces (M = 134 ms),
F(1, 18) = 208.08, p < 0.001, ηg2 = 0.48. Similarly total pinch durations were 84 ms longer
for pinches produced by the right than left hand, F(1, 18) = 117.84, p < 0.001, ηg2 = 0.32,
and 151 ms longer for the production of 30% than 10% MVC forces, F(1, 18) = 449.66,
p < 0.001, ηg2 = 0.61.
TMS advances responses across a wide range of TMS‐response latencies 25
Table 2 Means and standard deviations (in brackets) for pinch onset times in each condition, in
milliseconds. TMS was either withheld (none) or administered 350 ms, 300 ms, 250 ms, 200 ms,
or 150 ms before the target pinch onset time. Target forces are expressed as a percentage of MVC.
TMS
(ms)
Left hand onset (ms) Right hand onset (ms)
10% MVC
target
30% MVC
target
10% MVC
target
30% MVC
target
None ‐63 (56) ‐70 (61) ‐60 (61) ‐64 (51)
350 ‐96 (70) ‐76 (81) ‐62 (64) ‐92 (64)
300 ‐91 (59) ‐79 (75) ‐71 (62) ‐83 (61)
250 ‐93 (49) ‐84 (64) ‐82 (48) ‐95 (61)
200 ‐81 (67) ‐87 (60) ‐83 (53) ‐75 (51)
150 ‐70 (60) ‐81 (58) ‐74 (53) ‐78 (65)
TMS significantly advanced pinch onsets by an average of 18 ms across all TMS
conditions, F(5, 90) = 3.99, p < 0.01, ηg2 = 0.02. TMS advanced the entire distribution of
pinch onset times for both the ipsilateral and contralateral hand (Fig. 2) The effects of
TMS on pinch onsets in the ipsilateral and contralateral hand did not significantly differ,
as indicated by the absence of a significant TMS × hand condition interaction,
F(5, 90) = 0.41, p = 0.84, ηg2 = 0.00. A mixed‐effect model did not find any significant
linear, t(18.13) = 0.59, p = 0.56, or quadratic effect, t(47.81) = 1.68, p = 0.10, of TMS
administration time on pinch onsets, across both hands. Although pinch onsets were
advanced in time, the integrity of the response was unaffected by TMS. TMS did not
significantly affect the size of peak forces, F(5, 90) = 0.33, p = 0.89, ηg2 = 0.00, the precision
of peak forces, F(5, 90) = 0.59, p = 0.71, ηg2 = 0.00, force rise times, F(5, 90) = 1.20, p = 0.32,
ηg2 = 0.00, or total pinch durations F(5, 90) = 1.09, p = 0.37, ηg2 = 0.00.
Electrophysiological data
The mean TMS intensity required to elicit a 1 ±33% mV MEP in the FDI muscle
of the right hand was 50.4% maximum simulator output (SD = 8.9%). This intensity was
equivalent to 109.1% rMT, on average (SD = 4.4%). RMS EMG activity in the right FDI
muscle, measured immediately prior to the administration of TMS, increased as TMS
was administered closer to the target response time for a pinch with the right hand, from
56.6 μV at 350 ms before the target response time to 164.7 μV at 150 ms before the target
response time. RMS EMG activity in the right FDI varied between 53.6 μV and 57.2 μV
before the administration of TMS 350–200 ms prior to the target response time for a left‐
26 Chapter 3
hand response, and rose to 64.9 μV immediately prior to the administration of TMS at
150 ms before the target response time for this response. MEP amplitudes increased in
all muscles examined (FDI, APB, ADM) as TMS was administered closer to the target
pinch onset time for a pinch produced by the hand contralateral to TMS. MEP
amplitudes were similar for 10% and 30% MVC pinches (Fig. 3).
Fig. 2 Kernel density estimates showing that TMS shifted the distribution of pinch onset times
towards earlier responses when administered over a wide range of latencies prior to the target
response time. The panels show, from top to bottom, conditions in which TMS was not
administered and conditions in which it was administered 350 ms, 300 ms, 250 ms, 200 ms,
150 ms before the target pinch onset time. Data were pooled across force conditions. The solid
dots mark the median pinch onset time in each condition. Dotted vertical lines indicate the time
at which TMS was administered in each condition.
Left Hand Right Hand
0.000
0.002
0.004
0.000
0.002
0.004
0.000
0.002
0.004
0.000
0.002
0.004
0.000
0.002
0.004
0.000
0.002
0.004
No TMS
350
300
250
200
150
−400 −200 0 200 −400 −200 0 200
Pinch onset time (ms to target)
Den
sity
TMS advances responses across a wide range of TMS‐response latencies 27
Fig. 3 Mean MEP amplitudes for conditions in which either a left or right hand pinch was
required at 10% or 30% of the MVC for that hand. Recordings were taken from the ADM, APB
and FDI muscles of the right hand. The data show that MEPs increased as TMS was administered
closer to the target response time for a right‐hand response, and that the rate of this increase was
not affected by the force of the required response. Error bars show the within‐subjects SEM for
TMS condition comparisons. These error bars were calculated separately for each muscle using
the Greenhouse–Geisser correction. The data were square‐root‐transformed prior to calculation
of these values and have been back‐transformed for presentation here.
Discussion
The current study investigated the effect of left M1 TMS on the timing of pinch
onsets in a timed‐response task. TMS was found to advance pinch onsets in both the
ipsilateral and contralateral hand by a constant amount, when administered over a
200 ms range of latencies between TMS and the target pinch onset time. This finding
does not support the hypothesis that TMS would trigger the premature execution of the
prepared response, as this would have resulted in greater facilitation when TMS was
administered further before the target response time. Furthermore, pinch onsets did not
follow TMS by a constant interval, as would be expected if TMS triggered the response,
but were distributed around a point which slightly preceded the target response time.
As proactive inhibition is thought to prevent the premature execution of the response,
these findings suggest that that TMS did not disrupt proactive inhibition or any other
process which prevents the premature execution of the response.
ADM APB FDI
0
1
2
3
4
5
350 300 250 200 150 350 300 250 200 150 350 300 250 200 150
TMS administration time (ms to target)
Mea
n M
EP
am
plitu
de (m
V)
Response (% MVC)Left hand 10Left hand 30Right hand 10Right hand 30
28 Chapter 3
In contrast to the hypothesis that TMS would delay responses when
administered close to the expected onset of the response, TMS was found not to delay
responses at any interval, even when administered at the latest interval, 150 ms before
the target response time. This time point corresponded to approximately 70 ms before
the mean response onset time, as responses typically preceded the target response time.
There was also no reduction in the frequency of responding in the interval immediately
following TMS (Fig. 2), indicating that responses were not suppressed over this period.
In contrast, TMS has been found to delay responses when administered within
approximately 120 ms of movement onset in RT tasks (Burle et al., 2002; Day et al., 1989;
Hashimoto et al., 2004; Leocani et al., 2000; Romaiguère et al., 1997; Schluter et al., 1998,
1999; J. L. Taylor et al., 1995; Ziemann et al., 1997). The absence of this effect in the current
study could result from a reduction in the activity of inhibitory circuits which mediate
this delay in responding (Burle et al., 2002; Day et al., 1989; Ziemann et al., 1997). These
circuits are likely to be distinct from those mediating proactive inhibition, as delays in
responding following TMS appear to result from an interruption of late motor processes
(Ziemann et al., 1997), whereas proactive inhibition appears to be withdrawn before
these process are initiated (Criaud et al., 2012; Wardak et al., 2012).
The advancement of responses by TMS in the current study cannot be attributed
the results of a TMS‐evoked twitch, as TMS did not disrupt the integrity of the response.
Responses onset times also did not tend to coincide with the interval over which MEPs
were observed, which further demonstrates that the advancement of responses is not the
result of a TMS‐evoked twitch. This advancement of responses following TMS could be
explained by a reduction in the duration of preparation or execution‐related motor
processes, which will be discussed in turn. Reduced preparation time appears unlikely
to contribute to the advancement of responses in the timed‐response task used in the
present study, although it has been hypothesized to mediate the advancement of
responses in RT tasks (Pascual‐Leone, Valls‐Solé, et al., 1992; Sawaki et al., 1999; Soto et
al., 2010). Responses in timed‐response tasks must be withheld until the appropriate
execution time, irrespective of the time at which preparation is completed, which limits
the influence of preparation time on the timing of the response, as long as sufficient
preparation time is provided. In the timed‐response task used in the present study,
motor preparation appears to be completed within 400 ms following the presentation of
the force target, as previous studies using similar tasks have found that force accuracy
TMS advances responses across a wide range of TMS‐response latencies 29
ceases to improve following this period (Hening, Favilla, et al., 1988; Steglich et al., 1999).
TMS was not administered until at least 450 ms after the presentation of the force target
in the present study, suggesting that motor preparation was essentially complete at the
time TMS was administered. Therefore, reduced motor preparation time appears
unlikely to mediate the advancement of response onsets following TMS in the present
study. However, TMS could have facilitated some late preparatory processes, such as
the transfer of the prepared motor program to M1 (Pascual‐Leone, Valls‐Solé, et al.,
1992), which might not have been completed until close to the execution of the response.
TMS could have advanced responses by reducing the duration of motor
processes required to execute the response. M1 cell activity gradually increases from
approximately 100 ms prior to EMG onset, indicating a block of time normally required
to execute the response (R. Chen & Hallett, 1999; R. Chen et al., 1998; Evarts, 1966;
Hoshiyama et al., 1996). TMS could abbreviate this process by increasing M1 excitability,
which would contribute to the increase in M1 excitability required to execute the
response. TMS was found to advance responses by a constant amount, across a wide
range of intervals prior to the response, whereas CME in the contralateral hand
gradually increased over this period. These findings demonstrate that TMS advanced
responses when administered both prior to and during the development of changes in
CME, associated with the execution of the response. These findings also indicate that the
advancement of response onsets by TMS does not depend upon the level of M1
excitability at the time of TMS administration. These findings are consistent with a long‐
lasting increase in M1 excitability that is cumulative with changes in M1 excitability
related to the voluntary initiation of the response. Previous research has found evidence
for such long‐lasting changes in cortical activity following single‐pulse TMS, with some
effects of TMS exceeding 100 ms in duration (Cash, Ziemann, Murray, & Thickbroom,
2010; Fuggetta, Fiaschi, & Manganotti, 2005; Thut et al., 2003; Vallence, Schneider,
Pitcher, & Ridding, 2014).
TMS was found to advance responses over a wider range of TMS‐response
latencies than has been observed in RT tasks. In RT tasks, TMS has typically been found
to advance responses only when administered within a narrow interval close to the
presentation of an imperative signal (Foltys et al., 2001; Leocani et al., 2000; Pascual‐
Leone, Brasil‐Neto, et al., 1992; Sawaki et al., 1999; Soto et al., 2010). The longer interval
over which responses were advanced in the in the current study may relate to the
30 Chapter 3
advanced preparation of the motor response in the timed‐response task used in this
study (Carlsen & MacKinnon, 2010; Hening, Favilla, et al., 1988; Steglich et al., 1999). The
advanced preparation of responses in this task provides a wide range of intervals over
which a well‐prepared motor response must be maintained prior to the commencement
of motor processes required for the execution of the response. TMS may advance
response over a wider interval in tasks which require this preparatory state to be
maintained over an extended period, consistent with findings that the effects of TMS
depend on the state of the motor system at the time of administration (Silvanto,
Muggleton, & Walsh, 2008). In contrast, responses must be executed rapidly in RT tasks,
which could limit the interval over which TMS facilitates responses.
In RT tasks, TMS has been found to advance responses through non‐specific
mechanisms, which may result from the sound or tactile stimulation produced by TMS.
The presence of non‐specific effects is supported by findings that TMS similarly
advances responses when it is delivered off‐scalp or over non‐motor areas (Romaiguère
et al., 1997; Terao et al., 1997). Non‐specific effects have been primarily attributed to
intersensory facilitation (Burle et al., 2002; Romaiguère et al., 1997; Terao et al., 1997), the
advancement of a response by an accessory stimulus presented in close proximity to an
imperative signal (Nickerson, 1973). Intersensory facilitation is unlikely to explain the
advancement of responses in the timed‐response task used in current study, as there is
no imperative stimulus in this task and responses typically commenced before the
response‐synchronization signal, which may be considered the closest analogue to an
imperative signal in this task. While the force targets used in the current study are similar
to imperative signals used in some choice RT tasks, in that they specify the required
response, ample time was provided to prepare responses following the presentation of
these targets (800 ms). Furthermore, the duration between the presentation of the force
targets and the administration of TMS (550 ms) was well in excess of the maximum
interval over which intersensory facilitation is observed (Diederich & Colonius, 2008;
Nickerson, 1973), suggesting that intersensory facilitation did not contribute to the
present findings.
In addition to intersensory facilitation, the loud sound produced by TMS might
evoke a startle response, a pattern of bilateral muscle activity in response to an intense
stimulus (Carlsen et al., 2011; Valls‐Solé et al., 2008). Loud acoustic stimuli, capable of
producing a startle response, have been found to advance responses in both RT and
TMS advances responses across a wide range of TMS‐response latencies 31
timed‐response tasks (Carlsen & MacKinnon, 2010; Valls‐Solé, Kofler, Kumru,
Castellote, & Sanegre, 2005; Valls‐Solé, Rothwell, Goulart, Cossu, & Muñoz, 1999). A
loud acoustic stimulus has been found to trigger the execution of voluntary responses in
a timed‐response task in which responses were cued with a slowly flashing signal
(1000 ms ISI), such that responses were executed within 150 ms of the presentation of the
loud acoustic stimulus (Carlsen & MacKinnon, 2010). TMS had a much weaker influence
on response onset times in the current study, with responses frequently observed more
than 150 ms following TMS. This suggests that the effect of TMS on response onset times
in the current study differs from the effect produced by a loud acoustic stimulus in a
similar task (Carlsen & MacKinnon, 2010). However, a loud acoustic stimulus has also
been found to produce similar advancement of responses to that observed in the current
study in a timed‐response task in which responses were cued with a continuously
updated clock display (Carlsen & MacKinnon, 2010). While this cueing method is
thought to discourage advanced motor preparation, in contrast to the cueing method
used in the current study (Carlsen & MacKinnon, 2010), this finding nevertheless
suggests a mechanism through which a loud acoustic stimulus can facilitate responses
which could contribute to the present findings.
In summary, the present findings demonstrate that TMS advances the onset of a
prepared response in a timed‐response task. The extent to which responses were
advanced was not affected by the time of TMS administration, which is not consistent
with the hypothesis that TMS triggers responses by disrupting proactive inhibition. TMS
may instead advance response onsets by reducing the duration of processes required to
execute the response. This effect may be produced by an increase in M1 excitability,
which abbreviates an interval of increasing M1 excitability preceding the execution of
the response.
33
Chapter 4.
The effect of single‐pulse transcranial magnetic
stimulation over the left or right M1 on the timing
of unimanual and bimanual pinches
Single‐pulse TMS over M1 has been found to advance the onset of unimanual
responses when delivered early in the response latency of an RT task (Burle et al., 2002;
Foltys et al., 2001; Leocani et al., 2000; Pascual‐Leone, Valls‐Solé, et al., 1992; Pascual‐
Leone et al., 1994). As shown in the previous chapter, TMS similarly advances the onset
of a unimanual response when TMS is delivered prior to the expected response time in
a timed‐response task. TMS has also been found to delay unimanual responses when
administered close to the expected onset of the response in an RT task (Burle et al., 2002;
Day et al., 1989; Foltys et al., 2001; Hashimoto et al., 2004; Romaiguère et al., 1997;
Ziemann et al., 1997), but this effect was not observed in the experiment presented in the
previous chapter.
Bimanual coordination differs from unimanual coordination in that it engages
intermanual interactions which are reflected in the tendency towards the production of
synchronous, symmetrical actions (Swinnen, 2002). Temporal coupling, the tendency
towards synchronous action, is observed during reaching and force production tasks.
Temporal coupling is even observed for movements which typically have different
durations when performed unimanually (Corcos, 1984; Fowler, Duck, Mosher, &
Mathieson, 1991; Kelso, Southard, & Goodman, 1979a; Marteniuk, MacKenzie, & Baba,
1984). In reaching tasks, the initiation and termination of reaching movements occurs
almost simultaneously (Kelso et al., 1979b). Similarly, in force production tasks, the times
taken by each hand to reach peak force from the onset of a response are closely
associated. This association is also preserved when subjects are instructed to increase the
forces produced by each hand over different time periods, demonstrating the persistence
of temporal coupling in these tasks (Diedrichsen et al., 2003; Rinkenauer et al., 2001;
Steglich et al., 1999).
Interactions which mediate temporal coupling could cause TMS to differentially
affect the timing of responses in unimanual and bimanual tasks. Bimanual coordination
34 Chapter 4
requires interactions between the hemispheres, as motor actions are primarily controlled
by the contralateral hemisphere (Brinkman & Kuypers, 1973). These interactions may
allow the ipsilateral hemisphere to exert greater control over the timing of motor
responses during the performance of bimanual actions. Consistent with this hypothesis,
a study which used an rhythmic tapping task found that TMS over either M1 disrupted
tapping in the hand ipsilateral to TMS more during the performance of bimanual in‐
phase tapping than during unimanual tapping, while opposite effects were observed for
the contralateral hand (J.‐T. Chen et al., 2005). In a simple RT task, however, TMS over
either M1 was found to similarly affect the timing of unimanual and bimanual
movements, suggesting that each hemisphere is similarly involved in the control of
unimanual and bimanual movements in this task (Foltys et al., 2001). The difference in
these findings may be due to the requirement to maintain a constant rhythm in the study
conducted by J.‐T Chen and colleagues (2005), which may invoke additional coupling
mechanisms that are not involved in the performance of a simple RT task. In particular,
the requirement to maintain a constant rhythm with each hand is thought to require
interhemispheric interactions to keep the time‐keeping mechanisms of each hemisphere
in synchrony (J.‐T. Chen et al., 2005; Helmuth & Ivry, 1996; Ivry, 1996; Ivry & Hazeltine,
1999; Ivry & Richardson, 2002), which may influence the effect of TMS on the timing of
responses in the ipsilateral and contralateral hand.
The current study investigated the effect of single‐pulse TMS on ipsilateral and
contralateral response onset times in a timed‐response task, which required the onset of
a unimanual or bimanual pinch to be synchronized with a predictable auditory tone. It
was expected that TMS would advance ipsilateral responses more and contralateral
responses less in the bimanual than unimanual response conditions, consistent with the
hypothesis that the ipsilateral hemisphere has greater influence over the timing of
bimanual than unimanual responses. The study also investigated whether the bimanual
coupling of forces or response durations interacts with the effect of TMS on the timing
of response onsets. This was accomplished through the manipulation of bimanual force
targets so that forces of either equal or unequal magnitude were required. These
responses have been associated with different levels of force coupling in previous
research (Diedrichsen et al., 2003; Rinkenauer et al., 2001). It was expected that TMS
would also advance responses to a similar extent in both equal and unequal force
conditions, consistent with research suggesting force coupling is mediated by different
The effect of TMS on the timing of unimanual and bimanual pinches 35
neural pathways to those mediating the coupling of response onsets (Diedrichsen et al.,
2003; Kennerley et al., 2002).
Methods
Subjects
Fourteen right‐handed first‐year psychology undergraduates (3 male, 11 female)
participated in the study. The subjects’ ages ranged from 17 to 28 years (median = 19).
Experimental design
The study was completed over two sessions, the order of which was randomized
for each subject. The sessions were identical except that TMS was applied to the left M1
during one session and to the right M1 during the other. Muscle recordings were always
taken from the FDI contralateral to the stimulated M1. All possible combinations of 0%,
10% and 30% force targets for the left and right hand, including no pinch, unimanual
pinch and bimanual pinch conditions, were included in the experiment. Only unimanual
conditions were included in the practice trials to limit the effects of practice on bimanual
coupling (Wenderoth, Puttemans, Vangheluwe, & Swinnen, 2003).
Materials and procedures
Twenty trials were completed for each of the nine force conditions (all
combinations of 0%, 10% or 30% MVC targets for each hand) giving a total of 180
experimental trials. TMS was administered 250 ms before the final tone on 50% of the
trials in each force condition. This administration time was selected to precede the onset
of EMG activity for responses occurring within the target response time interval. Trials
were arranged into blocks of 18 trials, each of which contained all possible combinations
of force and TMS conditions. Condition order was randomized within blocks.
Feedback was given with LED‐style indicators which showed whether responses
were made with the correct hand, the responses for each hand were less than 600 ms in
duration, the onset of the response for at least one hand occurred within 150 ms of the
final (target) tone and the response onset times for each hand were separated by less
than 150 ms. Trials were discarded and repeated if any of these criteria, apart from the
response duration criterion, was not met. A more lenient criterion (800 ms) was used to
36 Chapter 4
exclude trials with excessive response durations, as some subjects had difficulty
consistently meeting the 600 ms response duration criterion and visual inspection of the
data indicated that responses with durations between 600 ms and 800 ms were similar
to other trials that were included in the analysis.
Data analysis
Data for right M1 (left hand) recordings were missing for two subjects who failed
to attend the second session. Missing data were excluded listwise for repeated‐measures
ANOVAs and pairwise for all other analyses. Data for the no‐TMS condition were
combined across sessions prior to further analysis.
Results
Summary statistics for pinch onset times are shown in Table 3. Pinch onset times
did not significantly differ between the left and right hand, across all TMS conditions,
F(1, 11) = 0.37, p = 0.55, ηg2 = 0.00. Pinch onset times significantly varied across force
conditions, F(5, 55) = 19.20, p < 0.001, ηg2 = 0.17, with pinch onset times occurring
significantly later in the bimanual unequal conditions than in all other force conditions
(g = 0.69–1.13). The bimanual coupling of pinch onset times, measured by the SD of onset
asynchronies between the hands (Diedrichsen et al., 2003), varied significantly across
force conditions, F(3, 33) = 10.26, p < 0.001, ηg2 = 0.16, with significantly weaker coupling
(higher SDs) in the two unequal force conditions (M = 26 ms) than in the two equal force
conditions (M = 17 ms) (g = 0.80–1.03).
The effect of TMS on the timing of unimanual and bimanual pinches 37
Table 3 Means and standard deviations (in brackets) for pinch onset times for each condition,
in milliseconds, relative to the target time. ʺLʺ and ̋ Rʺ denote the target force for the left and right
hand. Target forces are expressed as a percentage of MVC.
Response
condition
Force
condition
(% MVC)
No TMS Left M1 TMS Right M1 TMS
Left
hand
Right
hand
Left
hand
Right
hand
Left
hand
Right
hand
Unimanual L10 or R10 ‐44 (41) ‐43 (42) ‐91 (33) ‐89 (33) ‐65 (34) ‐76 (32)
L30 or R30 ‐43 (38) ‐43 (34) ‐87 (36) ‐86 (36) ‐64 (48) ‐79 (39)
Bimanual
equal
L10 & R10 ‐34 (47) ‐34 (43) ‐75 (28) ‐93 (42) ‐49 (40) ‐49 (41)
L30 & R30 ‐40 (42) ‐38 (35) ‐80 (28) ‐89 (35) ‐71 (41) ‐70 (39)
Bimanual
unequal
L10 & R30 ‐2 (43) 0 (42) ‐54 (35) ‐60 (45) ‐35 (59) ‐31 (58)
L30 & R10 ‐8 (44) 6 (51) ‐52 (40) ‐49 (45) ‐22 (64) ‐15 (61)
Summary statistics for pinch durations are shown in Table 4. Supplementary
statistics, describing other characteristics of the response, are listed in Appendix 2. Pinch
durations were significantly longer in the right hand than in the left hand,
F(1, 11) = 120.62, p < 0.001, ηg2 = 0.43, and varied significantly across force conditions,
F(5, 55) = 127.93, p < 0.001, ηg2 = 0.60. Pinch durations were significantly longer for the
production of a 30% force than a 10% MVC force, in both unimanual and bimanual
conditions (g = 1.27–2.82). Pinch durations for the production of a 10% MVC force were
significantly longer when the other hand produced a 30% MVC force than when the it
produced a 10% MVC force (g = 1.42) or no response at all (g = 1.33). These findings
demonstrate convergence (assimilation) between pinch durations in the unequal force
conditions. Significant correlations between the pinch durations for each hand, reflecting
bimanual coupling, were observed in all bimanual conditions. Duration correlations
varied significantly across force conditions, F(3, 33) = 5.72, p < 0.01, ηg2 = 0.08, and were
significantly larger in the condition in which both hands produced a 10% MVC force
(r = 0.63) than in the conditions in which the hands produced unequal forces (left 10%,
right 30%: r = 0.43, g = 0.79; left 30%, right 10%: r = 0.42, g = 0.81). There were no
significant differences between duration correlations in the condition in which both
hands produced a 30% MVC force (r = 0.57) and conditions in which the hands produced
unequal forces (left 10%, right 30%: p = 0.19, g = 0.52; left 30%, right 10%: p = 0.19,
g = 0.53). There were also no significant differences between duration correlations in the
38 Chapter 4
condition in which both hand produced a 30% MVC force and the condition in which
both hands produced a 10% MVC force (p = 0.60; g = 0.28).
Table 4 Means and standard deviations (in brackets) for total pinch durations for each
condition, in milliseconds. ʺLʺ and ʺRʺ denote the target force for the left and right hand. Target
forces are expressed as a percentage of MVC.
Response
condition
Force
condition
(% MVC)
No TMS Left M1 TMS Right M1 TMS
Left
hand
Right
hand
Left
hand
Right
hand
Left
hand
Right
hand
Unimanual L10 or R10 354 (46) 418 (47) 347 (48) 423 (45) 362 (51) 430 (52)
L30 or R30 474 (37) 557 (27) 465 (46) 559 (34) 459 (41) 550 (37)
Bimanual
Equal
L10 & R10 355 (43) 416 (48) 351 (44) 421 (44) 362 (66) 410 (61)
L30 & R30 472 (34) 550 (27) 467 (40) 555 (36) 464 (36) 538 (31)
Bimanual
Unequal
L10 & R30 418 (49) 546 (42) 419 (44) 560 (39) 414 (56) 525 (50)
L30 & R10 465 (41) 471 (51) 461 (42) 479 (46) 462 (51) 477 (67)
TMS was administered at similar intensities, as a percentage of maximum
stimulator output, for the stimulation of both the left (M = 50.7%, SD = 12.3%) and right
M1 (M = 48.4%, SD = 11.3%). These intensities were set to produce a 1 ±33% mV MEP in
the contralateral FDI muscle. TMS significantly advanced the entire distribution of pinch
onset times (Fig. 4), F(2, 22) = 13.45, p < 0.001, ηg2 = 0.23. No significant TMS × force
condition interaction was found, F(10, 110) = 1.02, p = 0.43, ηg2 = 0.01, indicating that
there was no differences in the effect of TMS across unimanual and bimanual force
conditions or between bimanual conditions in which forces were of equal or unequal
magnitude. Left M1 and right M1 TMS significantly advanced pinch onsets by an
average of 53 ms (g = 0.61) and 26 ms (g = 0.30), respectively. Left M1 TMS advanced
pinch onset times significantly more than right M1 TMS (g = 0.31). TMS similarly
advanced pinches in the ipsilateral and contralateral hand, as indicated by the absence
of a TMS × hand condition interaction, F(2, 22) = 1.18, p = 0.33, ηg2 = 0.00. Although TMS
advanced pinches in time, it did not affect the integrity of the response. TMS did not
produce any significant effect on the size of peak forces, F(2, 22) = 1.28, p = 0.30, ηg2 = 0.01,
the precision of peak forces (measured by the coefficient of variation), F(2, 22) = 0.26,
p = 0.68, ηg2 = 0.00, or pinch durations, F(2, 22) = 0.15, p = 0.74, ηg2 = 0.00.
The effect of TMS on the timing of unimanual and bimanual pinches 39
Fig. 4 Kernel density estimates showing that TMS advanced pinch onset times in all force
conditions (unimanual, bimanual equal, bimanual unequal), particularly when TMS was
administered over the left M1. From top to bottom, the panels shown conditions which required
unimanual pinches, bimanual pinches of equal force and bimanual pinches of unequal force.
Equivalent conditions have been combined across both sessions. The dotted vertical line marks
the time at which TMS was administered.
Discussion
The current study investigated the effect of TMS on the timing of unimanual and
bimanual pinch onsets in a timed‐response task which required the onset of a force
response to be synchronized with a predictable auditory signal. TMS was found to
significantly advance both ipsilateral and contralateral responses in all conditions,
consistent with previous findings (Chapter 3). TMS was found not to affect the
kinematics of the response, suggesting that it advanced the execution of the prepared
response, consistent with previous findings (Chapter 3).
TMS advanced responses by a similar amount in both bimanual and unimanual
conditions, in contrast to the hypothesis that TMS would advance ipsilateral responses
more and contralateral responses less in bimanual than unimanual conditions, as a result
Left hand Right hand
0.000
0.002
0.004
0.006
0.008
0.000
0.002
0.004
0.006
0.008
0.000
0.002
0.004
0.006
0.008
Unimanual
BimanualEqual
BimanualUnequal
−400 −200 0 200 400 −400 −200 0 200 400
Pinch onset time (ms relative to target)
Den
sity
TMSNoneLeft M1Right M1
40 Chapter 4
of intermanual interactions associated with temporal coupling. Although responses
occurred slightly later in the bimanual unequal force condition than in the bimanual
equal force or unimanual condition, all of these responses were similarly advanced by
TMS. The tendency to respond later in the bimanual unequal force condition could
suggest that insufficient time was provided to permit the complete preparation of
responses in this condition, although the amount of preparation time permitted in this
study (600 ms) was greater than RTs observed for unequal bimanual forces in a previous
study (Diedrichsen et al., 2003) and the time required to produce clearly differentiated
bimanual forces in a timed‐response task (Heuer, Spijkers, Kleinsorge, van der Loo, &
Steglich, 1998; Steglich et al., 1999). It is likely, however, that unimanual and bimanual
equal responses, which exhibit shorter preparation times (Diedrichsen et al., 2003;
Hening, Favilla, et al., 1988), were consistently prepared in advance in the current study.
The absence of any differences in the effect of TMS on the timing of response onsets
between unimanual and bimanual conditions is consistent with previous observations
in a simple RT task (Foltys et al., 2001). The current findings suggest that intermanual
interactions, related to the synchronization of bimanual responses with a rhythmic cue,
do not moderate the effect of TMS on the timing of these responses. Thus, previous
finding that TMS disrupted ipsilateral responses more and contralateral responses less
during the bimanual than unimanual performance of a rhythmic tapping task cannot be
attributed to the coupling of response timing processes that are engaged in both timed‐
response and rhythmic tapping tasks (J.‐T. Chen et al., 2005). The finding that TMS
differentially affected bimanual and unimanual responses in a rhythmic tapping task
could instead be explained by the coupling of feedback processes, such as conflict or
reinforcement between the sensory signals originating from each hand (Klapp et al.,
1985). The coupling of these feedback processes could affect responses on later cycles of
a periodic task (Heuer & Klein, 2005), such as that used by Chen and colleagues (2005),
but would have minimal effect on the performance of the brief, solitary responses
required for the timed‐response task used in the current study.
Left and right M1 TMS were both found to advance ipsilateral and contralateral
responses suggesting that both hemispheres contribute to the control of the timing of
these responses in the task used in the current study. Effects of TMS on the timing of
ipsilateral responses could be mediated by either interhemispheric cortico‐cortical
connections or ipsilateral motor pathways (Bawa, Hamm, Dhillon, & Gross, 2004;
The effect of TMS on the timing of unimanual and bimanual pinches 41
Kagerer, Summers, & Semjen, 2003; Pascual‐Leone, Valls‐Solé, et al., 1992). However,
interhemispheric cortico‐cortical connections appear more likely to mediate this effect
since increased M1 excitability has been found during the performance of ipsilateral
motor tasks in the absence of ipsilateral MEPs, ipsilateral silent periods, or changes in
ipsilateral spinal excitability (Carson et al., 2004; Kobayashi, Hutchinson, Schlaug, &
Pascual‐Leone, 2003; Tinazzi & Zanette, 1998; Ziemann & Hallett, 2001). It has been
suggested that TMS may enhance motor preparation through these connections or that
TMS may enhance the transfer of motor information between the hemispheres (Foltys et
al., 2001; Pascual‐Leone, Valls‐Solé, et al., 1992). However, this suggestion is inconsistent
with findings suggesting that the timed‐response task used in the present study permits
advanced preparation (Carlsen & MacKinnon, 2010; Hening, Vicario, et al., 1988;
Schluter et al., 2001), which would be expected to limit effects of enhanced preparation
on the timing of the response. TMS may instead advance ipsilateral responses through
interhemispheric effects on the execution of the response, consistent with evidence that
interhemispheric pathways contribute to the initiation of a motor response (Tazoe &
Perez, 2013).
The effects of TMS on the timing of ipsilateral and contralateral responses were
not significantly different, as reflected by the absence of any significant interaction
between the effects of the TMS location and the responding hand on the time at which
the response was executed. The absence of this observation could be due to the stimulus
intensity used in the present study, as differences in the effects of TMS on ipsilateral and
contralateral responses may only be apparent at specific stimulus intensities. In an RT
task, TMS was found to advance responses more in the ipsilateral than contralateral
hand early in the response latency and delayed responses more in the contralateral than
ipsilateral hand later in the response latency, when delivered at an intensity of 120% rMT
(Foltys et al., 2001). In the current study, TMS was delivered at an intensity which
produced an MEP of approximately 1 mV in the resting FDI, which is equivalent to
approximately 109% rMT (Chapter 3). In RT studies, TMS has been found to advance
responses in the ipsilateral hand more at higher stimulus intensities and to advance
responses in the contralateral hand more at lower stimulus intensities (Foltys et al., 2001;
Hashimoto et al., 2004; Leocani et al., 2000; Pascual‐Leone, Valls‐Solé, et al., 1992). TMS
has also been found to advance ipsilateral and contralateral responses by a similar extent
at slightly suprathreshold stimulus intensities, similar to those used in the current study
42 Chapter 4
(Burle et al., 2002; Pascual‐Leone, Valls‐Solé, et al., 1992; Romaiguère et al., 1997). These
findings suggest that differences in the relative effects of TMS on the timing of ipsilateral
and contralateral responses between the current study and those of Foltys and
colleagues (2001) can be accounted for by differences in stimulus intensity and are
therefore unlikely to be due to the differences in the tasks used in each of these studies.
Left M1 TMS advanced responses more than right M1 TMS. This finding is
consistent with findings that the left hemisphere is more involved than the right
hemisphere in the control of both the ipsilateral and contralateral hand (Callaert et al.,
2011; Haaland, 2006; Haaland et al., 2000; Koeneke et al., 2004; Serrien et al., 2006;
Swinnen et al., 2010). As the timed‐response task used in the current study permits the
advanced preparation of a motor response (Carlsen & MacKinnon, 2010; Hening,
Vicario, et al., 1988; Schluter et al., 2001), this finding suggests that the left M1 makes
greater contributions than the right M1 to the control of late motor processes, related to
the execution of the response. In contrast to this finding, no differences between the
effects of left and right M1 TMS were observed in a study which used a simple RT task
(Foltys et al., 2001). However, left M1 TMS also produced stronger effects than right M1
TMS on the timing of unimanual responses in a rhythmic tapping task (J.‐T. Chen et al.,
2005). The stronger effects of left M1 TMS in the current study could be influenced by
the requirement to control the timing of the response, which was present in both the
current study and in the study conducted by J.‐T Chen and colleagues (2005), as previous
imaging findings have shown that precise temporal control requirements can increase
left M1 involvement in a motor task (Macar et al., 2004).
The finding that left M1 TMS advanced responses more than right M1 TMS
suggest that the effects of left M1 TMS cannot be entirely explained by non‐specific
effects such as intersensory facilitation or a startle‐like response. Previous studies have
found that non‐specific effects are either not lateralized (Nickerson, 1973; Nijhuis et al.,
2007; Stoffels, Van Der Molen, & Keuss, 1985) or are stronger for right‐side stimulus
presentations (Maslovat, Carlsen, & Franks, 2012), in contrast to the findings for the
effects of TMS in the current study. Some non‐specific effects have been found to be
stronger when the side of presentation and the side of the response are compatible
(Nickerson, 1973). However, no such interaction between the side of stimulation and the
side of the response was observed in the present study, which further suggests that the
The effect of TMS on the timing of unimanual and bimanual pinches 43
effect of left M1 TMS on the timing of responses onsets cannot be accounted for by non‐
specific effects.
In conclusion, the present findings show that M1 TMS advances unimanual,
bimanual equal and bimanual unequal responses to a similar extent when administered
prior to the performance of responses in a timed‐response task, suggesting that each
hemisphere makes similar contributions to the control of the timing of unimanual and
bimanual actions. Left M1 TMS was also found to advance responses more than right
M1 TMS, consistent with findings that the left hemisphere makes stronger contributions
to the control of motor actions than the right hemisphere.
45
Chapter 5.
Corticomotor excitability during the preparation of
bimanual forces of equal and unequal magnitude
Bimanual actions tend towards symmetrical coordination patterns, a
phenomenon referred to as force or spatial coupling, depending on the feature of the
response being measured (Swinnen, 2002). Force and spatial coupling are forms of
bimanual coupling which are reflected in correlations between the amplitude of the
responses produced by each hand in both force production and reaching tasks
(Diedrichsen et al., 2003; Sherwood, 2006; Sherwood & Nishimura, 1992). These
intermanual interactions may reflect common input to the motor cortices or direct
interaction between them (Cardoso de Oliveira, 2002; Carson, 2005). Force and spatial
coupling persist, albeit to a lesser extent, when the hands are required to produce
asymmetrical responses such as bimanual forces or reaches of unequal magnitudes
(Diedrichsen et al., 2003; Sherwood & Nishimura, 1992), demonstrating that intermanual
interactions are suppressed but not eliminated during the production of asymmetric
responses.
The preparation of a bimanual motor response engages intermanual interactions
associated with the selection and specification of the response (Hazeltine, Diedrichsen,
Kennerley, & Ivry, 2003; Heuer & Klein, 2006; Heuer et al., 1998; Swinnen, 2002) which
may be reflected in CME. CME, as determined by the amplitude of the MEP to TMS, has
been used to investigate the preparation of both bimanual and unimanual actions. CME
has been found to be suppressed during the preparation of bimanual responses in mirror
but not parallel directions (Duque et al., 2005). Excitability in the right M1 has also been
found to be greater during the production of a left‐hand force when the hand performs
a unimanual task than when performing the same force in a bimanual task (Soteropoulos
& Perez, 2011; Yedimenko & Perez, 2010). Furthermore, this effect was stronger during
the production of forces in the same extrinsic direction (parallel directions), rather than
in opposite extrinsic (mirror) directions (Yedimenko & Perez, 2010), suggesting that
CME is modulated differently during motor preparation and execution.
46 Chapter 5
Studies examining CME during motor production have required the production
of unequal forces with each hand across all bimanual conditions (Soteropoulos & Perez,
2011; Yedimenko & Perez, 2010), whereas the amplitude of the response was not
restricted in the study examining CME during motor preparation (Duque et al., 2005).
The production of unequal forces may involve interhemispheric interactions necessary
to overcome the tendency towards symmetrical movements resulting in the suppression
of CME, similar to the hypothesized interactions regulating bimanual coupling of
movement direction (Duque et al., 2005; Swinnen, 2002; Yedimenko & Perez, 2010). The
current study examined the effect of force coupling on CME by measuring CME during
the preparation of unimanual isometric forces and bimanual isometric forces of equal
and unequal magnitudes. In order to limit variation in voluntary response times across
conditions, the study used a timed‐response task which required responses to be
synchronized with an auditory pacing cue, similar to that used in previous behavioral
experiments (Hening, Favilla, et al., 1988; Steglich et al., 1999). This synchronization task
permits the measurement of CME at an advanced and stable state of response
preparation, as demonstrated in tasks which used similar methods of response cueing
(Carlsen & MacKinnon, 2010; Hening, Favilla, et al., 1988; Steglich et al., 1999). It was
hypothesized that CME prior to the response would be lower for bimanual than
unimanual force preparation, consistent with previous findings. It was also
hypothesized that the suppression of bimanual coupling, to produce unequal forces,
would lead to lower CME in the unequal than equal force conditions.
Methods
The data used in the present study were extracted from the dataset collected for
the study presented in Chapter 4. The same subjects were used in both studies.
Data for the right M1 session were missing for two subjects who failed to attend
the second session. Missing data were excluded listwise for analyses directly comparing
left and right M1 TMS conditions and pairwise for all other analyses. Analyses of
behavioral data were performed on the no‐TMS condition, to exclude any possible
effects of TMS on the pinch response. Data for the no‐TMS condition were combined
across both sessions. Trials were excluded from analyses of MEP data if RMS EMG
activity was greater than 50 μV in the period 45–15 ms prior to the administration of
TMS. Less than 2% of trials were discarded for this reason.
CME during the preparation of bimanual forces 47
Results
Behavioral data
Pinch onsets in unimanual and bimanual equal‐force conditions in which TMS
was not administered preceded the target time by a mean of 40 ms, across all trials in
these conditions, whereas pinch onset times in bimanual unequal‐force conditions
preceded the target time by 1 ms (Fig. 5). Pinch onset times varied significantly across
force conditions, F(5, 65) = 17.88, p < 0.001, ηg2 = 0.17, with pinch onsets occurring
significantly later, by an average of 39 ms, in the two unequal force conditions (left 10%
MVC, right 30% MVC and left 30% MVC, right 10% MVC) than in all other force
conditions (g = 1.17–1.78). No significant differences in pinch onsets times were found
between any other force conditions (p ≥ 0.99, g ≤ 0.38) or between pinches performed
with the left and right hand, F(1, 13) = 0.78, p = 0.39, ηg2 = 0.00.
Fig. 5 Means of median pinch onset times relative to the target onset time for no‐TMS
conditions across both testing sessions. Pinch onsets occurred significantly later in the two
bimanual unequal conditions than in all other conditions. Onset times are displayed
in milliseconds, relative to the target onset time (the fourth auditory tone). Error bars show the
within‐subjects SEM for the force condition comparison. ʺLʺ and ʺRʺ denote the target force for
the left and right hand, as a percentage of MVC.
UnimanualBimanual
equalBimanualunequal
−60
−40
−20
0
20
L10 o
r R10
L30 o
r R30
L10 &
R10
L30 &
R30
L10 &
R30
L30 &
R10
Force condition (% MVC)
Pin
ch o
nset
asy
nchr
ony
(ms)
HandLeftRight
48 Chapter 5
Right hand MVCs were 20.5% greater (SD = 24.9%), on average, than left hand
MVCs. No significant differences were observed between left and right hand forces,
expressed as a percentage of MVC, during the experimental task, F(1, 13) = 1.42, p = 0.25,
ηg2 = 0.01. However, the 30% MVC force was consistently under‐produced by both hands
in all relevant force conditions (Fig. 6). Forces produced in response to the 10% MVC
target were significantly stronger (overproduced) in the unequal force conditions than
in the equal (g = 1.48) and unimanual force conditions (g = 1.49) but there were no
significant differences in the production of forces in response to the 30% MVC target
across conditions (ps ≥ 0.15, g ≤ 0.56). These findings demonstrate convergence
(assimilation) between the left and right hand forces in the unequal force conditions.
Significant correlations, reflecting bimanual coupling, were observed between the peak
forces produced by each hand in all bimanual force conditions. Peak force correlations
were consistently stronger in the equal than unequal force conditions (Table 5).
Fig. 6 Means of each subjectʹs median left and right hand peak forces as a percentage of MVC
in no‐TMS conditions, across both testing sessions. The data show a tendency for subjects to
underproduce forces in the 30% MVC force conditions, as well as assimilation of the 10% MVC
force in the bimanual unequal force conditions. Horizontal dotted lines indicate the target forces
(10% and 30% MVC). Error bars show the within‐subjects SEM for the force condition
comparison, calculated with the Greenhouse–Geisser correction.
UnimanualBimanual
equalBimanualunequal
0
10
20
30
40
L10 o
r R10
L30 o
r R30
L10 &
R10
L30 &
R30
L10 &
R30
L30 &
R10
Force condition (% MVC)
Peak
forc
e (%
MV
C)
HandLeftRight
CME during the preparation of bimanual forces 49
Table 5 Means and within‐subjects 95% confidence intervals of the correlations between the
peak forces produced by each hand in the no‐TMS condition, across both testing sessions.
Force Condition (% MVC) Mean force
correlation 95% CI
Left 10%, Right 10% 0.63 0.54 – 0.70
Left 30%, Right 30% 0.67 0.59 – 0.74
Left 10%, Right 30% 0.29 0.16 – 0.40
Left 30%, Right 10% 0.45 0.34 – 0.55
Electrophysiological data
Immediately prior to the administration of TMS, mean RMS EMG activity in the
hand contralateral to TMS varied between 17.5 μV (SD = 5.5 μV) and 23.0 μV
(SD = 10.0 μV), across all conditions. MEP amplitudes were substantially larger when a
response was being prepared for the hand contralateral to the stimulated M1 (Fig. 7). A
2 (side of TMS stimulation) × 2 (10% or 30% MVC force) × 3 (unimanual, bimanual equal
force, bimanual unequal force) ANOVA revealed that MEPs were significantly larger for
recordings taken from the right than left hand, F(1, 11) = 10.13, p < 0.01, ηg2 = 0.06. MEPs
were not significantly affected by the force of the response produced by the contralateral
hand, F(1, 11) = 0.89, p = 0.37, ηg2 = 0.00, or by whether the response was unimanual
(contralateral), bimanual equal or bimanual unequal, F(2, 22) = 3.18, p = 0.06, ηg2 = 0.03
(Fig. 7). No significant interactions were found. Bonferroni‐Holm‐corrected pairwise
comparisons found that the difference in MEPs between the unimanual pinch condition
and the bimanual unequal force condition fell slightly short of significance (p = 0.06,
g = 0.51) whereas the comparison between the bimanual equal force condition and the
bimanual unequal force condition was clearly non‐significant (p = 0.42, g = 0.25). The
comparison between the unimanual condition and the bimanual equal force condition
was also non‐significant (p = 0.42, g = 0.26). A 2 (side of TMS stimulation) × 9 (response
condition) ANOVA, with the no pinch and ipsilateral pinch conditions included,
revealed that MEPs were affected by the response condition, F(8, 88) = 17.40, p < 0.001,
ηg2 = 0.28, with significantly larger MEPs being found in all conditions in which a pinch
was being prepared for the hand contralateral to TMS than when an ipsilateral pinch or
no pinch was being prepared (g = 1.22–2.04).
50 Chapter 5
Fig. 7 Mean MEP amplitudes for FDI of each hand in each response condition. Error bars show
the SEM. ʺIʺ denotes the force target for the hand ipsilateral to TMS and ʺCʺ denotes the force
target for the hand contralateral to TMS. Target forces are expressed as a percentage of MVC.
Error bars show the within‐subjects SEM for the response condition comparison, calculated with
the Greenhouse–Geisser correction.
Discussion
The current study investigated the effect of intermanual interactions on CME
during the preparation of isometric forces in a timed‐response task, which permits the
advanced preparation of a response. Significantly larger MEPs were recorded in the
hand for which a response was being prepared. MEPs were also larger in the right than
left hand, consistent with previous research (De Gennaro et al., 2004; Perez & Cohen,
2009; van den Berg et al., 2011; Ziemann & Hallett, 2001). However, no differences in
MEP amplitudes were found between the active hand in unimanual response conditions
and either hand in bimanual response conditions. There were also no significant
differences between MEP amplitudes recorded during the preparation of bimanual
forces of unequal and equal magnitudes, despite differences in force coupling between
the equal and unequal force conditions.
The absence of any observed differences in CME between unequal and equal
bimanual force conditions, when considered with previous findings, suggests that
different processes control the coupling of the force and direction of a motor response.
Previous research has found that responses in mirror directions are associated with
Left hand (Right M1) Right hand (Left M1)
0
1
2
3
I00 C
00
I10 C
00
I30 C
00
I00 C
10
I00 C
30
I10 C
10
I30 C
30
I10 C
30
I30 C
10
I00 C
00
I10 C
00
I30 C
00
I00 C
10
I00 C
30
I10 C
10
I30 C
30
I10 C
30
I30 C
10
Force condition (% MVC)
Mea
n M
EP
am
plitu
de (m
V)
ResponseNo pinchIpsilateral onlyContralateral onlyBimanual equal forceBimanual unequal force
CME during the preparation of bimanual forces 51
lower CME than parallel movements during preparation and with greater CME during
sustained contraction (Duque et al., 2005; Yedimenko & Perez, 2010), in contrast to the
absence of any comparable effects of force on CME in the present study. While the corpus
callosum appears to mediate both the coupling of force and the coupling of response
direction (Diedrichsen et al., 2003; Eliassen et al., 1999, 2000; Franz et al., 1996), different
neural networks have been implicated in each of these forms of bimanual coupling
(Wenderoth, Debaere, Sunaert, & Swinnen, 2005). This dissociation may explain
differences between the present findings and those from previous studies concerning
response direction. The suppression of mirror contractions for the production of either
parallel or strictly unimanual responses appears to involve inhibitory interhemispheric
interactions which suppress the excitability of homologous motor representations
ipsilateral to an active hand (Hinder, Schmidt, Garry, & Summers, 2010; Hübers,
Orekhov, & Ziemann, 2008; Yedimenko & Perez, 2010). As different movement
directions appear to have separate representations in motor cortex (Kakei, Hoffman, &
Strick, 1999), these interactions may help resolve conflict between competing directional
representations. Different forces, however, appear to be represented by differences in
the neural firing rate or through the recruitment of additional neurons (Milner‐Brown,
Stein, & Yemm, 1973) so the suppression of contralateral force representation during the
control of unequal force responses may inhibit the production of these responses, rather
than helping to resolve conflict. This may also explain the recent finding that individuals
who exhibited high levels of interhemispheric inhibition performed more poorly on an
asymmetric force production task, despite displaying less mirror activity during the
production of strictly unimanual forces (Fling & Seidler, 2012).
The absence of any significant differences in CME between the preparation of
unimanual and bimanual forces contrasts with findings that CME differs between
unimanual and bimanual conditions during motor execution. In particular, CME in the
right M1 has been found to be greater during the production of a unimanual left hand
force than during the production of unequal bimanual forces (Soteropoulos & Perez,
2011; Yedimenko & Perez, 2010). The difference between these findings and those of the
present study suggests that additional or different intermanual interactions are engaged
in the preparation and execution of a force response, which may include increased
communication between the motor cortices during response execution (Serrien &
Brown, 2004). The presence of different intermanual interactions during motor
52 Chapter 5
preparation and execution is supported by findings that CME in the inactive hand is
suppressed during the preparation of a unimanual response (Duque et al., 2005; Leocani
et al., 2000) but facilitated during sustained unimanual contraction (Hess, Mills, &
Murray, 1986; Hortobágyi, Taylor, Petersen, Russell, & Gandevia, 2003; Muellbacher et
al., 2002; Perez & Cohen, 2008, 2009; Stedman, Davey, & Ellaway, 1998; Tinazzi &
Zanette, 1998). Differences between the effect of intermanual interactions on CME
between motor preparation and execution may be related to changes in the function of
interhemispheric inhibition. Interhemispheric inhibition targeting the active hand has
been found to decrease or even shift to facilitation between the preparation and
execution of a unimanual response (Duque et al., 2007; Tazoe & Perez, 2013), whereas
greater interhemispheric inhibition is observed during the production of bimanual
forces, which appears to contribute to lower CME in these conditions (Soteropoulos &
Perez, 2011; Yedimenko & Perez, 2010).
No differences in CME were observed in an active hand between unimanual and
bimanual conditions in the current study. In contrast, Duque and colleagues (2005)
observed lower CME during the preparation of bimanual movements in mirror
directions than during the preparation of unimanual movements (Duque et al., 2005).
This difference in findings may be due to the activation of opposing effectors to produce
the pinch responses in the present study, which mean that the pinch responses in the
current study lacked an overall extrinsic response direction, unlike the index‐finger
movements required by Duque and colleagues (2005). This lack of a global extrinsic
response direction may have contributed to a smaller reduction in CME in the bimanual
conditions of the present study, as Duque and colleagues (2005) observed that reductions
in CME were dependent on the extrinsic direction of the response, rather than the
effectors involved. The responses used in the current study also required isometric
muscles contractions whereas those in the study conducted by Duque and colleagues
(2005), involved isotonic contractions, which may have also influenced CME findings.
Isometric contractions have been found to have a lower tendency to transition towards
in‐phase movements patterns during rhythmic movements than isotonic movements
(Byblow, Carson, & Goodman, 1994; Carson, 1990). These phase transitions appear to
have a neural rather than biomechanical origin (Carson, 1990), suggesting that isotonic
and isometric responses involve different neural interactions (Perez, 2012), which may
extend to the control of CME.
CME during the preparation of bimanual forces 53
In conclusion, the present findings show that CME does not differ substantially
during the preparation of forces with equal and unequal force magnitudes. These results
suggest that the intermanual interactions involved in the coupling of bimanual forces
differ from those involved in the control of movement direction (Duque et al., 2005;
Yedimenko & Perez, 2010), which may reflect differences in the way force and movement
direction are represented in motor cortex. The finding of this study extend previous
findings, which similarly suggest that intermanual interactions involved in the control
of these responses do not alter the effects of TMS on the timing of the response (Chapter
4).
55
Chapter 6.
Specific and non‐specific mechanisms of
transcranial magnetic stimulation induced response
facilitation
In previous chapters of this thesis, TMS was found to advance responses when
administered prior to the target response time in a timed‐response task. As noted in
these chapters, TMS could advance responses in this task through mechanisms that are
either specific or non‐specific to the stimulation of M1.
In RT tasks, TMS appears to advance responses through both M1‐specific and
non‐specific mechanisms, when administered early in the response latency (Davey,
Romaiguère, Maskill, & Ellaway, 1994; Foltys et al., 2001; Hallett et al., 1991; Leocani et
al., 2000; Pascual‐Leone, Valls‐Solé, et al., 1992; Pascual‐Leone, Brasil‐Neto, et al., 1992;
Pascual‐Leone et al., 1994; Sawaki et al., 1999, 1999; Terao et al., 1997; Ziemann et al.,
1997). The presence of M1‐specific effects has been supported by findings that TMS
advances responses more when delivered over M1 than when discharged off‐scalp or
over non‐motor areas (Hashimoto et al., 2004; Pascual‐Leone, Valls‐Solé, et al., 1992;
Sawaki et al., 1999; Soto et al., 2010). M1‐specific effects could be mediated by the
facilitation of motor preparation or execution as a result of the magnetic stimulation of
M1 neurons (Pascual‐Leone, Valls‐Solé, et al., 1992; Sawaki et al., 1999). The presence of
non‐specific effects has been supported by findings that TMS also advances responses
when discharged off‐scalp or over non‐motor areas (Romaiguère et al., 1997; Sawaki et
al., 1999; Terao et al., 1997). Non‐specific effects of TMS have commonly been attributed
to intersensory facilitation (Romaiguère et al., 1997; Sawaki et al., 1999; Terao et al., 1997),
although it has also been suggested that TMS could advance responses by evoking of a
startle‐like response (Leocani et al., 2000). In RT tasks, intersensory facilitation appears
to facilitate responses through faster detection of the imperative stimulus (multisensory
integration) or through advanced preparation to respond to this stimulus, which is
enabled by the presentation of an accessory stimulus that warns of its arrival (temporal
preparation; Diederich & Colonius, 2008; Los & Van der Burg, 2013; Nickerson, 1973).
Timed‐response tasks, however, do not require rapid stimulus detection, as they do not
56 Chapter 6
require responses to be rapidly executed, and they permit temporal preparation by
presenting a series of evenly‐spaced tones that can be used to predict the onset of the
synchronization signal. These characteristics make it appear unlikely that intersensory
facilitation would facilitate responses in timed‐response tasks. In contrast, a loud
(startling) acoustic stimulus has been found to advance responses in both timed‐
response and RT tasks (Carlsen & MacKinnon, 2010; Castellote, Van den Berg, & Valls‐
Solé, 2013; Valls‐Solé et al., 2008) and could therefore contribute to the facilitatory effects
of TMS in both tasks. Facilitatory effects of a loud acoustic stimulus have been commonly
associated with a startle response, although a loud acoustic stimulus can advance
responses in the absence of an observable startle response (Delval et al., 2012; Kumru &
Valls‐Solé, 2006; Marinovic, Rugy, Lipp, & Tresilian, 2013; Maslovat, Kennedy, Forgaard,
Chua, & Franks, 2012; Nijhuis et al., 2007; R. F. Reynolds & Day, 2007; Valls‐Solé et al.,
2005).
The current study investigated the contribution of M1‐specific and non‐specific
mechanisms to the facilitation of responses produced by TMS in a timed‐response task.
Non‐specific effects were measured by administering TMS over a non‐motor area.
Active stimulation was used in this condition, with the TMS coil in direct contact with
the scalp, to ensure that all non‐specific effects related to the sound or tactile stimulation
produced by TMS were adequately controlled for. In particular, TMS produces sounds
that are conducted through both the air and through bone (Nikouline et al., 1999), as
well as tactile‐stimulation, which are difficult to reproduce with sham or off‐scalp
stimulation (Arana et al., 2008; Burle et al., 2002; N. J. Davis, Gold, Pascual‐Leone, &
Bracewell, 2013; Herwig, Cardenas‐Morales, Connemann, Kammer, & Schönfeldt‐
Lecuona, 2010) but may contribute to non‐specific effects such as startle (B. K. Taylor et
al., 1991; Yeomans et al., 2002). The occipital cortex was selected as the non‐motor area
over which TMS was administered as this site does not appear to be involved in the
preparation of a motor response (Busan, Monti, Semenic, Pizzolato, & Battaglini, 2009).
It was hypothesized that TMS would advance responses through M1‐specific
mechanisms, such that M1 TMS, but not occipital TMS, would advance the onset of the
motor response.
Specific and non‐specific mechanisms of TMS‐induced response facilitation 57
Methods
Subjects
Nineteen right‐handed psychology undergraduates and postgraduates (7 male,
12 female) participated in the study. The subjectsʹ ages ranged from 18 to 28 years
(median = 20).
Experimental design
TMS was administered over the left M1, the left occipital cortex, or withheld
completely, to quantify M1‐specific and non‐specific effects of TMS on the timing of a
force response. Unimanual force targets were presented for both the left and right hand.
Materials and procedures
Experimental trials
Forty trials were completed for each combination of force (10% MVC; 30% MVC)
and hand condition (2 force × 2 hand), giving a total of 160 trials. TMS was administered
over either the left M1 or left occipital cortex on 50% of these trials. TMS was
administered over these sites on an equal number of trials and was always administered
250 ms before the target response time. Trials were arranged into blocks of 16 trials, each
of which contained all possible combinations of conditions, in the same proportions as
in the experiment as a whole. Condition order was randomized within each block.
Feedback was given on whether the response was made with the correct hand
and had a force rise time of less than 300 ms. Trials in which these criteria was not met
were discarded and repeated. Feedback was also given on whether the onset of the
response occurred within 150 ms of the target time. However, trials were only discarded
and repeated if the onset of the response did not occur within 250 ms of the target time.
Stimulation and recording
The EMG signal was recorded from the FDI and the APB muscles of the right
hand. TMS was delivered over the left M1 using the same procedures as in previous
experiments. TMS was delivered to the left occipital cortex at the same intensity used for
M1 stimulation, over the O1 site of the international 10‐20 system for EEG recording. The
58 Chapter 6
coil was oriented with the handle lateral during occipital stimulation, which induces
current flow in the latero‐medial direction, and therefore avoids current flow towards
the parietal and motor areas of the cortex (Kammer et al., 2001; Mills, Boniface, &
Schubert, 1992).
Results
Behavioral data
Summary statistics for pinch onset times are shown in Table 6. Summary
statistics for other characteristics of the response are listed in Appendix 3. Pinch onset
times in the no‐TMS condition were approximately normally distributed around the
target time (Fig. 8). Pinch onsets occurred significantly earlier when 30% MVC forces
were required than when 10% MVC forces were required, F(1, 18) = 19.46, p < 0.001,
ηg2 = 0.02, and did not significantly differ between the hands, F(1, 18) = 1.43, p = 0.25,
ηg2 = 0.00. A significant hand × force interaction was found, F(1, 18) = 6.36, p = 0.02,
ηg2 = 0.00, reflecting the presence of earlier pinch onsets for the left hand than the right
hand in the 10% MVC condition but not the 30% MVC condition. No other significant
interactions were found.
Fig. 8 Kernel density estimates showing that the distributions of pinch onset times were shifted
towards earlier responses in both M1 TMS and occipital TMS conditions for both the left and right
hand. Data were pooled across force conditions. The dotted vertical line marks the time at which
TMS was administered.
Left Hand Right Hand
0.000
0.002
0.004
0.006
−400 −200 0 200 400 −400 −200 0 200 400
Pinch onset time (ms relative to target)
Den
sity
TMSNoneM1Occipital
Specific and non‐specific mechanisms of TMS‐induced response facilitation 59
Table 6 Means and standard deviations (in brackets) for pinch onset times in each condition, in
milliseconds, relative to the target time. Target forces are expressed as a percentage of MVC.
TMS Target force
(% MVC)
Left hand
onset (ms)
Right hand
onset (ms)
None 10 7 (51) 9 (59)
30 ‐8 (51) ‐15 (57)
M1 10 ‐27 (53) ‐15 (54)
30 ‐43 (54) ‐44 (49)
Occipital 10 ‐44 (47) ‐24 (63)
30 ‐45 (59) ‐42 (69)
Forces were typically under‐produced during the experimental task, particularly
in the 30% MVC force condition (Fig. 9). Peak forces did not significantly differ between
the hands, when expressed as a percentage of MVC, F(1, 18) = 11.37, p < 0.01, ηg2 = 0.02.
Peak forces were less precise, as measured by the coefficient of variation, in the 10%
MVC (M = 0.28) than in the 30% MVC force condition (M = 0.21), F(1, 18) = 53.40,
p < 0.001, ηg2 = 0.27. The precision of peak forces did not significantly differ between the
hands, F(1, 18) = 0.10, p = 0.75, ηg2 = 0.00.
Fig. 9 Means of each subjectʹs median left and right hand peak forces, as a percentage of MVC,
for each TMS condition. Peak forces were significantly larger in occipital TMS conditions than in
both no‐TMS and M1 TMS conditions. Horizontal dotted lines indicate the target forces (10% and
30% MVC). Error bars show the within‐subjects SEM for the TMS condition comparison.
Left Hand Right Hand
0
10
20
30
10 30 10 30
Force condition (% MVC)
Peak
forc
e (%
MV
C) TMS
NoneM1Occipital
60 Chapter 6
Pinch onset times were significantly affected by TMS (Fig. 8), F(2, 36) = 22.57,
p < 0.001, ηg2 = 0.08. M1 TMS significantly advanced pinch onsets by 30 ms (g = 0.84) and
occipital TMS significantly advanced pinch onsets by 37 ms, over those in the no‐TMS
condition (g = 1.02). Pinch onset times did not significantly differ between the M1 and
occipital TMS conditions (p = 0.26, g = 0.18), with pinches in the occipital TMS condition
preceding those in the M1 TMS condition by a mean of 7 ms. There was no significant
difference between the effect of TMS on pinch onset times for responses produced by the
ipsilateral and contralateral hand, as indicated by the absence of a significant TMS ×
hand condition interaction, F(2, 36) = 2.47, p = 0.10, ηg2 = 0.00. TMS did not significantly
affect force rise times, F(2, 36) = 0.44, p = 0.65, ηg2 = 0.00, total pinch durations
F(2, 36) = 0.96, p = 0.39, ηg2 = 0.00, or the precision of peak forces, F(2, 36) = 1.87, p = 0.17,
ηg2 = 0.02.
The size of peak forces significantly varied across TMS conditions (Fig. 9),
F(2, 36) = 7.01, p < 0.01, ηg2 = 0.01. Peak forces were 0.9% MVC larger in the occipital TMS
condition than in the no‐TMS condition (g = 0.59) and 0.6% MVC larger in the occipital
than M1 TMS condition (g = 0.42). Visual inspection of the force traces did not reveal any
other differences in the force profile between these conditions (Fig. 10). Mean peak forces
were higher in the occipital TMS condition than in the no‐TMS condition in 89% of
subjects. Left M1 TMS did not significantly affect the size of peak forces (p = 0.29,
g = 0.17).
Electrophysiological data
The mean TMS intensity required to produce a 1 ±33% mV MEP in the FDI
muscle in the left M1 was 53.2% maximum stimulator output (SD = 10.6%). This intensity
was equivalent to 114.0% rMT, on average (SD = 6.0%). Only one subject reported that
left occipital TMS (O1) produced visual sensations, which they described as movement
in the right periphery.
Immediately prior to the administration of TMS, mean RMS EMG activity in the
hand that produced a response varied between 60.1 μV (SD = 62.1 μV) and 83.8 μV
(SD = 92.2 μV), across all force and TMS conditions. Mean RMS EMG activity in the hand
that did not produce a response varied between 48.1 μV (SD = 66.1 μV) and 65.0 μV
(SD = 79.4 μV). FDI MEP amplitudes were larger when a pinch was prepared for the
hand contralateral to TMS (right hand; M = 3.50 mV) than when a pinch was prepared
Specific and non‐specific mechanisms of TMS‐induced response facilitation 61
for the hand ipsilateral to TMS (left hand; M = 1.47 mV), F(1, 18) = 32.99, p < 0.001,
ηg2 = 0.25. APB MEP amplitudes were also larger when a pinch was being prepared for
the contralateral (M = 2.11 mV) than ipsilateral hand (M = 0.88 mV), F(1, 18) = 35.57,
p < 0.001, ηg2 = 0.17. MEP amplitudes were not significantly affected by the size of the
target force, for recordings taken from both the FDI, F(1, 18) = 0.09, p = 0.76, ηg2 = 0.00,
and the APB, F(1, 18) = 0.06, p = 0.81, ηg2 = 0.00.
Fig. 10 Force traces from a single subject for trials that were representative of the forces produced
in each TMS and force condition. Forces are represented as a percentage of MVC. The data have
been smoothed using a 20 ms rolling average to eliminate electrical noise from the recordings.
Dotted vertical lines indicate the time at which TMS was administered in each condition.
Discussion
The current study investigated the specificity of TMS‐induced response
facilitation in a timed‐response task. TMS over the left M1 was found to advance
responses by approximately 30 ms, consistent with previous findings in this thesis
Left Hand Right Hand
0
10
20
30
0
10
20
30
0
10
20
30
No TMS
M1 TMS
OccipitalTMS
0 500 1000 0 500 1000
Time (ms relative to target)
Forc
e (%
MV
C)
Target (% MVC)1030
62 Chapter 6
(Chapter 3, 4). However, the hypothesis that this advancement of responses would be
specific to the stimulation of M1 was not supported, as occipital TMS was found to
advance responses to a similar extent to M1 TMS. Although this indicates that the effects
of TMS were solely non‐specific, peak forces were slightly larger in the occipital TMS
condition than in M1 TMS and no‐TMS conditions, indicating that occipital TMS may
not be an appropriate control for non‐specific effects of M1 TMS in the task used in the
current study. In contrast to occipital TMS, M1 TMS did not affect peak forces or
otherwise disrupt the integrity of the response, consistent with previous findings
(Chapter 3, 4), suggesting that the effect of TMS on peak forces is specific to the
stimulation of the occipital cortex.
There are several ways in which occipital TMS might have increased the size of
peak forces. Occipital TMS could have facilitated force production, as the increase in
force in the occipital TMS condition improved the accuracy of the response, since forces
were typically underproduced across all force conditions. Occipital TMS could have also
disrupted or counteracted an adaptive strategy to minimize effort as mean forces were
already within the range of forces required by the task in the no‐TMS condition. Occipital
TMS could have increased the size of peak forces by altering the perception or processing
of the visual force target, which may influence subsequent preparation of the force
response. Occipital TMS has previously been found to both improve (Abrahamyan,
Clifford, Arabzadeh, & Harris, 2011; Mullin & Steeves, 2011; Perini, Cattaneo, Carrasco,
& Schwarzbach, 2012) and disrupt the perception of visual stimuli, depending upon the
type of visual stimulus and the stimulation parameters used (Amassian et al., 1989;
Beckers & Hömberg, 1991; Corthout, Uttl, Walsh, Hallett, & Cowey, 1999; de Graaf,
Cornelsen, Jacobs, & Sack, 2011; Kammer & Nusseck, 1998; Kammer, Puls, Strasburger,
Hill, & Wichmann, 2005; Kammer, Scharnowski, & Herzog, 2003; Masur, Papke, &
Oberwittler, 1993). Occipital TMS could have also affected visuomotor processing
through connection to parietal areas (Glickstein, 2000), which appear to be involved in
the translation of visual information into a motor response (Busan et al., 2009; Galletti et
al., 2001; Galletti, Kutz, Gamberini, Breveglieri, & Fattori, 2003). However, additional
research is needed to determine the reliability and precise mechanism of the increase in
pinch forces observed following occipital TMS in the present study.
The finding that occipital TMS increased the size of peak forces raises the
possibility that occipital TMS may have advanced responses through direct cortical
Specific and non‐specific mechanisms of TMS‐induced response facilitation 63
effects, rather than through the sound or tactile stimulation produced by TMS. Thus,
occipital and left M1 TMS may have advanced responses through the stimulation of
different cortical regions involved in the control of a visuomotor response, rather than
through shared non‐specific effects. This possibility is consistent with the finding that
left M1 TMS produced stronger facilitation than right M1 TMS (Chapter 4), since this
finding indicates that the facilitation produced by TMS is at least partially specific to the
stimulation of the left M1. However, the findings of a previous RT study indicate that
occipital TMS only advances responses through non‐specific mechanisms (Busan et al.,
2009). This study found that occipital TMS advanced responses when delivered in close
proximity to the imperative signal. However, this effect was shared with sham‐
stimulation and TMS over other cortical areas, suggesting that it was produced by
intersensory facilitation (Busan et al., 2009). Another RT study found that occipital TMS
advanced responses to auditory but not visual stimuli (Romei, Murray, Merabet, & Thut,
2007). However, the current study cued responses with visual force targets suggesting
that the effect observed by Romei and colleagues (2007) did not contribute to facilitation
in the current study. Specific facilitatory effects of occipital TMS may be specific to the
task or visual stimuli used in the current study. Unlike the current study, previous
studies did not observe any effects of occipital TMS on the motor response (Busan et al.,
2009; Xivry, Criscimagna‐Hemminger, & Shadmehr, 2011), suggesting that occipital
TMS produces some distinct effects in the task used in the current study.
The possibility that M1 and occipital TMS both advanced responses through non‐
specific mechanisms, related to the sound or tactile stimulation produced by TMS,
cannot be excluded on the basis of the present findings. The present finding that TMS
advanced ipsilateral and contralateral responses by a similar amount is consistent with
the advancement of responses through a startle‐like response, as a loud acoustic
stimulus, capable of producing a startle response, has been found to similarly advance
responses produced by either side of the body, apart from some stimulus‐response
compatibility effects that are observed under some monaural stimulus presentation
conditions (Maslovat, Carlsen, et al., 2012; Nijhuis et al., 2007). A loud acoustic stimulus
has previously been found to advance responses in both timed‐response and RT tasks
(Carlsen & MacKinnon, 2010; Valls‐Solé et al., 2005, 1999). This effect has been attributed
to a reduction in the duration of processes required for motor execution, which may be
mediated by an increase in M1 or subcortical excitability (Carlsen, Chua, Inglis,
64 Chapter 6
Sanderson, & Franks, 2004; Marinovic, Tresilian, de Rugy, Sidhu, & Riek, 2014; Maslovat,
Carter, Kennefick, & Carlsen, 2014), similar to the previously proposed mechanism of
M1‐stimulation‐specific effects of TMS (Chapter 4).
The sound produced by TMS could have also altered the timing of responses in
the task used in the current study by distorting temporal judgments concerning the
timing of the pacing stimuli. An accessory sound can influence response times through
the filled duration illusion, the tendency for filled durations to appear longer (Adams,
1977; Buffardi, 1971; Craig, 1973; Goldfarb & Goldstone, 1963; Hall & Jastrow, 1886;
Nakajima, 1987; Thomas & Brown, 1974; Wearden, Norton, Martin, & Montford‐Bebb,
2007), or temporal integration, the integration of multiple adjacent stimuli into one
percept (Mates, Müller, Radil, & Pöppel, 1994; Repp, 2004; Yabe et al., 1998). However,
filling a duration with the sound produced by TMS would be expected to delay, rather
than advance, responses (Repp, 2008; Repp & Bruttomesso, 2009; Wohlschläger & Koch,
2000). Temporal integration is unlikely to have affected the timing of responses, as TMS
was presented outside of the temporal integration window of approximately 150 ms
around the auditory pacing tones (Repp, 2004). Thus, it appears unlikely that perceptual
illusions contributed to the facilitation produced by TMS in the present study.
In summary, the present study found that both M1 and occipital TMS advance
responses in a timed‐response task. These effects could have been produced through
either shared non‐specific effects or through the stimulation of different cortical areas
involved in the processing and preparation of a visuomotor response. Occipital TMS
appears to have increased the size of peak forces, which indicates that TMS over non‐
M1 sites may not be a suitable control condition for non‐specific effects of TMS in a
visuomotor force‐production task. Non‐specific effects of TMS in timed‐response tasks
are most likely to be mediated through a startle‐like response.
65
Chapter 7.
Mechanisms of transcranial magnetic stimulation
induced changes in the timing of a voluntary motor
response
In the previous chapters of this thesis, TMS was found to advance the onset of a
response when delivered over M1 prior to the required response time in a timed‐
response task, similar to previous findings in RT tasks. M1 TMS could advance responses
by reducing the time taken to transfer the motor program to the output structures or by
facilitating the execution of the motor response by abbreviating the duration of changes
in M1 excitability that precede the execution of the response (Pascual‐Leone, Valls‐Solé,
et al., 1992; Pascual‐Leone et al., 1994; Sawaki et al., 1999; Soto et al., 2010). The execution
of the response could be facilitated through either the direct stimulation of M1 or
through non‐specific effects related to a startle‐like response, as discussed in previous
chapters. Previous studies demonstrating the advancement of responses following TMS
have all used responses that require the contraction of one or more muscles. Muscle
contractions are preceded by an increase in M1 excitability, indicating a period of time
required to execute the response (R. Chen & Hallett, 1999; R. Chen et al., 1998; Evarts,
1966; Hoshiyama et al., 1996; Leocani et al., 2000; Pascual‐Leone, Valls‐Solé, et al., 1992).
TMS might therefore facilitate the execution of these responses by increasing M1
excitability (Pascual‐Leone, Valls‐Solé, et al., 1992; Sawaki et al., 1999).
In contrast to a muscle contraction, the relaxation of a sustained contraction
appears to require a reduction in M1 excitability (Begum et al., 2005; Buccolieri,
Abbruzzese, & Rothwell, 2004; Motawar, Hur, Stinear, & Seo, 2012; Suzuki, Sugawara,
Takagi, & Higashi, 2015; Yamanaka et al., 2002), and therefore the relaxation of a
sustained contraction would not be advanced, and could even be delayed, by an increase
in M1 excitability. However, muscle contraction and relaxation appear to involve shared
preparatory processes and, therefore, both responses could be advanced by processes
which facilitate motor preparation or the transfer of the prepared motor program to the
output structures. The presence of shared preparatory processes is supported by
findings that both contraction and relaxation responses are preceded by similar
66 Chapter 7
lateralized readiness potentials (Pope, Holton, Hassan, Kourtis, & Praamstra, 2007;
Terada, Ikeda, Nagamine, & Shibasaki, 1995; Terada, Ikeda, Yazawa, Nagamine, &
Shibasaki, 1999), which appear to share neural generators in M1 and the supplementary
motor areas (SMA) (Yazawa et al., 1998). Similarly, beta and alpha activity have been
found to decrease 1.5 s and 1 s prior to the onset of both contraction and relaxation
responses (Alegre et al., 2003). Increased activation in the pre‐SMA, SMA proper and
contralateral sensorimotor cortex has also been found for both contraction and relaxation
responses (Oga et al., 2002; Toma et al., 1999, 2000), which further supports the
involvement of shared preparatory processes in the generation of each of these
responses.
The current study investigated the effect of TMS on the timing of responses in a
timed‐response task that required either muscle contraction or relaxation in synchrony
with a predictable auditory tone. As timed‐response tasks have been found permit
advanced motor preparation (Hening, Favilla, et al., 1988; Steglich et al., 1999), it was
hypothesized that TMS primarily advances responses in this task by facilitating motor
execution through an increase in M1 excitability. Therefore, it was expected that TMS
would advance contraction responses, which require an increase in M1 excitability, but
delay relaxation responses, which require an opposing decrease in M1 excitability.
Methods
Subjects
Twelve right‐handed psychology postgraduates (4 male, 8 female) participated
in the study. The subjectsʹ ages ranged from 23 to 40 years (median = 26.5).
Experimental design
The study was completed over two sessions. In each session, subjects completed
a timed‐response task that required either the onset of a sustained muscle contraction
(contraction condition) or the relaxation of a sustained contraction (relaxation condition)
to be synchronized with the last of four auditory tones. These conditions were performed
in alternating blocks. The hand that was required to produce or release a contraction (left
or right) was randomized from trial to trial while the other hand was required to
maintain a relaxed or contracted state. In one session, TMS was administered at the same
Mechanisms of TMS‐induced changes in the timing of a motor response 67
intensity in contraction and relaxation conditions. In the other session, the intensity of
TMS was reduced during the relaxation condition so that matched MEP amplitudes
were obtained in contraction and relaxation conditions. The order of these sessions was
counterbalanced across subjects.
Materials and procedures
Maximum voluntary contraction determination
MVC determination was performed using the same method as previous
experiments except MVCs were measured in the first 500 ms of a sustained, rather than
brief, response.
Task
Contraction trials started with both hands relaxed, which was taken as less than
5% MVC. Relaxation trials started with both hands applying a force of 20–30% MVC.
These force thresholds were displayed on the thermometer‐style force displayed used in
previous experiments, along with the current force. Contraction or relaxation responses
were performed with one hand, while the other hand remained in its starting, relaxed or
contracted, state. Subjects were instructed to avoid moving their fingers in the antagonist
direction during relaxation.
Subjects were required to synchronize the onset of their response with the last of
four auditory tones, which were identical to those used in previous experiments.
Contraction onsets were taken as the first time at which forces exceeded 5% MVC and
relaxation onsets were taken as the first time at which forces fell below 20% MVC. These
thresholds were marked on the force targets and represented the first point at which
forces exceeded or fell below the range in which forces were maintained prior to each
contraction or relaxation response. This provided a clear and consistent indicator as to
when the onset of the response was recorded, to aid subjects in synchronizing their
responses with the final auditory tone. The required response hand was indicated with
a horizontal line that was presented on the force display for the appropriate hand 600 ms
before the onset of the final (fourth) tone. Trials were restarted if pinch forces were not
kept within the starting range until this line was presented. The horizontal line was
placed at the height which indicated a 20% MVC force during contraction trials and 5%
68 Chapter 7
MVC on relaxation trials and also served to indicate the minimum force required for a
contraction or the maximum force permitted following relaxation. These forces were
required to be reached within 300 ms of the onset of the response and maintained for at
least 1 s. Trials were discarded and repeated if this criterion was not met. Trials were
also discarded and repeated if the response onset time did not fall within 150 ms of the
target time (the final tone). Feedback on these criteria was provided using the LED‐
display used in previous experiments.
Practice trials
Subjects practiced contraction trials, followed by relaxation trials, in separate
blocks, using the same procedures as previous experiments. Subjects were provided
with verbal feedback on their hand movements during the relaxation trials to help them
learn to complete these responses without moving their fingers in the antagonist
direction.
Experimental trials
Forty trials were completed for each combination of hand (left, right) and
response type (contraction, relaxation) giving a total of 160 experimental trials. TMS was
administered 250 ms before the final tone on 50% of the trials in each response condition.
Contraction and relaxation trials were performed in alternating blocks of 8 trials. Each
block contained all combinations of TMS and hand conditions (2 × 2) in equal numbers.
Condition order was randomized within each block and the response performed during
the first block (contraction or relaxation) was counterbalanced across subjects. Trials
were discarded and repeated if any of the criteria for which feedback was given were
not met. Fatigue was managed with five‐minute breaks, which were given when the
experimental trials were 25%, 50% and 75% complete. Fatigue was assessed by re‐
measuring MVCs immediately following the completion of the experimental trials.
Stimulation and recording
In addition to the stimulation parameters determined in previous experiments,
the active motor threshold and the intensity which produced a MEP of 1 mV ±33% in the
active FDI (1‐mV active intensity), were measured during a 20–30% MVC lateral pinch
with the right hand. These parameters were measured using the same procedures that
Mechanisms of TMS‐induced changes in the timing of a motor response 69
were used to determine the resting motor threshold and intensity which produced a
MEP of 1 mV ±33% in the resting FDI (1‐mV resting intensity) in previous experiments.
TMS was administered at the intensity which produced a 1 mV MEP in the
resting FDI in the contraction condition of both sessions. This intensity was also used in
the relaxation condition in one session. TMS was administered at the intensity which
produced a 1 mV MEP in the active FDI in the relaxation condition of the other session.
This intensity was taken as the intensity which produced a MEP of 1 mV ±33% in the
right FDI during the performance of a 20–30% MVC lateral pinch with the right hand.
The 1‐mV resting and active intensities were intended to produce matched MEP
amplitudes when administered prior to the execution of a contraction and relaxation
response during the experimental task. EMG activity was recorded from both FDI
muscles. EMG activity was amplified at a lower amplification factor (500×) than in
previous experiments to prevent clipping of the larger MEPs elicited during active
contraction at the 1‐mV resting intensity.
Cortical silent periods (CSPs) were calculated as an index of intracortical
inhibition at the time of TMS, to explore potential relationships between intracortical
inhibition and the effect of TMS on the timing of the response. CSPs for the hand
contralateral to TMS (right hand) were cursored manually from graphical displays of the
EMG trace. The CSP was defined as an interruption of EMG activity of at least 50 ms,
from the onset of the MEP until the return of EMG activity to the sustained background
EMG level. CSPs could only be measured on trials in which EMG activity re‐emerged
following TMS. This prevented CSPs being measured on some trials in which the right
hand relaxed, as EMG activity failed to re‐emerge when this hand was relaxed prior to
the end of the silent period. CSPs were also measured outside the experimental task,
over ten trials, during a sustained 20–30% MVC lateral pinch. CSPs were measured for
each of the TMS intensities used in the relaxation condition.
Data analysis
Data for equivalent conditions were combined across both sessions prior to
subsequent analysis. Contraction and relaxation conditions were analyzed separately in
repeated measures ANOVAs due to an unequal number of TMS conditions for each of
these response types.
70 Chapter 7
Grand‐average force waveforms were calculated to investigate the effect of TMS
on the force response. To compute these waveforms, the forces produced for each trial
was normalized to each subjects’ MVC and the arithmetic mean was calculated for each
time‐point, across all trials in each condition. Within‐subject correlations were calculated
between CSP durations and response onset times for each condition and subject, to
examine the relationship between the CSP and changes in response onset times
produced by TMS. Only trials in which the duration of the CSP could be determined
were included in this analysis.
Results
Behavioral data
Right hand MVCs were 1.8% greater (SD = 16.7%), on average, than left hand
MVCs. Mean MVCs, across both hands, were 44.3 N prior to the commencement of the
experimental task and 41.4 N immediately after completion of the experimental task.
There was no significant fatigue across these time points, F(1, 23) = 3.71, p = 0.07,
ηg2 = 0.02.
Summary statistics for response onset times are shown in Table 7. Response
onsets in no‐TMS conditions were approximately normally distributed around the target
time in both the contraction and relaxation conditions (Fig. 11). Contraction onsets did
not significantly differ between the hands, F(1, 11) = 2.78, p = 0.12, ηg2 = 0.01, whereas
relaxation onsets occurred significantly earlier in the left than right hand, F(1, 11) = 5.17,
p = 0.04, ηg2 = 0.01.
TMS significantly advanced the entire distribution of contraction onsets (Fig. 11),
F(1, 11) = 20.68, p < 0.001, ηg2 = 0.28. TMS advanced contraction onsets by 44 ms in the
ipsilateral (left) hand (p < 0.01, g = 1.49) and by 42 ms in the contralateral (right) hand
(p = 0.02, g = 1.01). No significant hand × TMS condition interaction was found for
contraction onsets, F(1, 11) = 0.09, p = 0.77, ηg2 = 0.00. TMS advanced the execution of the
entire contraction response, as indicated by the attainment of larger forces at earlier
intervals in the TMS condition (Fig. 12). There was no significant main effect of TMS on
relaxation onsets, F(2, 22) = 0.93, p = 0.41, ηg2 = 0.03, although TMS appears to have
reduced the frequency of late relaxation responses, occurring more than 100 ms after the
target time (Fig. 11). A significant hand × TMS condition interaction was also found,
Mechanisms of TMS‐induced changes in the timing of a motor response 71
F(2, 22) = 3.80, p = 0.04, ηg2 = 0.03, which appears to reflect a reduction in the frequency of
early right hand relaxation onsets that was only present in the 1‐mV resting TMS
condition (Fig. 11). This effect was associated with a transient increase in force in the
contralateral (right) hand (Fig. 12), which commenced within 50 ms following the
administration of TMS. However, no significant difference in relaxation onsets was
observed between the hands in the 1‐mV resting TMS condition (p = 0.15, g = 0.89) or
between any other combination of hand and TMS condition (ps ≥ 0.74, g ≤ 0.63) in post‐
hoc pairwise‐t‐tests.
Fig. 11 Kernel density estimates showing that TMS advanced the entire distribution of
contraction onsets but only advanced the onset of late relaxation responses. The top panels show
trials in which a timed muscle contraction was required and the bottom panels show trials in
which a muscle relaxation was required. Equivalent conditions have been combined across both
sessions. The intensity of TMS was adjusted to produce a MEP of approximately 1 mV in resting
or active FDI in the 1‐mV resting and active conditions. The dotted vertical line marks the time at
which TMS was administered.
Left Hand Right Hand
0.000
0.002
0.004
0.006
0.008
0.000
0.002
0.004
0.006
0.008
Contraction
Relaxation
−400 −200 0 200 400 −400 −200 0 200 400
Response onset (ms relative to target)
Den
sity
TMSNone1mV resting1mV active
72 Chapter 7
Table 7 Means and standard deviations (in brackets) for response onset times in conditions in
which a contraction or relaxation of a sustained contraction was required. Response onset times
are in milliseconds, relative to the target time. TMS was delivered over the left M1. The intensity
of TMS was adjusted to produce a MEP of approximately 1 mV in resting or active FDI in the
1‐mV resting and active conditions.
Response TMS Left hand
onset (ms)
Right hand
onset (ms)
Contraction None ‐14 (43) ‐7 (38)
1‐mV resting ‐59 (27) ‐49 (32)
Relaxation
None ‐5 (44) ‐11 (49)
1‐mV active ‐26 (42) ‐24 (42)
1‐mV resting ‐27 (26) ‐1 (22)
Fig. 12 Grand‐average force waveforms for each response and TMS condition showing that TMS
caused higher forces to be achieved earlier in contraction conditions and that TMS produced a
transient increase in right‐hand forces in the relaxation condition. Forces were normalized as a
percentage of each subjectsʹ maximum voluntary contraction strength before averaging. The top
panels show trials in which a timed muscle contraction was required and the bottom panels show
trials in which a muscle relaxation was required. The intensity of TMS was adjusted to produce
a MEP of approximately 1 mV in resting or active FDI in the 1‐mV resting and active conditions.
The dotted vertical line marks the time at which TMS was administered.
Left Hand Right Hand
0
10
20
30
40
0
10
20
30
40
Contraction
Relaxation
−400 −200 0 200 400 −400 −200 0 200 400
Time (ms relative to target)
Forc
e (%
MV
C)
TMSNone1mV resting1mV active
Mechanisms of TMS‐induced changes in the timing of a motor response 73
Electrophysiological data
Motor evoked potentials
The TMS intensity which produced a 1 ±33% mV MEP in the resting FDI muscle
was 57.3% (SD = 12.7%) of maximum stimulator output. This intensity was equivalent to
108.9% (SD = 4.8%) of resting motor threshold and 142.8% (SD = 17.5%) of active motor
threshold. The TMS intensity which produced a 1 ±33% mV MEP in the active FDI
muscle was 41.8% (SD = 8.8%) of maximum stimulator output. This intensity was
equivalent to 80.9% (SD = 8.6%) of resting motor threshold and 103.6% (SD = 3.0%) of
active motor threshold.
In the contraction condition, MEP amplitudes were larger when a response was
prepared for the hand contralateral to TMS (M = 2.98 mV) than when a response was
prepared for the hand ipsilateral to TMS (M = 1.23 mV), t(11) = 3.73, p < 0.01, g = 1.08. In
the relaxation condition, the size of MEPs was similar between trials in which the
contralateral and ipsilateral hand responded, F(1, 11) = 2.72, p = 0.13, ηg2 = 0.02. MEPs in
the relaxation condition were substantially larger when TMS was administered at the
1‐mV resting intensity (contralateral hand response M = 8.74 mV; ipsilateral hand
M = 9.43 mV) than when administered at the weaker, 1‐mV active intensity (contralateral
hand response M = 1.35 mV; ipsilateral hand M = 1.78 mV), F(1, 11) = 82.81, p < 0.001,
ηg2 = 0.75.
Cortical silent periods
Representative EMG traces showing the CSP during trials in which TMS was
administered at the 1‐mV resting intensity are shown in Fig. 13. Table 8 shows the
proportion of trials in which the CSP was present in each condition and the duration of
the CSP in conditions in which TMS was administered at the 1‐mV resting intensity. CSP
durations are only shown for this TMS condition as the CSP was present on too few trials
(≤ 5.0%) to accurately estimate its duration in the 1‐mV active condition. CSP durations
in the 1‐mV resting condition, in which the contralateral hand performed a relaxation
response, were determined from 32.8% of trials in which a CSP was present as EMG
activity did not re‐emerge on the remaining 67.2% of trials. There was no significant
relationship between the duration of the CSP and the timing of relaxation onsets in the
hand contralateral to TMS for trials in which TMS was administered at the 1‐mV resting
74 Chapter 7
intensity (r = ‐0.02, 95% CI = ‐0.37–0.34). Similarly, there was no significant relationship
between CSP durations in the hand contralateral to TMS and the timing of relaxation
onsets for the ipsilateral hand for trials in which TMS was administered at this intensity
(r = ‐0.03, 95% CI = ‐0.28–0.23).
Fig. 13 Representative EMG traces showing the CSP in the right hand in conditions in which
TMS was set to produce a MEP of approximately 1 mV in the resting FDI muscle. CSPs were
measured during sustained contraction, in the absence of any task (no response), or during the
experimental task, prior to the relaxation of the hand ipsilateral or contralateral to TMS. The
dotted vertical lines mark the time at which TMS was administered and the asterisks mark the
return of sustained EMG activity.
****************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************
********************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************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********************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************
−5.0
−2.5
0.0
2.5
5.0
−5.0
−2.5
0.0
2.5
5.0
−5.0
−2.5
0.0
2.5
5.0
No response
Ipsilateral response
Contralateral response
0 100 200 300
Time (ms)
EM
G a
ctiv
ity (m
V)
Mechanisms of TMS‐induced changes in the timing of a motor response 75
Table 8 Percentage of trials in which the CSP was present and the mean and standard deviation
of the CSP duration, in milliseconds. CSPs were measured during sustained contraction, in the
absence of any task (none), or during the experimental task, prior to the relaxation of the hand
ipsilateral or contralateral to TMS. The intensity of TMS was adjusted to produce a MEP of
approximately 1 mV in resting or active FDI in the 1‐mV resting and active conditions.
1‐mV active TMS 1‐mV resting TMS
Responding hand % CSP present % CSP present Mean (ms) SD (ms)
None 5.0 78 116 35
Ipsilateral 4.9 89.2 94 31
Contralateral 3.6 87.4 98 41
Discussion
The current study investigated the effect of TMS on the timing of contraction and
relaxation responses in a timed‐response task that permits the advanced preparation of
a motor response. TMS advanced the onset of a muscle contraction but did not advance
the onset of a muscle relaxation. Force waveforms for contraction responses were similar
across TMS and no‐TMS condition, showing again that TMS did not just advance the
onset of a contraction response by producing a transient rise in force, such as that which
may be associated with the MEP, but advanced the execution of the entire contraction
response (Chapter 3–6). This finding demonstrates that TMS does not affect the
kinematics of a sustained (> 1 s) contraction, consistent with previous findings that TMS
does not affect the rise time, duration, force or precision of a brief pinch response
(Chapter 3–6).
The finding that TMS advanced contraction but not relaxation responses is
consistent with the hypothesis that TMS advances the onset of a contraction by
facilitating execution‐related processes (Alegre et al., 2003; Buccolieri et al., 2004;
Motawar et al., 2012; Suzuki et al., 2015), rather than by facilitating preparatory processes
that are shared between contraction and relaxation. This finding is consistent with the
expectation that responses would be prepared in advance the timed‐response task used
in this thesis (Carlsen & MacKinnon, 2010; Hening, Favilla, et al., 1988; Steglich et al.,
1999), thereby limiting the effects of faster preparation on the timing of the response
(Chapter 3).
The specificity of the advancement of response onsets to the contraction
condition provides further evidence against the role of intersensory facilitation in the
76 Chapter 7
advancement of responses in this task since the hypothesized mechanisms of
intersensory facilitation, including multisensory integration (Diederich & Colonius,
2008) and facilitated preparation (Los & Van der Burg, 2013), would be expected to
advance response equally in both contraction and relaxation conditions. This finding
also excludes the advancement of responses through the effect of perceptual illusions,
such as temporal integration, on the prediction of the pacing signal (Mates et al., 1994;
Repp, 2004; Yabe et al., 1998), as these illusions would also be expected to affect the
timing of both contraction and relaxation responses.
TMS could have facilitated the execution of contraction responses through an
increase in M1 excitability, which could result from the magnetic stimulation of M1 or
the elicitation of a startle‐like response, and could differentially affect the execution of
contraction and relaxation responses. A startle‐like response could be produced by the
loud sound associated with TMS and, unlike other non‐specific effects of TMS, this effect
has been associated with an increase in both M1 and subcortical excitability (Carlsen et
al., 2004; Marinovic et al., 2014; Maslovat et al., 2014). A loud acoustic stimulus has only
been found to increase M1 excitability when presented at a high state of motor
preparedness (Marinovic et al., 2014), similar to the conditions in which TMS was
presented in the current study, whereas this stimulus appears to suppress M1
excitability when presented at rest (Furubayashi et al., 2000; Ilic et al., 2011). The increase
in M1 excitability following the presentation of a loud acoustic stimulus appears to be
mediated by a reduction in intracortical inhibition and an increase in intracortical
facilitation (Marinovic et al., 2014). An increase in CME and reduction in intracortical
inhibition has similarly been observed following the magnetic stimulation of M1 (Cash
et al., 2010; Chin, Cash, & Thickbroom, 2012), which may indicate that M1 stimulation
and loud acoustic stimuli advance contraction responses through a shared mechanism.
This increase in CME and reduction in intracortical inhibition could facilitate the
execution of a contraction response by contributing to the rise in M1 excitability that
precedes the execution of these responses (R. Chen & Hallett, 1999; R. Chen et al., 1998;
Hoshiyama et al., 1996; C. Reynolds & Ashby, 1999; Ridding et al., 1995; Zoghi et al.,
2003). These changes in CME and intracortical inhibition would not be expected to
advance the onset of a relaxation response, consistent with the present findings, as these
responses require opposing changes in CME and intracortical inhibition (Begum et al.,
2005; Motawar et al., 2012; Suzuki et al., 2015).
Mechanisms of TMS‐induced changes in the timing of a motor response 77
TMS was found to reduce the frequency of early relaxation onsets in the
contralateral (right) hand, when delivered at the intensity which produced a 1 mV MEP
in the resting FDI, without significantly delaying the mean or modal response onset time
in this condition. TMS also did not affect the frequency of early relaxation onsets when
delivered at the intensity which produced a 1 mV MEP in the active FDI. TMS appears
to have delayed only the initial execution of a muscle relaxation in the resting 1‐mV
condition, rather than the response as a whole, as forces converged across TMS
conditions later in the response (Fig. 12). The delay in the execution of a muscle
relaxation can be accounted for by the transient increase in force that was observed
following TMS, which could have resulted from the large MEPs that were elicited by
TMS in this condition. This interpretation is consistent with the absence of any delay in
early relaxation onsets in the contralateral hand in the active 1‐mV TMS condition or in
the ipsilateral hand in either TMS condition, as MEPs were smaller or absent in these
conditions. As the delay in relaxation onsets is confined to the period immediately
following TMS and can be attributed to the MEP, it appears unlikely to reflect the
influence of sustained changes in CME following TMS, which are hypothesized to
mediate the advancement of responses in the contraction condition.
The finding that TMS did not delay mean response onset times in the relaxation
condition does not support the hypothesis that TMS would delay relaxation responses
by increasing CME, thereby counteracting a reduction in CME that is required for the
response (Begum et al., 2005; Buccolieri et al., 2004; Motawar et al., 2012; Suzuki et al.,
2015; Yamanaka et al., 2002). However, recent research has found that the reduction in
CME required for muscle relaxation is preceded by a transient increase in CME (Suzuki
et al., 2015). A TMS‐induced increase in CME could therefore facilitate processes
associated with this early increase in CME, while impeding the subsequent reduction in
CME, leading to the absence of any net change in the timing of the response. TMS might
also increase CME in the contraction condition, without affecting CME in the relaxation
condition, as a result of differences between the levels of CME in each condition at the
time of TMS administration. This hypothesis is consistent with findings that the effects
of TMS, and the associated loud acoustic stimulus, depend upon cortical activity at the
time of stimulation (Ilic et al., 2011; Kühn, Sharott, Trottenberg, Kupsch, & Brown, 2004;
Marinovic et al., 2014; Silvanto, Cattaneo, et al., 2008; Silvanto, Muggleton, et al., 2008).
The absence of a delay in mean relaxation onsets cannot be accounted for by the
78 Chapter 7
activation of inhibitory circuits associated with the CSP, which could counteract an
increase in CME, as there was no significant relationship between CSP durations and
response times. CSPs were also observed much more frequently when TMS was
delivered at a higher stimulus intensity (1‐mV resting condition), but relaxation onsets
did not occur earlier in this condition, which further suggests that CSP‐related inhibition
did not affect the timing of relaxation onsets.
TMS was observed to reduce the frequency of responses occurring more than
100 ms after the target time in all TMS conditions and both response conditions. While
late responses occurred less frequently following TMS in both contraction and relaxation
conditions, the entire distribution of responses was advanced in the contraction
condition, similar to previous findings in this thesis, whereas only late responses were
advanced in the relaxation condition. The advancement of late responses could be
explained by the warning of the arrival of the synchronization signal by the
administration of TMS at a consistent interval (250 ms) prior to this signal. Although the
arrival of the synchronization signal was already warned by the presentation of the
preceding three auditory tones, these tones were played at a long ISI (1000 ms), which is
associated with greater variability in response onset times than the shorter ISI between
TMS and the synchronization signal (Repp, 2005). Thus, the administration of TMS may
have provided an additional warning signal which permits more accurate estimation of
the arrival time of the synchronization signal, reducing the deviation of response onset
times from the target response time. Although this effect could explain the reduction in
the frequency of late responses, it cannot explain the advancement of early response by
TMS, as this effect increased the deviation of the response onset from the target response
time and is therefore not consistent with the use of a strategy for minimizing error in the
timing of the response. This conclusion is also supported by the finding that the
advancement of early responses was unique to the contraction condition, whereas TMS
would have provided a cue to the timing of the synchronization signal in both
contraction and relaxation conditions.
In conclusion, the present findings show that TMS advanced the onset of
contraction but not relaxation responses in a timed‐response task. This finding suggests
that the effect of TMS on response times are not mediated by the facilitation of motor
preparation or the facilitation of the transfer of the prepared motor program to the
output structures. This finding is also consistent with the hypothesis that the timed‐
Mechanisms of TMS‐induced changes in the timing of a motor response 79
response tasks used in this study permits advanced preparation, thereby limiting the
effects of faster preparation on the timing of the response. The results are consistent with
the hypothesis that TMS facilitates motor execution by increasing CME.
81
Chapter 8.
General discussion
The experiments in this thesis used TMS to measure and perturb the activity of
the corticomotor system to investigate the role of M1 in the control of the timing of motor
actions. This was investigated in a timed‐response task which required the synchronized
execution of a pinch response with the last tone in a sequence of evenly spaced tones.
TMS was found to advance the onset of pinch responses, both ipsilateral and
contralateral to TMS, in all experiments of this thesis. M1 TMS did not disrupt the
integrity of the response in any experiment, indicating that M1 TMS does not disrupt the
motor plan or prematurely terminate an ongoing preparatory process. This chapter
briefly reviews the findings of this thesis, discusses the implications of these findings
with reference to previous RT studies, and discusses potential mechanisms for these
findings.
Overview of research
In Experiment 1 (Chapter 3), TMS was administered over a range of intervals,
from 350 ms to 150 ms prior to the target response onset time in a timed‐response task.
This experiment served two purposes: to determine whether previously established
effects of TMS on the timing of response onsets in RT tasks (Foltys et al., 2001; Hashimoto
et al., 2004; Leocani et al., 2000; Pascual‐Leone, Valls‐Solé, et al., 1992; Sawaki et al., 1999;
Soto et al., 2010) generalize to a timed‐response task, and to determine whether these
effects could be produced by the disruption of proactive inhibition by TMS. It was
expected that TMS would advance responses more when delivered further before the
expected onset of the response, consistent with the hypothesis that TMS would disrupt
proactive inhibition, triggering the execution of the response. In contrast to this
hypothesis, TMS was found to advance responses by a constant amount over the entire
200 ms range of intervals examined. This finding indicates that TMS does not disrupt
proactive inhibition as this would be expected to have resulted in earlier responding
when TMS was administered at earlier times. TMS was also found not to delay responses
82 Chapter 8
at any interval in this experiment, even when delivered close to the expected onset of the
response, in contrast to typical findings in RT tasks.
In Experiment 2, TMS was found to advance responses more when administered
over the left M1 than administered over the right M1 (Chapter 4), consistent with the
hypothesis that the left M1 makes a greater contribution to the control of the ipsilateral
and contralateral limb than the right M1 (Haaland, 2006). The effects of left and right M1
TMS did not differ between the performance of unimanual and bimanual pinches,
suggesting that each hemisphere makes similar contributions to the control of
unimanual and bimanual actions (Chapter 4). CME was also found to be similar between
the performance of bimanual pinches of unequal or equal magnitude, in contrast to the
hypothesis that the preparation of bimanual forces of unequal magnitude involve
interhemispheric interactions which suppress CME (Chapter 5). These findings suggest
that interhemispheric interactions involved in the preparation of bimanual forces do not
influence either the laterality of the control of the timing of these responses or changes
in CME related to the control of these responses.
Experiment 3 (Chapter 6) investigated the specificity of the advancement of
responses to M1 stimulation by comparing the effects of M1 and occipital TMS on the
timing of pinch responses. M1 and occipital TMS were both found to advance responses
to a similar extent, which may indicate that non‐specific mechanisms, such as a startle‐
like response, mediate the advancement of responses by TMS. However, occipital TMS
was also found to increase the force of the response in this experiment, which may
indicate that occipital TMS was an inappropriate control for non‐specific effects of M1
TMS in the timed‐response task used in this thesis.
Experiment 4 (Chapter 7) found that TMS advanced the onset of responses that
required muscle contraction but did not affect the timing of responses which required
the relaxation of a sustained contraction, for which equal motor preparation time was
provided. This finding suggests that TMS does not facilitate preparatory processes that
are shared between these responses, but facilitates execution‐related processes which
differ between the production of contraction and relaxation responses. These findings,
and those of the thesis as a whole, are consistent with the hypothesis that TMS advances
the onset of a contraction response by increasing M1 excitability, which could reduce the
duration of processes required to execute the response.
General discussion 83
Comparison of the effects of transcranial magnetic stimulation in
timed‐response and reaction time tasks
Advancement of responses following transcranial magnetic stimulation
This thesis extends previous findings demonstrating that TMS can advance
responses when delivered early in the response latency of an RT task (Foltys et al., 2001;
Leocani et al., 2000; Pascual‐Leone, Valls‐Solé, et al., 1992; Pascual‐Leone et al., 1994;
Sawaki et al., 1999; Soto et al., 2010; Ziemann et al., 1997). Timed‐response tasks differ
from RT tasks in that they require the timed‐execution of a well‐prepared motor
response (Carlsen & MacKinnon, 2010; Heuer et al., 1998; Steglich et al., 1999), rather
than the rapid execution of a response. However, both tasks require the execution of a
discrete motor response, with a rapid onset, suggesting that these tasks share late motor
processes. Thus, comparisons between findings from RT and timed‐response task may
provide insight as to whether TMS affects motor processes that are shared or not shared
between these tasks.
In this thesis, TMS was found to advance responses by a similar amount (20–
50 ms) to that which has been observed in RT tasks (Hashimoto et al., 2004; Pascual‐
Leone, Valls‐Solé, et al., 1992; Pascual‐Leone et al., 1994; Sawaki et al., 1999; Soto et al.,
2010). TMS over M1 also did not disrupt the integrity of the response in any study of this
thesis, similar to previous RT findings (Hashimoto et al., 2004; Pascual‐Leone, Valls‐Solé,
et al., 1992; Sawaki et al., 1999). The amplitude, precision, duration and rise time of the
pinch response did not significantly differ between TMS and no‐TMS conditions in all
studies of this thesis. This thesis extends previous RT findings, which have typically
used simple finger abduction movements, by demonstrating that TMS does not disrupt
the integrity of a precise force response. The similarity of these findings in timed‐
response and RT tasks suggests that TMS affects processes that are shared between the
performance of these tasks.
A few differences were observed between the effects of TMS on the timing of
responses in this thesis and on responses in previous RT studies. TMS was found to
advance responses when administered over a wider range of TMS‐response intervals
(350–150 ms) than has been found in previous RT studies, particularly simple RT tasks
(Hashimoto et al., 2004; Pascual‐Leone, Valls‐Solé, et al., 1992; Pascual‐Leone et al., 1994;
84 Chapter 8
Sawaki et al., 1999; Soto et al., 2010). This difference can be attributed to the prolonged
maintenance of a prepared response in a timed‐response task (Chapter 3). TMS was also
found to similarly advance the onset of ipsilateral and contralateral response in the
experiments in this thesis, whereas the majority of RT studies have found that TMS
advances contralateral responses more than ipsilateral responses (Foltys et al., 2001;
Hallett et al., 1991; Pascual‐Leone, Brasil‐Neto, et al., 1992; Sawaki et al., 1999). However,
pervious RT studies, which used slightly suprathreshold TMS intensities, similar to that
used in this thesis, have found that TMS similarly advances the onset of responses both
ipsilateral and contralateral to TMS (Burle et al., 2002; Romaiguère et al., 1997). Studies
which have manipulated the intensity of TMS have also found that the effects of TMS on
the contralateral hand are stronger at lower stimulus intensities whereas the effects of
TMS on the ipsilateral hand are stronger at higher stimulus intensities (Hashimoto et al.,
2004; Pascual‐Leone, Valls‐Solé, et al., 1992; Sawaki et al., 1999). Thus, differences in the
effect of TMS on contralateral and ipsilateral responses between the experiments in this
thesis and in previous RT experiments may be better attributed to differences in the TMS
intensity used between these experiments, rather than differences in the effects of TMS
between timed‐response and RT tasks.
Overall, the findings of this thesis, in comparison with previous finding from RT
tasks, suggest that TMS advances responses in timed‐response and RT tasks in similar
ways.
Delay in responses following transcranial magnetic stimulation
TMS was not observed to delay responses in any study of the current thesis, even
when delivered as late as 150 ms prior to the target response time, which corresponded
to approximately 70 ms before the mean pinch onset time (Chapter 3). Instead, TMS was
found to advance responses at this time. TMS also did not suppress responses over any
interval following TMS in any experiment of this thesis. In contrast, RT studies have
consistently found that TMS delays responses when delivered within 120 ms of
movement onset, both when the subject is at rest and during active contraction (Burle et
al., 2002; Day et al., 1989; Hashimoto et al., 2004; McMillan et al., 2004; Romaiguère et al.,
1997; Schluter et al., 1998, 1999; Ziemann et al., 1997). This difference between previous
RT findings and those observed in in the current thesis could be due to the need to
maintain a well‐prepared response during the timed‐response task used in this thesis.
General discussion 85
This requirement might reduce the activity of inhibitory circuits which mediate the delay
in responses following TMS (Burle et al., 2002; Day et al., 1989; Ziemann et al., 1997),
which would otherwise mask the advancement of responses that was produced by
administering TMS at late intervals, preceding the response, in the current thesis.
Specificity of effects of M1 stimulation
The experiments in this thesis produced mixed findings concerning whether the
advancement of responses following TMS in a timed‐response task is specific to the
stimulation of M1. The finding of Experiment 2 that left M1 advanced response onsets
more than right M1 TMS indicates that the advancement of responses produced by TMS
is at least partially specific to the magnetic stimulation of the left M1. Experiment 3,
however, found no difference between the effects of left M1 and left occipital TMS,
which, at first glance, suggests that TMS advances responses through exclusively non‐
specific mechanisms. The inconsistency between the implications of the Experiment 2
and 3 findings, regarding the specificity of the effects of TMS, is similar to the
inconsistency between the findings of previous RT studies investigating the specificity
of the advancement of responses by TMS to the stimulation of M1 (Burle et al., 2002;
Hashimoto et al., 2004; Pascual‐Leone et al., 1994; Sawaki et al., 1999; Terao et al., 1997).
Differences in the task and stimulation parameters used have been suggested as an
explanation for differences between the findings of different RT studies (Hashimoto et
al., 2004; Sawaki et al., 1999). However, differences in the methodologies used in the
experiments in this thesis are unlikely to account for this difference in findings since the
same task and stimulation parameters were used in both Experiment 2 and 3 of this
thesis. Experiment 2 and 3 required a fingertip and lateral pinch, respectively, which
could influence the effects of TMS in each of these experiments. However, a previous RT
study found that TMS similarly advanced arm flexion and thumb abduction responses,
suggesting that the effects of TMS are not moderated by the effector of the response
(Pascual‐Leone, Valls‐Solé, et al., 1992).
The findings that left M1 TMS advanced response more than right M1 TMS in
Experiment 2, but produced similar advancement to occipital TMS in Experiment 3,
could be explained by cortical‐stimulation mediated effects of left occipital TMS that
exceed the effects of right M1 TMS. Pinch forces were larger following occipital TMS
than M1 or no‐TMS in Experiment 3, which indicates that the magnetic stimulation of
86 Chapter 8
the occipital cortex affected the control of the pinch responses in this experiment.
Although the change in pinch amplitude was small, this finding indicates that occipital
stimulation affected the control of the pinch response through the magnetic stimulation
of the occipital cortex, rather than through non‐specific effects such as the sound
associated with TMS stimulation. Thus, occipital TMS may not be an appropriate control
for non‐specific effects of TMS in the visuomotor task used in the experiments of this
thesis.
A final possibility is that TMS primarily advanced pinch onsets through non‐
specific mechanisms that were stronger for left than right‐side presentations of the sound
and tactile stimulation associated with TMS. While this could explain findings that left
M1 and left occipital TMS produced stronger effects on the timing of the response than
right M1 TMS, non‐specific effects of TMS are unlikely to be stronger for left‐side
stimulus presentations. As the sound produced by TMS would have reached both ears,
albeit at different intensities, differences in the non‐specific effects related to the side of
TMS presentation are likely to be limited to those that depend on stimulus intensity,
such as those related to a startle response (Blumenthal, 1988). However, a loud acoustic
stimulus has typically been found to produce stronger startle effects when presented to
the right, rather than left, side (Bradley, Cuthbert, & Lang, 1996; Grillon & Davis, 1995).
A loud acoustic stimulus has also been found to similarly advance responses when
presented to either side (Nijhuis et al., 2007) or to advance responses more when
presented to the right, rather than the left, side (Maslovat, Carlsen, et al., 2012). These
findings suggest that the greater advancement of responses following left side TMS
cannot be accounted for by lateralized differences in non‐specific effects.
In summary, non‐specific effects cannot be excluded as a mechanism for the
effects of TMS observed in this thesis. However, the finding that left M1 TMS advanced
responses more than right M1 TMS suggests that at least some of effects are mediated
by the magnetic stimulation of M1. Differences between the findings of Experiment 2
and 3 could reflect cortical‐stimulation‐mediated effects of both left M1 and occipital
TMS on the timing of the pinch response. Future research, using alternative methods of
controlling for non‐specific effects of TMS, may be useful in clarifying the role of non‐
specific effects in the advancement of responses produced by TMS in timed‐response
tasks.
General discussion 87
Mechanisms of non‐specific effects
Non‐specific effects of TMS could include intersensory facilitation and the effects
of a startle‐like response. Non‐specific effects of TMS have been primarily attributed to
intersensory facilitation in studies using RT tasks (Burle et al., 2002; Romaiguère et al.,
1997; Terao et al., 1997). However, intersensory facilitation is unlikely to contribute to
the advancement of responses observed in this thesis, as the timed‐response task used
in the experiments in this thesis does not require rapid responses to an imperative signal.
The closest analogues to an imperative signal in the timed‐response task used in this
thesis are the final synchronization tone and the force targets. However, responses
typically occurred before the onset of the synchronization tone in each experiment and
TMS therefore could not have facilitated response to this signal. TMS was also
administered well after the presentation of the force targets in each study, at which the
effects of intersensory facilitation are likely to be absent (Diederich & Colonius, 2008;
Nickerson, 1973). Furthermore, the advancement of responses produced by TMS was
found to be specific to muscle contraction responses, whereas muscle relaxation
responses would be expected to be similarly advanced by intersensory facilitation. Thus,
the advancement of responses produced by TMS in this thesis cannot be accounted for
by the effects of intersensory facilitation.
The sound produced by TMS could also alter the timing of responses in a timed‐
response task by distorting temporal judgments concerning the timing of the pacing
stimuli. However, this mechanism is unlikely to account for the effects of TMS observed
in this thesis. Certain illusions, such as the filled duration illusion would be expected to
delay, rather than advance, responses following TMS (Repp, 2008; Repp & Bruttomesso,
2009; Wohlschläger & Koch, 2000) whereas others, such as temporal integration, have a
narrow window of effect and would not be expected to affect responses at the intervals
over which TMS was administered in the experiments in this thesis (Repp, 2004, 2008).
As these illusions are dependent on the timing of stimulus presentation, the role of these
illusions in the findings of this thesis is also inconsistent with the finding that TMS
advanced responses by a similar amount across a wide range of TMS‐response latencies
(Chapter 3). Further evidence against the role of these illusions in the findings of this
thesis is also demonstrated by the finding that TMS advanced contraction but not
relaxation responses (Chapter 7), as perceptual illusions would be expected to similarly
88 Chapter 8
influence the timing of different motor responses. This finding also excludes the
contribution of any other non‐specific mechanisms that primarily act on perceptual
processes and would be expected to similarly influence the timing of different motor
responses.
Non‐specific effects of TMS could be accounted for by a startle‐like effect that
may be produced by a loud acoustic stimulus, such as that associated with TMS. The
sound produced by TMS exceeds previously reported thresholds for eliciting a startle
response, although the intensity of the sound produced by TMS is below the optimal
intensity for eliciting an overt startle response (Blumenthal et al., 2005; Counter & Borg,
1992; Gilbert et al., 2004; Hoffman & Ison, 1980; Nikouline et al., 1999). A loud acoustic
stimulus has previously been shown to advance responses in both RT and timed‐
response tasks (Carlsen & MacKinnon, 2010; Valls‐Solé et al., 2005, 1999). This
mechanism could therefore account for non‐specific effects of TMS in both the
experiments of this thesis and in previous RT research. A loud acoustic stimulus appears
to advance responses by increasing cortical and subcortical excitability (Carlsen et al.,
2004; Marinovic et al., 2014; Maslovat et al., 2014; Valls‐Solé, Hallett, Phillip, Schomer, &
Massey, 2004), which is consistent with the finding that TMS only advanced the onset of
contraction responses which require an increase in motor excitability, but not relaxation
responses which involve opposing changes in motor excitability (Chapter 7). As M1‐
stimulation could also produce changes in motor excitability, startle‐mediated and M1‐
specific effects of TMS might advance response through similar mechanisms. The
similarity of these effects may have contributed to difficulty in distinguishing specific
and non‐specific effects of TMS, both in this thesis and in previous RT studies.
Mechanisms of M1‐specific effects
M1‐specific effects of TMS, resulting from the magnetic stimulation of neurons
in M1, could be mediated by the facilitation of processes required for the preparation or
execution of the motor response. Specific effects in previous RT studies have primarily
been attributed to the facilitation of late preparatory processes, particularly the transfer
of the motor program from premotor areas to the output circuitry in M1 (Pascual‐Leone,
Valls‐Solé, et al., 1992; Sawaki et al., 1999). In an RT task, TMS has been found to produce
the largest advancement of responses when administered slightly before the onset of the
lateralized movement related potential and increases in CME, associated with the
General discussion 89
execution of the response (Sawaki et al., 1999). These findings were cited in support of
the hypothesis that TMS facilitates the transfer of the motor program as this time
corresponds to that at which the transfer of the motor program is thought to occur
(Sawaki et al., 1999). However, TMS was found to advance responses across a range of
intervals, over which a large increase in CME was observed, in the timed‐response task
used in this thesis (Chapter 3). This finding could indicate that the time at which TMS
produces its maximal effects in RT tasks depends upon the coincidence of TMS with
other motor processes (Sawaki et al., 1999), or that different mechanisms mediate these
effects in timed‐response and RT tasks.
Reduced motor preparation time is unlikely to explain the advancement of
responses by TMS in a timed‐response task. Timed‐response tasks permit the advanced
preparation of a motor response (Carlsen & MacKinnon, 2010; Hening, Favilla, et al.,
1988; Steglich et al., 1999) and ample (≥600 ms) time was provided for motor preparation
in all experiments of this thesis. As the prepared motor response must be withheld until
the required response time, it appears unlikely that further advancing the completion of
motor preparation would advance the onset of the response. It therefore appears
unlikely that TMS advanced the onset of responses in the experiments in this thesis by
reducing the time required for motor preparation. Furthermore, Experiment 4 showed
that TMS advanced the onset of a contraction response but not a relaxation response,
which similarly requires motor preparation (Alegre et al., 2003; Pope et al., 2007; Suzuki
et al., 2015; Terada et al., 1995, 1999; Toma et al., 1999, 2000; Yazawa et al., 1998),
indicating that TMS did not facilitate preparatory processes that shared between these
responses.
The advancement of responses observed in this thesis may be explained by a
reduction in the duration of the processes required to execute a motor response. TMS
could increase M1 or subcortical excitability, which would contribute to the increase in
M1 excitability required to execute the response (R. Chen & Hallett, 1999; R. Chen et al.,
1998; Evarts, 1966; Hoshiyama et al., 1996), as outlined previously in this thesis. This
mechanism could also explain the advancement of responses produced by TMS in an RT
task (Molinuevo et al., 2000; Pascual‐Leone et al., 1994). This hypothesis that TMS
facilitates the execution of a response through an increase in M1 excitability is consistent
with the observation that TMS advanced contraction responses, which require an
increase in CME (R. Chen & Hallett, 1999; R. Chen et al., 1998; Evarts, 1966; Hoshiyama
90 Chapter 8
et al., 1996; Leocani et al., 2000; Pascual‐Leone, Valls‐Solé, et al., 1992), but not relaxation
responses, which require a decrease in CME (Begum et al., 2005; Buccolieri et al., 2004;
Motawar et al., 2012; Yamanaka et al., 2002).
Left and right M1 TMS were found to advance both ipsilateral and contralateral
pinches in all experiments of this thesis. These findings indicate that M1 contributes to
the initiation of both ipsilateral and contralateral motor responses. The effect of TMS on
ipsilateral responses may be mediated by interhemispheric cortico‐cortical connections,
which have previously been implicated in the control of motor actions by the ipsilateral
cortex, including the initiation of motor responses (Carson, 2005; Duque et al., 2007;
Kobayashi et al., 2003; Murase, Duque, Mazzocchio, & Cohen, 2004; Tazoe & Perez,
2013). The finding that left M1 TMS advanced responses more than right M1 TMS
suggests that the left M1 exerts greater control over the initiation of motor actions,
consistent with findings indicating that the left M1 contributes more strongly to the
control of ipsilateral and contralateral motor actions than right M1 (Callaert et al., 2011;
Haaland, 2006; Haaland et al., 2000; Koeneke et al., 2004; Serrien et al., 2006; Swinnen et
al., 2010; Wyke, 1968, 1971).
Conclusions
The experiments in this thesis have demonstrated that M1 TMS can advance the
onset of responses in a timed‐response task. The findings of this thesis suggest that TMS
advances responses by increasing M1 excitability, thereby abbreviating a period of rising
M1 excitability that precedes the execution of a response. The results also suggest that
M1 can make small modifications to the timing of a motor response by altering the time
taken to execute the prepared motor plan. Overall, the results of this thesis demonstrate
the importance of neural processes separable from the motor plan in cued sensorimotor
tasks.
91
References
Abel, K., Waikar, M., Pedro, B., Hemsley, D., & Geyer, M. (1998). Repeated testing of
prepulse inhibition and habituation of the startle reflex: a study in healthy
human controls. Journal of Psychopharmacology, 12(4), 330–337.
http://doi.org/10.1177/026988119801200402
Abrahamyan, A., Clifford, C. W. G., Arabzadeh, E., & Harris, J. A. (2011). Improving
visual sensitivity with subthreshold transcranial magnetic stimulation. The
Journal of Neuroscience, 31(9), 3290–3294.
http://doi.org/10.1523/JNEUROSCI.6256‐10.2011
Adams, R. D. (1977). Intervening stimulus effects on category judgments of duration.
Perception & Psychophysics, 21(6), 527–534. http://doi.org/10.3758/BF03198733
Alegre, M., Labarga, A., Gurtubay, I., Iriarte, J., Malanda, A., & Artieda, J. (2003).
Movement‐related changes in cortical oscillatory activity in ballistic, sustained
and negative movements. Experimental Brain Research, 148(1), 17–25.
http://doi.org/10.1007/s00221‐002‐1255‐x
Amassian, V. E., Cracco, R. Q., Maccabee, P. J., Cracco, J. B., Rudell, A., & Eberle, L.
(1989). Suppression of visual perception by magnetic coil stimulation of human
occipital cortex. Electroencephalography and Clinical Neurophysiology/Evoked
Potentials Section, 74(6), 458–462. http://doi.org/10.1016/0168‐5597(89)90036‐1
Arana, A. B., Borckardt, J. J., Ricci, R., Anderson, B., Li, X., Linder, K. J., … George, M.
S. (2008). Focal electrical stimulation as a sham control for rTMS: Does it truly
mimic the cutaneous sensation and pain of active prefrontal rTMS? Brain
Stimulation, 1(1), 44–51. http://doi.org/10.1016/j.brs.2007.08.006
Bawa, P., Hamm, J. D., Dhillon, P., & Gross, P. A. (2004). Bilateral responses of upper
limb muscles to transcranial magnetic stimulation in human subjects.
Experimental Brain Research, 158(3), 385–390. http://doi.org/10.1007/s00221‐004‐
2031‐x
Beckers, G., & Hömberg, V. (1991). Impairment of visual perception and visual short
term memory scanning by transcranial magnetic stimulation of occipital cortex.
Experimental Brain Research, 87(2), 421–432. http://doi.org/10.1007/BF00231859
92 References
Begum, T., Mima, T., Oga, T., Hara, H., Satow, T., Ikeda, A., … Shibasaki, H. (2005).
Cortical mechanisms of unilateral voluntary motor inhibition in humans.
Neuroscience Research, 53(4), 428–435. http://doi.org/10.1016/j.neures.2005.09.002
Blumenthal, T. D. (1988). The startle response to acoustic stimuli near startle threshold:
Effects of stimulus rise and fall time, duration, and intensity. Psychophysiology,
25(5), 607–611. http://doi.org/10.1111/j.1469‐8986.1988.tb01897.x
Blumenthal, T. D., Cuthbert, B. N., Filion, D. L., Hackley, S., Lipp, O. V., & Van Boxtel,
A. (2005). Committee report: Guidelines for human startle eyeblink
electromyographic studies. Psychophysiology, 42(1), 1–15.
http://doi.org/10.1111/j.1469‐8986.2005.00271.x
Blumenthal, T. D., & Goode, C. T. (1991). The Startle Eyeblink Response to Low
Intensity Acoustic Stimuli. Psychophysiology, 28(3), 296–306.
http://doi.org/10.1111/j.1469‐8986.1991.tb02198.x
Blumenthal, T. D., & Keith Berg, W. (1986). Stimulus rise time, intensity, and
bandwidth effects on acoustic startle amplitude and probability.
Psychophysiology, 23(6), 635–641. http://doi.org/10.1111/j.1469‐
8986.1986.tb00682.x
Bohning, D. E., Shastri, A., Wassermann, E. M., Ziemann, U., Lorberbaum, J. P., Nahas,
Z., … George, M. S. (2000). BOLD‐f MRI response to single‐pulse transcranial
magnetic stimulation (TMS). Journal of Magnetic Resonance Imaging, 11(6), 569–
574. http://doi.org/10.1002/1522‐2586(200006)11:6<569::AID‐JMRI1>3.0.CO;2‐3
Botev, Z. I., Grotowski, J. F., & Kroese, D. P. (2010). Kernel density estimation via
diffusion. The Annals of Statistics, 38(5), 2916–2957. http://doi.org/10.1214/10‐
AOS799
Boulinguez, P., Ballanger, B., Granjon, L., & Benraiss, A. (2009). The paradoxical effect
of warning on reaction time: Demonstrating proactive response inhibition with
event‐related potentials. Clinical Neurophysiology, 120(4), 730–737.
http://doi.org/10.1016/j.clinph.2009.02.167
Boulinguez, P., Jaffard, M., Granjon, L., & Benraiss, A. (2008). Warning signals induce
automatic EMG activations and proactive volitional inhibition: Evidence from
analysis of error distribution in simple RT. Journal of Neurophysiology, 99(3),
1572–1578. http://doi.org/10.1152/jn.01198.2007
References 93
Bradley, M. M., Cuthbert, B. N., & Lang, P. J. (1996). Lateralized startle probes in the
study of emotion. Psychophysiology, 33(2), 156–161. http://doi.org/10.1111/j.1469‐
8986.1996.tb02119.x
Brasil‐Neto, J. P., Pascual‐Leone, A., Valls‐Solé, J., Cohen, L. G., & Hallett, M. (1992).
Focal transcranial magnetic stimulation and response bias in a forced‐choice
task. Journal of Neurology, Neurosurgery & Psychiatry, 55(10), 964–966.
http://doi.org/10.1136/jnnp.55.10.964
Brinkman, J., & Kuypers, H. (1973). Cerebral control of contralateral and ipsilateral
arm, hand and finger movements in the split‐brain rhesus monkey. Brain, 96,
653.
Brown, P., Rothwell, J. C., Thompson, P. D., Britton, T. C., Day, B. L., & Marsden, C. D.
(1991). New observations on the normal auditory startle reflex in man. Brain,
114(4), 1891–1902. http://doi.org/10.1093/brain/114.4.1891
Buccolieri, A., Abbruzzese, G., & Rothwell, J. C. (2004). Relaxation from a voluntary
contraction is preceded by increased excitability of motor cortical inhibitory
circuits. The Journal of Physiology, 558(2), 685–695.
http://doi.org/10.1113/jphysiol.2004.064774
Buffardi, L. (1971). Factors affecting the filled‐duration illusion in the auditory, tactual,
and visual modalities. Perception & Psychophysics, 10(4), 292–294.
http://doi.org/10.3758/BF03212828
Burle, B., Bonnet, M., Vidal, F., Possamaï, C.‐A., & Hasbroucq, T. (2002). A transcranial
magnetic stimulation study of information processing in the motor cortex:
Relationship between the silent period and the reaction time delay.
Psychophysiology, 39(2), 207–217. http://doi.org/10.1111/1469‐8986.3920207
Busan, P., Monti, F., Semenic, M., Pizzolato, G., & Battaglini, P. P. (2009). Parieto‐
occipital cortex and planning of reaching movements: A transcranial magnetic
stimulation study. Behavioural Brain Research, 201(1), 112–119.
http://doi.org/10.1016/j.bbr.2009.01.040
Byblow, W. D., Carson, R. G., & Goodman, D. (1994). Expressions of asymmetries and
anchoring in bimanual coordination. Human Movement Science, 13(1), 3–28.
http://doi.org/10.1016/0167‐9457(94)90027‐2
Callaert, D. V., Vercauteren, K., Peeters, R., Tam, F., Graham, S., Swinnen, S. P., …
Wenderoth, N. (2011). Hemispheric asymmetries of motor versus nonmotor
94 References
processes during (visuo)motor control. Human Brain Mapping, 32(8), 1311–1329.
http://doi.org/10.1002/hbm.21110
Cardoso de Oliveira, S. (2002). The neuronal basis of bimanual coordination: recent
neurophysiological evidence and functional models. Acta Psychologica, 110, 139–
159. http://doi.org/10.1016/S0001‐6918(02)00031‐8
Carlsen, A. N., Chua, R., Inglis, J. T., Sanderson, D. J., & Franks, I. M. (2003). Startle
response is dishabituated during a reaction time task. Experimental Brain
Research, 152(4), 510–518. http://doi.org/10.1007/s00221‐003‐1575‐5
Carlsen, A. N., Chua, R., Inglis, J. T., Sanderson, D. J., & Franks, I. M. (2004). Can
prepared responses be stored subcortically? Experimental Brain Research, 159(3),
301–309. http://doi.org/10.1007/s00221‐004‐1924‐z
Carlsen, A. N., & MacKinnon, C. D. (2010). Motor preparation is modulated by the
resolution of the response timing information. Brain Research, 1322, 38–49.
http://doi.org/10.1016/j.brainres.2010.01.076
Carlsen, A. N., Maslovat, D., Lam, M. Y., Chua, R., & Franks, I. M. (2011).
Considerations for the use of a startling acoustic stimulus in studies of motor
preparation in humans. Neuroscience & Biobehavioral Reviews, 35(3), 366–376.
http://doi.org/10.1016/j.neubiorev.2010.04.009
Carson, R. G. (1990). The dynamics of isometric bimanual coordination. Experimental
Brain Research, 105(3), 465–476. http://doi.org/10.1007/BF00233046
Carson, R. G. (2005). Neural pathways mediating bilateral interactions between the
upper limbs. Brain Research Reviews, 49, 641–662.
http://doi.org/10.1016/j.brainresrev.2005.03.005
Carson, R. G., Riek, S., Mackey, D. C., Meichenbaum, D. P., Willms, K., Forner, M., &
Byblow, W. D. (2004). Excitability changes in human forearm corticospinal
projections and spinal reflex pathways during rhythmic voluntary movement
of the opposite limb. The Journal of Physiology, 560(3), 929–940.
http://doi.org/10.1113/jphysiol.2004.069088
Cash, R. F. H., Ziemann, U., Murray, K., & Thickbroom, G. W. (2010). Late cortical
disinhibition in human motor cortex: A triple‐pulse transcranial magnetic
stimulation study. Journal of Neurophysiology, 103(1), 511–518.
http://doi.org/10.1152/jn.00782.2009
References 95
Castellote, J. M., Van den Berg, M. E. L., & Valls‐Solé, J. (2013). The StartReact effect on
self‐initiated movements. BioMed Research International, 2013.
http://doi.org/10.1155/2013/471792
Cheng, D. T., Luis, M., & Tremblay, L. (2008). Randomizing visual feedback in manual
aiming: reminiscence of the previous trial condition and prior knowledge of
feedback availability. Experimental Brain Research, 189(4), 403–410.
http://doi.org/10.1007/s00221‐008‐1436‐3
Chen, J.‐T., Lin, Y.‐Y., Shan, D.‐E., Wu, Z.‐A., Hallett, M., & Liao, K.‐K. (2005). Effect of
transcranial magnetic stimulation on bimanual movements. Journal of
Neurophysiology, 93, 53–63. http://doi.org/10.1152/jn.01063.2003
Chen, R., Gerloff, C., Hallett, M., & Cohen, L. G. (1997). Involvement of the ipsilateral
motor cortex in finger movements of different complexities. Annals of Neurology,
41, 247–254. http://doi.org/10.1002/ana.410410216
Chen, R., & Hallett, M. (1999). The time course of changes in motor cortex excitability
associated with voluntary movement. The Canadian Journal of Neurological
Sciences, 26(3), 163–169.
Chen, R., Yaseen, Z., Cohen, L. G., & Hallett, M. (1998). Time course of corticospinal
excitability in reaction time and self‐paced movements. Annals of Neurology,
44(3), 317–325. http://doi.org/10.1002/ana.410440306
Chin, O., Cash, R. F. H., & Thickbroom, G. W. (2012). Electromyographic bursting
following the cortical silent period induced by transcranial magnetic
stimulation. Brain Research, 1446, 40–45.
http://doi.org/10.1016/j.brainres.2012.01.041
Chouinard, P. A., & Paus, T. (2010). What have we learned from ‘perturbing’ the
human cortical motor system with transcranial magnetic stimulation? Frontiers
in Human Neuroscience, 4, 173. http://doi.org/10.3389/fnhum.2010.00173.
Claffey, M. P., Sheldon, S., Stinear, C. M., Verbruggen, F., & Aron, A. R. (2010). Having
a goal to stop action is associated with advance control of specific motor
representations. Neuropsychologia, 48(2), 541–548.
http://doi.org/10.1016/j.neuropsychologia.2009.10.015
Corcos, D. M. (1984). Two‐handed movement control. Research Quarterly for Exercise and
Sport, 55(2), 117–122. http://doi.org/10.1080/02701367.1984.10608386
96 References
Corthout, E., Uttl, B., Walsh, V., Hallett, M., & Cowey, A. (1999). Timing of activity in
early visual cortex as revealed by transcranial magnetic stimulation. Neuroreport
August 20, 1999, 10(12), 2631–2634.
Counter, S. A., & Borg, E. (1992). Analysis of the coil generated impulse noise in
extracranial magnetic stimulation. Electroencephalography and Clinical
Neurophysiology/Evoked Potentials Section, 85(4), 280–288.
http://doi.org/10.1016/0168‐5597(92)90117‐T
Craig, J. C. (1973). A constant error in the perception of brief temporal intervals.
Perception & Psychophysics, 13(1), 99–104. http://doi.org/10.3758/BF03207241
Criaud, M., Wardak, C., Ballanger, B., & Boulinguez, P. (2012). Proactive inhibitory
control of response as the default state of executive control. Frontiers in
Cognitive Science, 3, 59. http://doi.org/10.3389/fpsyg.2012.00059
Dafotakis, M., Grefkes, C., Wang, L., Fink, G., & Nowak, D. (2008). The effects of 1 Hz
rTMS over the hand area of M1 on movement kinematics of the ipsilateral
hand. Journal of Neural Transmission, 115, 1269.
Davare, M., Duque, J., Vandermeeren, Y., Thonnard, J. L., & Olivier, E. (2007). Role of
the ipsilateral primary motor cortex in controlling the timing of hand muscle
recruitment. Cerebral Cortex, 17, 353–362.
Davey, N. J., Romaiguère, P., Maskill, D. W., & Ellaway, P. H. (1994). Suppression of
voluntary motor activity revealed using transcranial magnetic stimulation of
the motor cortex in man. The Journal of Physiology, 477(2), 223–235.
http://doi.org/10.1113/jphysiol.1994.sp020186
Davidoff, R. A. (1990). The pyramidal tract. Neurology, 40(2), 332–339.
http://doi.org/10.1212/WNL.40.2.332
Davis, M., & Heninger, G. R. (1972). Comparison of response plasticity between the
eyeblink and vertex potential in humans. Electroencephalography and Clinical
Neurophysiology, 33(3), 283–293. http://doi.org/10.1016/0013‐4694(72)90155‐1
Davis, N. J., Gold, E., Pascual‐Leone, A., & Bracewell, R. M. (2013). Challenges of
proper placebo control for non‐invasive brain stimulation in clinical and
experimental applications. European Journal of Neuroscience, 38(7), 2973–2977.
http://doi.org/10.1111/ejn.12307
Day, B. L., Rothwell, J. C., Thompson, P. D., Noordhout, A. M. D., Nakashima, K.,
Shannon, K., & Marsden, C. D. (1989). Delay in the execution of voluntary
References 97
movement by electrical or magnetic brain stimulation in intact man evidence
for the storage of motor programs in the brain. Brain, 112(3), 649–663.
http://doi.org/10.1093/brain/112.3.649
De Gennaro, L., Cristiani, R., Bertini, M., Curcio, G., Ferrara, M., Fratello, F., … Rossini,
P. M. (2004). Handedness is mainly associated with an asymmetry of
corticospinal excitability and not of transcallosal inhibition. Clinical
Neurophysiology, 115(6), 1305–1312. http://doi.org/10.1016/j.clinph.2004.01.014
de Graaf, T. A., Cornelsen, S., Jacobs, C., & Sack, A. T. (2011). TMS effects on subjective
and objective measures of vision: Stimulation intensity and pre‐ versus post‐
stimulus masking. Consciousness and Cognition, 20(4), 1244–1255.
http://doi.org/10.1016/j.concog.2011.04.012
Delval, A., Dujardin, K., Tard, C., Devanne, H., Willart, S., Bourriez, J.‐L., … Defebvre,
L. (2012). Anticipatory postural adjustments during step initiation: Elicitation
by auditory stimulation of differing intensities. Neuroscience, 219, 166–174.
http://doi.org/10.1016/j.neuroscience.2012.05.032
Diederich, A., & Colonius, H. (2008). Crossmodal interaction in saccadic reaction time:
separating multisensory from warning effects in the time window of integration
model. Experimental Brain Research, 186(1), 1–22. http://doi.org/10.1007/s00221‐
007‐1197‐4
Diedrichsen, J., Hazeltine, E., Nurss, W. K., & Ivry, R. B. (2003). The role of the corpus
callosum in the coupling of bimanual isometric force pulses. Journal of
Neurophysiology, 90, 2409–2418. http://doi.org/10.1152/jn.00250.2003
Duque, J., & Ivry, R. B. (2009). Role of corticospinal suppression during motor
preparation. Cerebral Cortex, 19(9), 2013–2024.
http://doi.org/10.1093/cercor/bhn230
Duque, J., Labruna, L., Verset, S., Olivier, E., & Ivry, R. B. (2012). Dissociating the role
of prefrontal and premotor cortices in controlling inhibitory mechanisms
during motor preparation. The Journal of Neuroscience, 32(3), 806–816.
http://doi.org/10.1523/JNEUROSCI.4299‐12.2012
Duque, J., Lew, D., Mazzocchio, R., Olivier, E., & Ivry, R. B. (2010). Evidence for two
concurrent inhibitory mechanisms during response preparation. The Journal of
Neuroscience, 30(10), 3793–3802. http://doi.org/10.1523/JNEUROSCI.5722‐09.2010
98 References
Duque, J., Mazzocchio, R., Dambrosia, J., Murase, N., Olivier, E., & Cohen, L. G. (2005).
Kinematically specific interhemispheric inhibition operating in the process of
generation of a voluntary movement. Cerebral Cortex, 15, 588–593.
http://doi.org/10.1093/cercor/bhh160
Duque, J., Murase, N., Celnik, P., Hummel, F., Harris‐Love, M., Mazzocchio, R., …
Cohen, L. G. (2007). Intermanual differences in movement‐related
interhemispheric inhibition. Journal of Cognitive Neuroscience, 19, 204–213.
http://doi.org/10.1162/jocn.2007.19.2.204
Eliassen, J. C., Baynes, K., & Gazzaniga, M. S. (1999). Direction information coordinated
via the posterior third of the corpus callosum during bimanual movements.
Experimental Brain Research, 128, 573–577. http://doi.org/10.1007/s002210050884
Eliassen, J. C., Baynes, K., & Gazzaniga, M. S. (2000). Anterior and posterior callosal
contributions to simultaneous bimanual movements of the hands and fingers.
Brain, 123, 2501–2511. http://doi.org/10.1093/brain/123.12.2501
Elliott, D., & Allard, F. (1985). The utilization of visual feedback information during
rapid pointing movements. The Quarterly Journal of Experimental Psychology
Section A, 37(3), 407–425. http://doi.org/10.1080/14640748508400942
Evarts, E. V. (1966). Pyramidal tract activity associated with a conditioned hand
movement in the monkey. J Neurophysiol, 29(6), 1011–1027.
Ferbert, A., Priori, A., Rothwell, J. C., Day, B. L., Colebatch, J. G., & Marsden, C. D.
(1992). Interhemispheric inhibition of the human motor cortex. The Journal of
Physiology, 453(1), 525–546.
Fling, B. W., & Seidler, R. D. (2012). Task‐dependent effects of interhemispheric
inhibition on motor control. Behavioural Brain Research, 226(1), 211–217.
http://doi.org/10.1016/j.bbr.2011.09.018
Foltys, H., Sparing, R., Boroojerdi, B., Krings, T., Meister, I. G., Mottaghy, F. M., &
Töpper, R. (2001). Motor control in simple bimanual movements: a transcranial
magnetic stimulation and reaction time study. Clinical Neurophysiology, 112(2),
265–274. http://doi.org/10.1016/S1388‐2457(00)00539‐3
Fowler, B., Duck, T., Mosher, M., & Mathieson, B. (1991). The coordination of bimanual
aiming movements: Evidence for progressive desynchronization. The Quarterly
Journal of Experimental Psychology Section A, 43(2), 205–221.
http://doi.org/10.1080/14640749108400967
References 99
Franks, I. M., Nagelkerke, P., Ketelaars, M., & Van Donkelaar, P. (1998). Response
preparation and control of movement sequences. Canadian Journal of
Experimental Psychology/Revue Canadienne de Psychologie Expérimentale, 52(2), 93–
102. http://doi.org/10.1037/h0087284
Franz, E. A. (1997). Spatial coupling in the coordination of complex actions. The
Quarterly Journal of Experimental Psychology Section A, 50(3), 684–704.
http://doi.org/10.1080/713755726
Franz, E. A., Eliassen, J. C., Ivry, R. B., & Gazzaniga, M. S. (1996). Dissociation of spatial
and temporal coupling in the bimanual movements of callosotomy patients.
Psychological Science, 7, 306–310. http://doi.org/10.1111/j.1467‐
9280.1996.tb00379.x
Franz, E. A., Zelaznik, H. N., & McCabe, G. (1991). Spatial topological constraints in a
bimanual task. Acta Psychologica, 77(2), 137–151. http://doi.org/10.1016/0001‐
6918(91)90028‐X
Fuggetta, G., Fiaschi, A., & Manganotti, P. (2005). Modulation of cortical oscillatory
activities induced by varying single‐pulse transcranial magnetic stimulation
intensity over the left primary motor area: A combined EEG and TMS study.
NeuroImage, 27(4), 896–908. http://doi.org/10.1016/j.neuroimage.2005.05.013
Furubayashi, T., Ugawa, Y., Terao, Y., Hanajima, R., Sakai, K., Machii, K., …
Kanazawa, I. (2000). The human hand motor area is transiently suppressed by
an unexpected auditory stimulus. Clinical Neurophysiology, 111(1), 178–183.
http://doi.org/10.1016/S1388‐2457(99)00200‐X
Galletti, C., Gamberini, M., Kutz, D. F., Fattori, P., Luppino, G., & Matelli, M. (2001).
The cortical connections of area V6: an occipito‐parietal network processing
visual information. European Journal of Neuroscience, 13(8), 1572–1588.
http://doi.org/10.1046/j.0953‐816x.2001.01538.x
Galletti, C., Kutz, D. F., Gamberini, M., Breveglieri, R., & Fattori, P. (2003). Role of the
medial parieto‐occipital cortex in the control of reaching and grasping
movements. Experimental Brain Research, 153(2), 158–170.
http://doi.org/10.1007/s00221‐003‐1589‐z
Gilbert, D. L., Garvey, M. A., Bansal, A. S., Lipps, T., Zhang, J., & Wassermann, E. M.
(2004). Should transcranial magnetic stimulation research in children be
100 References
considered minimal risk? Clinical Neurophysiology, 115(8), 1730–1739.
http://doi.org/10.1016/j.clinph.2003.10.037
Glickstein, M. (2000). How are visual areas of the brain connected to motor areas for
the sensory guidance of movement? Trends in Neurosciences, 23(12), 613–617.
http://doi.org/10.1016/S0166‐2236(00)01681‐7
Goble, D. J., & Brown, S. H. (2008). The biological and behavioral basis of upper limb
asymmetries in sensorimotor performance. Neuroscience & Biobehavioral Reviews,
32(3), 598–610. http://doi.org/10.1016/j.neubiorev.2007.10.006
Goldfarb, J. L., & Goldstone, S. (1963). Time judgment: a comparison of filled and
unfilled durations. Perceptual and Motor Skills, 16(2), 376–376.
http://doi.org/10.2466/pms.1963.16.2.376
Grillon, C., & Davis, M. (1995). Acoustic startle and anticipatory anxiety in humans:
Effects of monaural right and left ear stimulation. Psychophysiology, 32(2), 155–
161. http://doi.org/10.1111/j.1469‐8986.1995.tb03307.x
Haaland, K. Y. (2006). Left hemisphere dominance for movement. The Clinical
Neuropsychologist, 20(4), 609–622. http://doi.org/10.1080/13854040590967577
Haaland, K. Y., Elsinger, C. L., Mayer, A. R., Durgerian, S., & Rao, S. M. (2004). Motor
sequence complexity and performing hand produce differential patterns of
hemispheric lateralization. Journal of Cognitive Neuroscience, 16(4), 621–636.
http://doi.org/10.1162/089892904323057344
Haaland, K. Y., & Harrington, D. L. (1989). Hemispheric control of the initial and
corrective components of aiming movements. Neuropsychologia, 27(7), 961–969.
http://doi.org/10.1016/0028‐3932(89)90071‐7
Haaland, K. Y., & Harrington, D. L. (1994). Limb‐sequencing deficits after left but not
right hemisphere damage. Brain and Cognition, 24(1), 104–122.
http://doi.org/10.1006/brcg.1994.1006
Haaland, K. Y., Harrington, D. L., & Knight, R. T. (2000). Neural representations of
skilled movement. Brain, 123(11), 2306–2313.
http://doi.org/10.1093/brain/123.11.2306
Hallett, M., Cohen, L. G., & Bierner, S. M. (1991). Studies of sensory and motor cortex
physiology: with observations on akinesia in Parkinson’s disease.
Electroencephalography and Clinical Neurophysiology. Supplement, 43, 76–85.
Hall, G. S., & Jastrow, J. (1886). Studies of rhythm. Mind, 11(41), 55–62.
References 101
Hammond, G. R. (2002). Correlates of human handedness in primary motor cortex: a
review and hypothesis. Neuroscience & Biobehavioral Reviews, 26(3), 285–292.
http://doi.org/10.1016/S0149‐7634(02)00003‐9
Hashimoto, T., Inaba, D., Matsumura, M., & Naito, E. (2004). Two different effects of
transcranial magnetic stimulation to the human motor cortex during the pre‐
movement period. Neuroscience Research, 50(4), 427–436.
http://doi.org/10.1016/j.neures.2004.08.002
Hazeltine, E., Diedrichsen, J., Kennerley, S. W., & Ivry, R. B. (2003). Bimanual cross‐talk
during reaching movements is primarily related to response selection, not the
specification of motor parameters. Psychological Research, 67, 56–70.
http://doi.org/10.1007/s00426‐002‐0119‐0
Helmuth, L. L., & Ivry, R. B. (1996). When two hands are better than one: Reduced
timing variability during bimanual movements. Journal of Experimental
Psychology, 22(2), 278–293. http://doi.org/10.1037/0096‐1523.22.2.278
Hening, W., Favilla, M., & Ghez, C. (1988). Trajectory control in targeted force
impulses: V. Gradual specification of response amplitude. Experimental Brain
Research, 71(1), 116–128. http://doi.org/10.1007/BF00247527
Hening, W., Vicario, D., & Ghez, C. (1988). Trajectory control in targeted force
impulses. Experimental Brain Research, 71(1), 103–115.
http://doi.org/10.1007/BF00247526
Henry, F. M., & Rogers, D. E. (1960). Increased response latency for complicated
movements and a ‘memory drum’ theory of neuromotor reaction. Research
Quarterly. American Association for Health, Physical Education and Recreation, 31(3),
448–458. http://doi.org/10.1080/10671188.1960.10762052
Herwig, U., Cardenas‐Morales, L., Connemann, B. J., Kammer, T., & Schönfeldt‐
Lecuona, C. (2010). Sham or real—Post hoc estimation of stimulation condition
in a randomized transcranial magnetic stimulation trial. Neuroscience Letters,
471(1), 30–33. http://doi.org/10.1016/j.neulet.2010.01.003
Hess, C. W., Mills, K. R., & Murray, N. M. F. (1986). Magnetic stimulation of the human
brain: Facilitation of motor responses by voluntary contraction of ipsilateral and
contralateral muscles with additional observations on an amputee. Neuroscience
Letters, 71(2), 235–240. http://doi.org/10.1016/0304‐3940(86)90565‐3
102 References
Heuer, H., & Klein, W. (2005). Intermanual interactions in discrete and periodic
bimanual movements with same and different amplitudes. Experimental Brain
Research, 167, 220–237.
Heuer, H., & Klein, W. (2006). The influence of movement cues on intermanual
interactions. Psychological Research, 70(4), 229–244. http://doi.org/10.1007/s00426‐
005‐0218‐9
Heuer, H., Spijkers, W., Kleinsorge, T., van der Loo, H., & Steglich, C. (1998). The time
course of cross‐talk during the simultaneous specification of bimanual
movement amplitudes. Experimental Brain Research, 118(3), 381–392.
http://doi.org/10.1007/s002210050292
Hinder, M., Schmidt, M., Garry, M., & Summers, J. (2010). Unilateral contractions
modulate interhemispheric inhibition most strongly and most adaptively in the
homologous muscle of the contralateral limb. Experimental Brain Research,
205(3), 423–433. http://doi.org/10.1007/s00221‐010‐2379‐z
Hoffman, H. S., & Ison, J. R. (1980). Reflex modification in the domain of startle: I.
Some empirical findings and their implications for how the nervous system
processes sensory input. Psychological Review, 87(2), 175–189.
Holmes, G., & May, W. P. (1909). On the exact origin of the pyramidal tracts in man
and other mammals. Proceedings of the Royal Society of Medicine, 2(Neurol Sect),
92–100.
Hortobágyi, T., Taylor, J. L., Petersen, N. T., Russell, G., & Gandevia, S. C. (2003).
Changes in segmental and motor cortical output with contralateral muscle
contractions and altered sensory inputs in humans. Journal of Neurophysiology,
90(4), 2451–2459. http://doi.org/10.1152/jn.01001.2002
Hoshiyama, M., Kitamura, Y., Koyama, S., Watanabe, S., Shimojo, M., & Kakigi, R.
(1996). Reciprocal change of motor‐evoked potentials preceding voluntary
movement in humans. Muscle & Nerve, 19(2), 125–131.
http://doi.org/10.1002/(SICI)1097‐4598(199602)19:2<125::AID‐MUS1>3.0.CO;2‐G
Hübers, A., Orekhov, Y., & Ziemann, U. (2008). Interhemispheric motor inhibition: Its
role in controlling electromyographic mirror activity. European Journal of
Neuroscience, 28, 364–371. http://doi.org/10.1111/j.1460‐9568.2008.06335.x
Ilic, T. V., Pötter‐Nerger, M., Holler, I., Siebner, H. R., Ilic, N. V., Deuschl, G., &
Volkmann, J. (2011). Startle stimuli exert opposite effects on human cortical and
References 103
spinal motor system excitability in leg muscles. Physiological Research, 60, S101–
6.
Ivry, R. B. (1996). The representation of temporal information in perception and motor
control. Current Opinion in Neurobiology, 6(6), 851–857.
http://doi.org/10.1016/S0959‐4388(96)80037‐7
Ivry, R. B., & Hazeltine, E. (1999). Subcortical locus of temporal coupling in the
bimanual movements of a callosotomy patient. Human Movement Science, 18,
345–375.
Ivry, R. B., & Richardson, T. C. (2002). Temporal control and coordination: The
multiple timer model. Brain and Cognition, 48(1), 117–132.
http://doi.org/10.1006/brcg.2001.1308
Jaffard, M., Longcamp, M., Velay, J.‐L., Anton, J.‐L., Roth, M., Nazarian, B., &
Boulinguez, P. (2008). Proactive inhibitory control of movement assessed by
event‐related fMRI. NeuroImage, 42(3), 1196–1206.
http://doi.org/10.1016/j.neuroimage.2008.05.041
Jahfari, S., Stinear, C. M., Claffey, M., Verbruggen, F., & Aron, A. R. (2010). Responding
with restraint: What are the neurocognitive mechanisms? Journal of Cognitive
Neuroscience, 22(7), 1479–1492. http://doi.org/10.1162/jocn.2009.21307
Jäncke, L., Peters, M., Schlaug, G., Posse, S., Steinmetz, H., & Müller‐Gärtner, H.‐W.
(1998). Differential magnetic resonance signal change in human sensorimotor
cortex to finger movements of different rate of the dominant and subdominant
hand. Cognitive Brain Research, 6(4), 279–284. http://doi.org/10.1016/S0926‐
6410(98)00003‐2
Kagerer, F. A., Summers, J. J., & Semjen, A. (2003). Instabilities during antiphase
bimanual movements: are ipsilateral pathways involved? Experimental Brain
Research, 151, 489–500.
Kakei, S., Hoffman, D. S., & Strick, P. L. (1999). Muscle and movement representations
in the primary motor cortex. Science, 285(5436), 2136–2139.
http://doi.org/10.1126/science.285.5436.2136
Kammer, T., Beck, S., Thielscher, A., Laubis‐Herrmann, U., & Topka, H. (2001). Motor
thresholds in humans: a transcranial magnetic stimulation study comparing
different pulse waveforms, current directions and stimulator types. Clinical
Neurophysiology, 112(2), 250–258. http://doi.org/10.1016/S1388‐2457(00)00513‐7
104 References
Kammer, T., & Nusseck, H. (1998). Are recognition deficits following occipital lobe
TMS explained by raised detection thresholds? Neuropsychologia, 36(11), 1161–
1166. http://doi.org/10.1016/S0028‐3932(98)00003‐7
Kammer, T., Puls, K., Strasburger, H., Hill, N. J., & Wichmann, F. A. (2005).
Transcranial magnetic stimulation in the visual system. I. The psychophysics of
visual suppression. Experimental Brain Research, 160(1), 118–128.
http://doi.org/10.1007/s00221‐004‐1991‐1
Kammer, T., Scharnowski, F., & Herzog, M. H. (2003). Combining backward masking
and transcranial magnetic stimulation in human observers. Neuroscience Letters,
343(3), 171–174. http://doi.org/10.1016/S0304‐3940(03)00376‐8
Kaufman, M. T., Churchland, M. M., Ryu, S. I., & Shenoy, K. V. (2014). Cortical activity
in the null space: permitting preparation without movement. Nature
Neuroscience, 17(3), 440–448. http://doi.org/10.1038/nn.3643
Kazennikov, O., Wicki, U., Corboz, M., Hyland, B., Palmeri, A., Rouiller, E. M., &
Wiesendanger, M. (1994). Temporal structure of a bimanual goal‐directed
movement sequence in monkeys. European Journal of Neuroscience, 6(2), 203–210.
http://doi.org/10.1111/j.1460‐9568.1994.tb00262.x
Keele, S. W., & Posner, M. I. (1968). Processing of visual feedback in rapid movements.
Journal of Experimental Psychology, 77(1), 155.
Kelso, J. A. S., Southard, D. L., & Goodman, D. (1979a). On the coordination of two‐
handed movements. Journal of Experimental Psychology: Human Perception and
Performance, 5(2), 229–238. http://doi.org/10.1037/0096‐1523.5.2.229
Kelso, J. A. S., Southard, D. L., & Goodman, D. (1979b). On the nature of human
interlimb coordination. Science, 203, 1029–1031.
Kennerley, S. W., Diedrichsen, J., Hazeltine, E., Semjen, A., & Ivry, R. B. (2002).
Callosotomy patients exhibit temporal uncoupling during continuous bimanual
movements. Nature Neuroscience, 5, 376. http://doi.org/10.1038/nn822
Klapp, S. T., Hill, M. D., Tyler, J. G., Martin, Z. E., Jagacinski, R. J., & Jones, M. R.
(1985). On marching to two different drummers: perceptual aspects of the
difficulties. Journal of Experimental Psychology. Human Perception and Performance,
11(6), 814–827.
Klapp, S. T., & Zelaznik, H. N. (1996). Reaction time analysis of central motor control.
Advances in Motor Learning and Control, 21, (pp. 13–35).
References 105
Kobayashi, M., Hutchinson, S., Schlaug, G., & Pascual‐Leone, A. (2003). Ipsilateral
motor cortex activation on functional magnetic resonance imaging during
unilateral hand movements is related to interhemispheric interactions.
NeuroImage, 20, 2259–2270.
Koch, G., Franca, M., Fernandez Del Olmo, M., Cheeran, B., Milton, R., Alvarez Sauco,
M., & Rothwell, J. C. (2006). Time course of functional connectivity between
dorsal premotor and contralateral motor cortex during movement selection. The
Journal of Neuroscience, 26, 7452–7459. http://doi.org/10.1523/jneurosci.1158‐
06.2006
Koeneke, S., Lutz, K., Wüstenberg, T., & Jäncke, L. (2004). Bimanual versus unimanual
coordination: what makes the difference? NeuroImage, 22(3), 1336–1350.
http://doi.org/10.1016/j.neuroimage.2004.03.012
Kühn, A. A., Sharott, A., Trottenberg, T., Kupsch, A., & Brown, P. (2004). Motor cortex
inhibition induced by acoustic stimulation. Experimental Brain Research, 158(1),
120–124. http://doi.org/10.1007/s00221‐004‐1883‐4
Kujirai, T., Caramia, M., Rothwell, J., Day, B., Thompson, P., Ferbert, A., … Marsden,
C. (1993). Corticocortical inhibition in human motor cortex. The Journal of
Physiology, 471, 501. http://doi.org/10.1113/jphysiol.1993.sp019912
Kumru, H., & Valls‐Solé, J. (2006). Excitability of the pathways mediating the startle
reaction before execution of a voluntary movement. Experimental Brain Research,
169(3), 427–432. http://doi.org/10.1007/s00221‐005‐0156‐1
Leaton, R. N., Cassella, J. V., & Borszcz, G. S. (1985). Short‐term and long‐term
habituation of the acoustic startle response in chronic decerebrate rats.
Behavioral Neuroscience, 99(5), 901–912. http://doi.org/10.1037/0735‐7044.99.5.901
Leocani, L., Cohen, L. G., Wassermann, E. M., Ikoma, K., & Hallett, M. (2000). Human
corticospinal excitability evaluated with transcranial magnetic stimulation
during different reaction time paradigms. Brain, 123(6), 1161–1173.
http://doi.org/10.1093/brain/123.6.1161
Loftus, G. R., & Masson, M. E. J. (1994). Using confidence intervals in within‐subject
designs. Psychonomic Bulletin & Review, 1(4), 476–490.
http://doi.org/10.3758/BF03210951
106 References
Los, S. A., Hoorn, J. F., Grin, M., & Van der Burg, E. (2013). The time course of temporal
preparation in an applied setting: A study of gaming behavior. Acta
Psychologica, 144(3), 499–505. http://doi.org/10.1016/j.actpsy.2013.09.003
Los, S. A., & Van der Burg, E. (2013). Sound speeds vision through preparation, not
integration. Journal of Experimental Psychology, 39(6), 1612–1624.
http://doi.org/10.1037/a0032183
Macar, F., Anton, J.‐L., Bonnet, M., & Vidal, F. (2004). Timing functions of the
supplementary motor area: an event‐related fMRI study. Cognitive Brain
Research, 21(2), 206–215. http://doi.org/10.1016/j.cogbrainres.2004.01.005
Marinovic, W., Rugy, A. de, Lipp, O. V., & Tresilian, J. R. (2013). Responses to loud
auditory stimuli indicate that movement‐related activation builds up in
anticipation of action. Journal of Neurophysiology, 109(4), 996–1008.
http://doi.org/10.1152/jn.01119.2011
Marinovic, W., Tresilian, J. R., de Rugy, A., Sidhu, S., & Riek, S. (2014). Corticospinal
modulation induced by sounds depends on action preparedness. The Journal of
Physiology, 592(1), 153–169. http://doi.org/10.1113/jphysiol.2013.254581
Marteniuk, R. G., MacKenzie, C. L., & Baba, D. M. (1984). Bimanual movement control:
Information processing and interaction effects. The Quarterly Journal of
Experimental Psychology Section A, 36(2), 335–365.
http://doi.org/10.1080/14640748408402163
Maslovat, D., Carlsen, A. N., & Franks, I. M. (2012). Investigation of stimulus–response
compatibility using a startling acoustic stimulus. Brain and Cognition, 78(1), 1–6.
http://doi.org/10.1016/j.bandc.2011.10.010
Maslovat, D., Carter, M. J., Kennefick, M., & Carlsen, A. N. (2014). Startle neural
activity is additive with normal cortical initiation‐related activation.
Neuroscience Letters. http://doi.org/10.1016/j.neulet.2013.11.009
Maslovat, D., Kennedy, P. M., Forgaard, C. J., Chua, R., & Franks, I. M. (2012). The
effects of prepulse inhibition timing on the startle reflex and reaction time.
Neuroscience Letters, 513(2), 243–247. http://doi.org/10.1016/j.neulet.2012.02.052
Masur, H., Papke, K., & Oberwittler, C. (1993). Suppression of visual perception by
transcranial magnetic stimulation — experimental findings in healthy subjects
and patients with optic neuritis. Electroencephalography and Clinical
Neurophysiology, 86(4), 259–267. http://doi.org/10.1016/0013‐4694(93)90107‐7
References 107
Mates, J., Müller, U., Radil, T., & Pöppel, E. (1994). Temporal integration in
sensorimotor synchronization. Journal of Cognitive Neuroscience, 6(4), 332–340.
http://doi.org/10.1162/jocn.1994.6.4.332
McMillan, S., Nougier, V., & Byblow, W. D. (2004). Human corticospinal excitability
during a precued reaction time paradigm. Experimental Brain Research, 156(1),
80–87. http://doi.org/10.1007/s00221‐003‐1772‐2
Meyer, B. U., & Voss, M. (2000). Delay of the execution of rapid finger movement by
magnetic stimulation of the ipsilateral hand‐associated motor cortex.
Experimental Brain Research, 134(4), 477–482.
http://doi.org/10.1007/s002210000486
Miller, J. (1982). Discrete versus continuous stage models of human information
processing: In search of partial output. Journal of Experimental Psychology: Human
Perception and Performance, 8(2), 273–296. http://doi.org/10.1037/0096‐
1523.8.2.273
Mills, K. R., Boniface, S. J., & Schubert, M. (1992). Magnetic brain stimulation with a
double coil: the importance of coil orientation. Electroencephalography and
Clinical Neurophysiology/Evoked Potentials Section, 85(1), 17–21.
http://doi.org/10.1016/0168‐5597(92)90096‐T
Milner‐Brown, H. S., Stein, R. B., & Yemm, R. (1973). Changes in firing rate of human
motor units during linearly changing voluntary contractions. The Journal of
Physiology, 230(2), 371–390.
Molinuevo, J. L., Valls‐Solé, J., & Valldeoriola, F. (2000). The effect of transcranial
magnetic stimulation on reaction time in progressive supranuclear palsy.
Clinical Neurophysiology, 111(11), 2008–2013. http://doi.org/10.1016/S1388‐
2457(00)00443‐0
Mordkoff, J. T., & Yantis, S. (1991). An interactive race model of divided attention.
Journal of Experimental Psychology, 17(2), 520–538. http://doi.org/10.1037/0096‐
1523.17.2.520
Mostofsky, S. H., & Simmonds, D. J. (2008). Response inhibition and response selection:
Two sides of the same coin. Journal of Cognitive Neuroscience, 20(5), 751–761.
http://doi.org/10.1162/jocn.2008.20500
108 References
Motawar, B., Hur, P., Stinear, J., & Seo, N. J. (2012). Contribution of intracortical
inhibition in voluntary muscle relaxation. Experimental Brain Research, 221(3),
299–308. http://doi.org/10.1007/s00221‐012‐3173‐x
Muellbacher, W., Richards, C., Ziemann, U., Wittenberg, G., Weltz, D., Boroojerdi, B.,
… Hallett, M. (2002). Improving hand function in chronic stroke. Arch Neurol,
59, 1278–1282. http://doi.org/10.1001/archneur.59.8.1278
Mullin, C. R., & Steeves, J. K. E. (2011). TMS to the lateral occipital cortex disrupts
object processing but facilitates scene processing. Journal of Cognitive
Neuroscience, 23(12), 4174–4184. http://doi.org/10.1162/jocn_a_00095
Murase, N., Duque, J., Mazzocchio, R., & Cohen, L. G. (2004). Influence of
interhemispheric interactions on motor function in chronic stroke. Annals of
Neurology, 55(3), 400–409. http://doi.org/10.1002/ana.10848
Nakajima, Y. (1987). A model of empty duration perception. Perception, 16(4), 485 – 520.
http://doi.org/10.1068/p160485
Nakamura, H., Kitagawa, H., Kawaguchi, Y., & Tsuji, H. (1997). Intracortical
facilitation and inhibition after transcranial magnetic stimulation in conscious
humans. The Journal of Physiology, 498(3), 817–823.
http://doi.org/10.1113/jphysiol.1997.sp021905
Nickerson, R. S. (1973). Intersensory facilitation of reaction time: Energy summation or
preparation enhancement? Psychological Review, 80(6), 489–509.
http://doi.org/10.1037/h0035437
Nijhuis, L. B. O., Janssen, L., Bloem, B. R., Van Dijk, J. G., Gielen, S. C., Borm, G. F., &
Overeem, S. (2007). Choice reaction times for human head rotations are
shortened by startling acoustic stimuli, irrespective of stimulus direction. The
Journal of Physiology, 584(1), 97–109. http://doi.org/10.1113/jphysiol.2007.136291
Nikouline, V., Ruohonen, J., & Ilmoniemi, R. J. (1999). The role of the coil click in TMS
assessed with simultaneous EEG. Clinical Neurophysiology, 110(8), 1325–1328.
http://doi.org/10.1016/S1388‐2457(99)00070‐X
Oga, T., Honda, M., Toma, K., Murase, N., Okada, T., Hanakawa, T., … Shibasaki, H.
(2002). Abnormal cortical mechanisms of voluntary muscle relaxation in
patients with writer’s cramp: an fMRI study. Brain, 125(4), 895–903.
http://doi.org/10.1093/brain/awf083
References 109
O’Shea, J., Sebastian, C., Boorman, E. D., Johansen‐Berg, H., & Rushworth, M. F. S.
(2007). Functional specificity of human premotor–motor cortical interactions
during action selection. European Journal of Neuroscience, 26(7), 2085–2095.
http://doi.org/10.1111/j.1460‐9568.2007.05795.x
Otto, T. U., & Mamassian, P. (2012). Noise and correlations in parallel perceptual
decision making. Current Biology, 22(15), 1391–1396.
http://doi.org/10.1016/j.cub.2012.05.031
Pascual‐Leone, A., Brasil‐Neto, J. P., Valls‐Solé, J., Cohen, L. G., & Hallett, M. (1992).
Simple reaction time to focal transcranial magnetic stimulation comparison
with reaction time to acoustic, visual and somatosensory stimuli. Brain, 115(1),
109–122. http://doi.org/10.1093/brain/115.1.109
Pascual‐Leone, A., Valls‐Solé, J., Brasil‐Neto, J. P., Cohen, L. G., & Hallett, M. (1994).
Akinesia in Parkinson’s disease. I. Shortening of simple reaction time with
focal, single‐pulse transcranial magnetic stimulation. Neurology, 44(5), 884–884.
http://doi.org/10.1212/WNL.44.5.884
Pascual‐Leone, A., Valls‐Solé, J., Wassermann, E. M., Brasil‐Neto, J., Cohen, L. G., &
Hallett, M. (1992). Effects of focal transcranial magnetic stimulation on simple
reaction time to acoustic, visual and somatosensory stimuli. Brain, 115(4), 1045–
1059. http://doi.org/10.1093/brain/115.4.1045
Paulignan, Y., Jeannerod, M., MacKenzie, C., & Marteniuk, R. (1991). Selective
perturbation of visual input during prehension movements. 2. The effects of
changing object size. Experimental Brain Research, 87(2), 407–420.
http://doi.org/10.1007/BF00231858
Paus, T. (2005). Inferring causality in brain images: a perturbation approach.
Philosophical Transactions of the Royal Society B: Biological Sciences, 360(1457),
1109–1114. http://doi.org/10.1098/rstb.2005.1652
Pélisson, D., Prablanc, C., Goodale, M. A., & Jeannerod, M. (1986). Visual control of
reaching movements without vision of the limb II. Evidence of fast unconsious
processes correcting the trajectory of the hand to the final position of double‐
step stimulus. Experimental Brain Research, 62(2), 303–311.
http://doi.org/10.1007/BF00238849
Perez, M. A. (2012). The functional role of interhemispheric interactions in human
motor control. In R. Chen & J. C. Rothwell (Eds.), Cortical connectivity: Brain
110 References
stimulation for assessing and modulating cortical connectivity and function. New
York: Springer.
Perez, M. A., & Cohen, L. G. (2008). Mechanisms underlying functional changes in the
primary motor cortex ipsilateral to an active hand. The Journal of Neuroscience,
28, 5631–5640. http://doi.org/10.1523/JNEUROSCI.0093‐08.2008
Perez, M. A., & Cohen, L. G. (2009). Scaling of motor cortical excitability during
unimanual force generation. Cortex, 45(9), 1065–1071.
http://doi.org/10.1016/j.cortex.2008.12.006
Perini, F., Cattaneo, L., Carrasco, M., & Schwarzbach, J. V. (2012). Occipital transcranial
magnetic stimulation has an activity‐dependent suppressive effect. The Journal
of Neuroscience, 32(36), 12361–12365. http://doi.org/10.1523/JNEUROSCI.5864‐
11.2012
Perrig, S., Kazennikov, O., & Wiesendanger, M. (1999). Time structure of a goal‐
directed bimanual skill and its dependence on task constraints. Behavioural
Brain Research, 103(1), 95–104. http://doi.org/10.1016/S0166‐4328(99)00026‐1
Pollok, B. 1 2, Muller, K. 1, Aschersleben, G., Schnitzler, A., & Prinz, W. (2004).
Bimanual coordination: neuromagnetic and behavioral data. NeuroReport, 15(3),
449–452.
Pope, P. A., Holton, A., Hassan, S., Kourtis, D., & Praamstra, P. (2007). Cortical control
of muscle relaxation: A lateralized readiness potential (LRP) investigation.
Clinical Neurophysiology, 118(5), 1044–1052.
http://doi.org/10.1016/j.clinph.2007.02.002
Preilowski, B. F. B. (1972). Possible contribution of the anterior forebrain commissures
to bilateral motor coordination. Neuropsychologia, 10(3), 267–277.
http://doi.org/10.1016/0028‐3932(72)90018‐8
Repp, B. H. (2004). On the nature of phase attraction in sensorimotor synchronization
with interleaved auditory sequences. Human Movement Science, 23(3–4), 389–
413. http://doi.org/10.1016/j.humov.2004.08.014
Repp, B. H. (2005). Sensorimotor synchronization: A review of the tapping literature.
Psychonomic Bulletin & Review, 12(6), 969–992. http://doi.org/10.3758/BF03206433
Repp, B. H. (2008). Metrical subdivision results in subjective slowing of the beat. Music
Perception: An Interdisciplinary Journal, 26(1), 19–39.
http://doi.org/10.1525/mp.2008.26.1.19
References 111
Repp, B. H., & Bruttomesso, M. (2009). A filled duration illusion in music: Effects of
metrical subdivision on the perception and production of beat tempo. Advances
in Cognitive Psychology, 5, 114–134. http://doi.org/10.2478/v10053‐008‐0071‐7
Reynolds, C., & Ashby, P. (1999). Inhibition in the human motor cortex is reduced just
before a voluntary contraction. Neurology, 53(4), 730–730.
http://doi.org/10.1212/WNL.53.4.730
Reynolds, R. F., & Day, B. L. (2007). Fast visuomotor processing made faster by sound.
The Journal of Physiology, 583(3), 1107–1115.
http://doi.org/10.1113/jphysiol.2007.136192
Ridding, M. C., Taylor, J. L., & Rothwell, J. C. (1995). The effect of voluntary
contraction on cortico‐cortical inhibition in human motor cortex. The Journal of
Physiology, 487(2), 541–548. http://doi.org/10.1113/jphysiol.1995.sp020898
Rinkenauer, G., Ulrich, R., & Wing, A. M. (2001). Brief bimanual force pulses:
correlations between the hands in force and time. Journal of Experimental
Psychology, 27, 1485–1497. http://doi.org/10.1037/0096‐1523.27.6.1485
Romaiguère, P., Possamaı̈, C.‐A., & Hasbroucq, T. (1997). Motor cortex involvement
during choice reaction time: a transcranial magnetic stimulation study in man.
Brain Research, 755(2), 181–192. http://doi.org/10.1016/S0006‐8993(97)00095‐4
Romei, V., Murray, M. M., Merabet, L. B., & Thut, G. (2007). Occipital transcranial
magnetic stimulation has opposing effects on visual and auditory stimulus
detection: Implications for multisensory interactions. The Journal of Neuroscience,
27(43), 11465–11472. http://doi.org/10.1523/JNEUROSCI.2827‐07.2007
Rushworth, M. F. ., Johansen‐Berg, H., Göbel, S. ., & Devlin, J. . (2003). The left parietal
and premotor cortices: motor attention and selection. NeuroImage, 20,
Supplement 1, S89–S100. http://doi.org/10.1016/j.neuroimage.2003.09.011
Sawaki, L., Okita, T., Fujiwara, M., & Mizuno, K. (1999). Specific and non‐specific
effects of transcranial magnetic stimulation on simple and go/no‐go reaction
time. Experimental Brain Research, 127(4), 402–408.
http://doi.org/10.1007/s002210050808
Schieber, M. H. (2001). Constraints on somatotopic organization in the primary motor
cortex. Journal of Neurophysiology, 86(5), 2125–2143.
Schieppati, M., Nardone, A., & Musazzi, M. (1985). Modulation of the Hoffmann reflex
by rapid muscle contraction or release. Human Neurobiology, 5(1), 59–66.
112 References
Schluter, N. D., Rushworth, M. F., Passingham, R. E., & Mills, K. R. (1998). Temporary
interference in human lateral premotor cortex suggests dominance for the
selection of movements. A study using transcranial magnetic stimulation. Brain,
121(5), 785–799. http://doi.org/10.1093/brain/121.5.785
Schluter, N. ., Krams, M., Rushworth, M. F. ., & Passingham, R. . (2001). Cerebral
dominance for action in the human brain: the selection of actions.
Neuropsychologia, 39(2), 105–113. http://doi.org/10.1016/S0028‐3932(00)00105‐6
Schluter, N. ., Rushworth, M. F. ., Mills, K. ., & Passingham, R. . (1999). Signal‐, set‐,
and movement‐related activity in the human premotor cortex. Neuropsychologia,
37(2), 233–243. http://doi.org/10.1016/S0028‐3932(98)00098‐0
Schmidt, R. A. (2003). Motor schema theory after 27 years: reflections and implications
for a new theory. Research Quarterly for Exercise and Sport, 74(4), 366–375.
http://doi.org/10.1080/02701367.2003.10609106
Schmidt, R. A., & Lee, T. (2011). Motor control and learning (5th ed.). Champaign:
Human kinetics.
Serrien, D. J., & Brown, P. (2004). Changes in functional coupling patterns during
bimanual task performance. NeuroReport, 15(9), 1387–1390.
http://doi.org/10.1097/01.wnr.0000131009.44068.51
Serrien, D. J., Ivry, R. B., & Swinnen, S. P. (2006). Dynamics of hemispheric
specialization and integration in the context of motor control. Nature Reviews
Neuroscience, 7(2), 160–166. http://doi.org/10.1038/nrn1849
Serrien, D. J., Nirkko, A. C., & Wiesendanger, M. (2001). Role of the corpus callosum in
bimanual coordination: a comparison of patients with congenital and acquired
callosal damage. European Journal of Neuroscience, 14(11), 1897–1905.
http://doi.org/10.1046/j.0953‐816x.2001.01798.x
Sherwood, D. E. (2006). Intermovement interval and spatial assimilation effects in
sequential bimanual and unimanual movements. Human Movement Science,
25(2), 145–164. http://doi.org/10.1016/j.humov.2005.11.006
Sherwood, D. E., & Nishimura, K. M. (1992). EMG amplitude and spatial assimilation
effects in rapid bimanual movement. Research Quarterly for Exercise and Sport,
63(3), 284–291. http://doi.org/10.1080/02701367.1992.10608744
References 113
Siegmund, G. P., Inglis, J. T., & Sanderson, D. J. (2001). Startle response of human neck
muscles sculpted by readiness to perform ballistic head movements. The Journal
of Physiology, 535(1), 289–300. http://doi.org/10.1111/j.1469‐7793.2001.00289.x
Silvanto, J., Cattaneo, Z., Battelli, L., & Pascual‐Leone, A. (2008). Baseline cortical
excitability determines whether TMS disrupts or facilitates behavior. Journal of
Neurophysiology, 99(5), 2725–2730. http://doi.org/10.1152/jn.01392.2007
Silvanto, J., Muggleton, N., & Walsh, V. (2008). State‐dependency in brain stimulation
studies of perception and cognition. Trends in Cognitive Sciences, 12(12), 447–454.
http://doi.org/10.1016/j.tics.2008.09.004
Sinclair, C., & Hammond, G. R. (2009). Excitatory and inhibitory processes in primary
motor cortex during the foreperiod of a warned reaction time task are unrelated
to response expectancy. Experimental Brain Research, 194(1), 103–113.
http://doi.org/10.1007/s00221‐008‐1684‐2
Singh, L. N., Higano, S., Takahashi, S., Kurihara, N., Furuta, S., Tamura, H., …
Yamadori, A. (1998). Comparison of ipsilateral activation between right and left
handers: a functional MR imaging study. NeuroReport, 9(8), 1861–1866.
Soteropoulos, D. S., & Perez, M. A. (2011). Physiological changes underlying bilateral
isometric arm voluntary contractions in healthy humans. Journal of
Neurophysiology, 105, 1594–1602. http://doi.org/10.1152/jn.00678.2010
Soto, O., Valls‐Solé, J., & Kumru, H. (2010). Paired‐pulse transcranial magnetic
stimulation during preparation for simple and choice reaction time tasks.
Journal of Neurophysiology, 104(3), 1392–1400.
http://doi.org/10.1152/jn.00620.2009
Starr, A., Caramia, M., Zarola, F., & Rossini, P. M. (1988). Enhancement of motor
cortical excitability in humans by non‐invasive electrical stimulation appears
prior to voluntary movement. Electroencephalography and Clinical
Neurophysiology, 70(1), 26–32. http://doi.org/10.1016/0013‐4694(88)90191‐5
Stedman, A., Davey, N. J., & Ellaway, P. H. (1998). Facilitation of human first dorsal
interosseous muscle responses to transcranial magnetic stimulation during
voluntary contraction of the contralateral homonymous muscle. Muscle &
Nerve, 21(8), 1033–1039. http://doi.org/10.1002/(SICI)1097‐
4598(199808)21:8<1033::AID‐MUS7>3.0.CO;2‐9
114 References
Steglich, C., Heuer, H., Spijkers, W., & Kleinsorge, T. (1999). Bimanual coupling during
the specification of isometric forces. Experimental Brain Research, 129(2), 302–316.
http://doi.org/10.1007/s002210050900
Sternberg, S., Monsell, S., Knoll, R. L., & Wright, C. E. (1978). The latency and duration
of rapid movement sequences: Comparisons of speech and typewriting.
Information Processing in Motor Control and Learning, 117–152.
Stinear, C. M., Coxon, J. P., & Byblow, W. D. (2009). Primary motor cortex and
movement prevention: Where Stop meets Go. Neuroscience & Biobehavioral
Reviews, 33(5), 662–673. http://doi.org/10.1016/j.neubiorev.2008.08.013
Stinear, C. M., Walker, K., & Byblow, W. (2001). Symmetric facilitation between motor
cortices during contraction of ipsilateral hand muscles. Experimental Brain
Research, 139(1), 101–105. http://doi.org/10.1007/s002210100758
Stoffels, E. J., Van Der Molen, M. W., & Keuss, P. J. G. (1985). Intersensory facilitation
and inhibition: Immediate arousal and location effects of auditory noise on
visual choice reaction time. Acta Psychologica, 58(1), 45–62.
http://doi.org/10.1016/0001‐6918(85)90033‐2
Suzuki, T., Sugawara, K., Takagi, M., & Higashi, T. (2015). Excitability changes in
primary motor cortex just prior to voluntary muscle relaxation. Journal of
Neurophysiology, 113(1), 110–115. http://doi.org/10.1152/jn.00489.2014
Swinnen, S. P. (2002). Intermanual coordination: From behavioural principles to
neural‐network interactions. Nature Reviews Neuroscience, 3, 348–359.
http://doi.org/10.1038/nrn807
Swinnen, S. P., Vangheluwe, S., Wagemans, J., Coxon, J. P., Goble, D. J., Van Impe, A.,
… Wenderoth, N. (2010). Shared neural resources between left and right
interlimb coordination skills: The neural substrate of abstract motor
representations. NeuroImage, 49(3), 2570–2580.
http://doi.org/10.1016/j.neuroimage.2009.10.052
Tandonnet, C., Davranche, K., Meynier, C., Burle, B., Vidal, F., & Hasbroucq, T. (2012).
How does temporal preparation speed up response implementation in choice
tasks? Evidence for an early cortical activation. Psychophysiology, 49(2), 252–260.
http://doi.org/10.1111/j.1469‐8986.2011.01301.x
References 115
Tandonnet, C., Garry, M. I., & Summers, J. J. (2010). Cortical activation during
temporal preparation assessed by transcranial magnetic stimulation. Biological
Psychology, 85(3), 481–486. http://doi.org/10.1016/j.biopsycho.2010.08.016
Tandonnet, C., Garry, M. I., & Summers, J. J. (2011). Selective suppression of the
incorrect response implementation in choice behavior assessed by transcranial
magnetic stimulation. Psychophysiology, 48(4), 462–469.
http://doi.org/10.1111/j.1469‐8986.2010.01121.x
Taylor, B. K., Casto, R., & Printz, M. P. (1991). Dissociation of tactile and acoustic
components in air puff startle. Physiology & Behavior, 49(3), 527–532.
http://doi.org/10.1016/0031‐9384(91)90275‐S
Taylor, J. L., Wagener, D. S., & Colebatch, J. G. (1995). Mapping of cortical sites where
transcranial magnetic stimulation results in delay of voluntary movement.
Electroencephalography and Clinical Neurophysiology/Electromyography and Motor
Control, 97(6), 341–348. http://doi.org/10.1016/0924‐980X(95)00123‐3
Tazoe, T., & Perez, M. A. (2013). Speed‐dependent contribution of callosal pathways to
ipsilateral movements. The Journal of Neuroscience, 33(41), 16178–16188.
http://doi.org/10.1523/JNEUROSCI.2638‐13.2013
Terada, K., Ikeda, A., Nagamine, T., & Shibasaki, H. (1995). Movement‐related cortical
potentials associated with voluntary muscle relaxation. Electroencephalography
and Clinical Neurophysiology, 95(5), 335–345. http://doi.org/10.1016/0013‐
4694(95)00098‐J
Terada, K., Ikeda, A., Yazawa, S., Nagamine, T., & Shibasaki, H. (1999). Movement‐
related cortical potentials associated with voluntary relaxation of foot muscles.
Clinical Neurophysiology, 110(3), 397–403. http://doi.org/10.1016/S1388‐
2457(98)00017‐0
Terao, Y., Ugawa, Y., Suzuki, M., Sakai, K., Hanajima, R., Gemba‐Shimizu, K., &
Kanazawa, I. (1997). Shortening of simple reaction time by peripheral electrical
and submotor‐threshold magnetic cortical stimulation. Experimental Brain
Research, 115(3), 541–545. http://doi.org/10.1007/PL00005724
Thomas, E. C., & Brown, I. (1974). Time perception and the filled‐duration illusion.
Perception & Psychophysics, 16(3), 449–458. http://doi.org/10.3758/BF03198571
Thut, G., Northoff, G., Ives, J. R., Kamitani, Y., Pfennig, A., Kampmann, F., … Pascual‐
Leone, A. (2003). Effects of single‐pulse transcranial magnetic stimulation
116 References
(TMS) on functional brain activity: a combined event‐related TMS and evoked
potential study. Clinical Neurophysiology, 114(11), 2071–2080.
http://doi.org/10.1016/S1388‐2457(03)00205‐0
Tinazzi, M., & Zanette, G. (1998). Modulation of ipsilateral motor cortex in man during
unimanual finger movements of different complexities. Neuroscience Letters,
244(3), 121–124. http://doi.org/10.1016/S0304‐3940(98)00150‐5
Toma, K., Honda, M., Hanakawa, T., Okada, T., Fukuyama, H., Ikeda, A., … Shibasaki,
H. (1999). Activities of the primary and supplementary motor areas increase in
preparation and execution of voluntary muscle relaxation: An event‐related
fMRI study. The Journal of Neuroscience, 19(9), 3527–3534.
Toma, K., Nagamine, T., Yazawa, S., Terada, K., Ikeda, A., Honda, M., … Shibasaki, H.
(2000). Desynchronization and synchronization of central 20‐Hz rhythms
associated with voluntary muscle relaxation: a magnetoencephalographic
study. Experimental Brain Research, 134(4), 417–425.
http://doi.org/10.1007/s002210000483
Tuller, B., & Kelso, J. A. S. (1989). Environmentally‐specified patterns of movement
coordination in normal and split‐brain subjects. Experimental Brain Research, 75,
306–316.
Vallence, A.‐M., Schneider, L. A., Pitcher, J. B., & Ridding, M. C. (2014). Long‐interval
facilitation and inhibition are differentially affected by conditioning stimulus
intensity over different time courses. Neuroscience Letters, 570, 114–118.
http://doi.org/10.1016/j.neulet.2014.03.060
Valls‐Solé, J., Hallett, M., Phillip, L. H., Schomer, D. L., & Massey, J. M. (2004).
Contribution of subcortical motor pathways to the execution of ballistic
movements. Supplements to Clinical Neurophysiology, Volume 57, 554–562.
Valls‐Solé, J., Kofler, M., Kumru, H., Castellote, J. M., & Sanegre, M. T. (2005). Startle‐
induced reaction time shortening is not modified by prepulse inhibition.
Experimental Brain Research, 165(4), 541–548. http://doi.org/10.1007/s00221‐005‐
2332‐8
Valls‐Solé, J., Kumru, H., & Kofler, M. (2008). Interaction between startle and voluntary
reactions in humans. Experimental Brain Research, 187(4), 497–507.
http://doi.org/10.1007/s00221‐008‐1402‐0
References 117
Valls‐Solé, J., Pascual‐Leone, A., Wassermann, E. M., & Hallett, M. (1992). Human
motor evoked responses to paired transcranial magnetic stimuli.
Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section,
85(6), 355–364. http://doi.org/10.1016/0168‐5597(92)90048‐G
Valls‐Solé, J., Rothwell, J. C., Goulart, F., Cossu, G., & Muñoz, E. (1999). Patterned
ballistic movements triggered by a startle in healthy humans. The Journal of
Physiology, 516(3), 931–938. http://doi.org/10.1111/j.1469‐7793.1999.0931u.x
Valls‐Solé, J., Valldeoriola, F., Tolosa, E., & Nobbe, F. (1997). Habituation of the
auditory startle reaction is reduced during preparation for execution of a motor
task in normal human subjects. Brain Research, 751(1), 155–159.
http://doi.org/10.1016/S0006‐8993(97)00027‐9
van den Berg, F. E., Swinnen, S. P., & Wenderoth, N. (2011). Excitability of the motor
cortex ipsilateral to the moving body side depends on spatio‐temporal task
complexity and hemispheric specialization. PLoS ONE, 6(3), e17742.
http://doi.org/10.1371/journal.pone.0017742
Viviani, P., Perani, D., Grassi, F., Bettinardi, V., & Fazio, F. (1998). Hemispheric
asymmetries and bimanual asynchrony in left‐ and right‐handers. Experimental
Brain Research, 120, 531–536. http://doi.org/10.1007/s002210050428
Volkmann, J., Schnitzler, A., Witte, O. W., & Freund, H.‐J. (1998). Handedness and
asymmetry of hand representation in human motor cortex. Journal of
Neurophysiology, 79(4), 2149–2154.
Wand, M. P. (1997). Data‐based choice of histogram bin width. The American
Statistician, 51(1), 59–64. http://doi.org/10.1080/00031305.1997.10473591
Wand, M. P., & Jones, M. C. (1995). Kernel smoothing. London: Chapman & Hall.
Wardak, C., Ramanoël, S., Guipponi, O., Boulinguez, P., & Ben Hamed, S. B. (2012).
Proactive inhibitory control varies with task context. European Journal of
Neuroscience, 36(11), 3568–3579. http://doi.org/10.1111/j.1460‐9568.2012.08264.x
Wearden, J. H., Norton, R., Martin, S., & Montford‐Bebb, O. (2007). Internal clock
processes and the filled‐duration illusion. Journal of Experimental Psychology:
Human Perception and Performance, 33(3), 716–729. http://doi.org/10.1037/0096‐
1523.33.3.716
Weiss, P., & Jeannerod, M. (1998). Getting a grasp on coordination. Physiology, 13(2),
70–75.
118 References
Wenderoth, N., Debaere, F., Sunaert, S., & Swinnen, S. P. (2005). Spatial interference
during bimanual coordination: Differential brain networks associated with
control of movement amplitude and direction. Human Brain Mapping, 26(4),
286–300. http://doi.org/10.1002/hbm.20151
Wenderoth, N., Puttemans, V., Vangheluwe, S., & Swinnen, S. P. (2003). Bimanual
training reduces spatial interference. Journal of Motor Behavior, 35, 296–308.
http://doi.org/10.1080/00222890309602142
Wilcox, R. R. (2012). Introduction to Robust Estimation and Hypothesis Testing. Academic
Press.
Wohlschläger, A., & Koch, R. (2000). Synchronization error: An error in time
perception. Rhythm Perception and Production, 115–127.
Wyke, M. (1968). The effect of brain lesions in the performance of an arm‐hand
precision task. Neuropsychologia, 6(2), 125–134. http://doi.org/10.1016/0028‐
3932(68)90054‐7
Wyke, M. (1971). The effects of brain lesions on the performance of bilateral arm
movements. Neuropsychologia, 9(1), 33–42. http://doi.org/10.1016/0028‐
3932(71)90059‐5
Xivry, J.‐J. O. de, Criscimagna‐Hemminger, S. E., & Shadmehr, R. (2011). Contributions
of the motor cortex to adaptive control of reaching depend on the perturbation
schedule. Cerebral Cortex, 21(7), 1475–1484. http://doi.org/10.1093/cercor/bhq192
Yabe, H., Tervaniemi, M., Sinkkonen, J., Huotilainen, M., Ilmoniemi, R. J., & Näätänen,
R. (1998). Temporal window of integration of auditory information in the
human brain. Psychophysiology, 35(5), 615–619.
http://doi.org/10.1017/S0048577298000183
Yamanaka, K., Kimura, T., Miyazaki, M., Kawashima, N., Nozaki, D., Nakazawa, K., …
Yamamoto, Y. (2002). Human cortical activities during Go/NoGo tasks with
opposite motor control paradigms. Experimental Brain Research, 142(3), 301–307.
http://doi.org/10.1007/s00221‐001‐0943‐2
Yazawa, S., Ikeda, A., Kunieda, T., Mima, T., Nagamine, T., Ohara, S., … Shibasaki, H.
(1998). Human supplementary motor area is active in preparation for both
voluntary muscle relaxation and contraction: subdural recording of
Bereitschaftspotential. Neuroscience Letters, 244(3), 145–148.
http://doi.org/10.1016/S0304‐3940(98)00149‐9
References 119
Yedimenko, J. A., & Perez, M. A. (2010). The effect of bilateral isometric forces in
different directions on motor cortical function in humans. Journal of
Neurophysiology, 104, 2922–2931. http://doi.org/10.1152/jn.00020.2010
Yeomans, J. S., Li, L., Scott, B. W., & Frankland, P. W. (2002). Tactile, acoustic and
vestibular systems sum to elicit the startle reflex. Neuroscience & Biobehavioral
Reviews, 26(1), 1–11. http://doi.org/10.1016/S0149‐7634(01)00057‐4
Zelaznik, H. N., Hawkins, B., & Kisselburgh, L. (1983). Rapid visual feedback
processing in single‐aiming movements. Journal of Motor Behavior, 15(3), 217–
236. http://doi.org/10.1080/00222895.1983.10735298
Ziemann, U., & Hallett, M. (2001). Hemispheric asymmetry of ipsilateral motor cortex
activation during unimanual motor tasks: further evidence for motor
dominance. Clinical Neurophysiology, 112, 107–113.
Ziemann, U., Tergau, F., Netz, J., & Hömberg, V. (1997). Delay in simple reaction time
after focal transcranial magnetic stimulation of the human brain occurs at the
final motor output stage. Brain Research, 744(1), 32–40.
http://doi.org/10.1016/S0006‐8993(96)01062‐1
Zoghi, M., Pearce, S. L., & Nordstrom, M. A. (2003). Differential modulation of
intracortical inhibition in human motor cortex during selective activation of an
intrinsic hand muscle. The Journal of Physiology, 550(Pt 3), 933–946.
http://doi.org/10.1113/jphysiol.2003.042606
121
Appendix 1.
Supplementary statistics for Experiment 1
Summary statistics, describing characteristics of the pinch responses recorded in
Experiment 1 (presented in Chapter 3), are shown below.
Table 9 Means and standard deviations (in brackets) of pinch rise times in each condition, in
milliseconds. TMS was either withheld (none) or administered 350 ms, 300 ms, 250 ms, 200 ms,
or 150 ms before the target pinch onset time. Target forces are expressed as a percentage of MVC.
TMS
(ms)
Left hand rise time (ms) Right hand rise time (ms)
10% MVC
target
30% MVC
target
10% MVC
target
30% MVC
target
None 128 (17) 167 (21) 141 (22) 185 (20)
350 129 (18) 168 (25) 142 (22) 182 (25)
300 126 (15) 164 (24) 138 (20) 186 (25)
250 124 (16) 167 (25) 144 (19) 179 (24)
200 126 (20) 164 (23) 140 (23) 180 (25)
150 126 (17) 167 (24) 140 (20) 183 (24)
Table 10 Means and standard deviations (in brackets) of total pinch durations in each condition,
in milliseconds. TMS was either withheld (none) or administered 350 ms, 300 ms, 250 ms, 200 ms,
or 150 ms before the target pinch onset time. Target forces are expressed as a percentage of MVC.
TMS
(ms)
Left hand duration (ms) Right hand duration (ms)
10% MVC
target
30% MVC
target
10% MVC
target
30% MVC
target
None 378 (57) 514 (52) 441 (75) 618 (63)
350 384 (56) 523 (54) 449 (79) 611 (75)
300 380 (53) 516 (49) 446 (71) 621 (63)
250 372 (59) 517 (54) 456 (57) 605 (68)
200 374 (54) 510 (62) 446 (65) 610 (69)
150 374 (55) 515 (55) 452 (74) 610 (65)
122 Appendix 1
Table 11 Means and standard deviations (in brackets) of the coefficient of variation of peak forces
in each condition. TMS was either withheld (none) or administered 350 ms, 300 ms, 250 ms,
200 ms, or 150 ms before the target pinch onset time. Target forces are expressed as a percentage
of MVC.
TMS
(ms)
Left hand coef. variation Right hand coef. variation
10% MVC
target
30% MVC
target
10% MVC
target
30% MVC
target
None 0.29 (0.10) 0.24 (0.06) 0.28 (0.07) 0.20 (0.06)
350 0.28 (0.09) 0.19 (0.05) 0.27 (0.08) 0.23 (0.07)
300 0.28 (0.09) 0.20 (0.07) 0.28 (0.06) 0.22 (0.05)
250 0.25 (0.06) 0.23 (0.08) 0.29 (0.08) 0.21 (0.07)
200 0.26 (0.07) 0.20 (0.06) 0.31 (0.08) 0.21 (0.05)
150 0.30 (0.09) 0.23 (0.07) 0.26 (0.07) 0.23 (0.06)
123
Appendix 2.
Supplementary statistics for Experiment 2
Summary statistics, describing characteristics of the pinch responses recorded
Experiment 2 (presented in Chapter 4 and Chapter 5), are shown below.
Table 12 Means and standard deviations (in brackets) of pinch rise times for each condition, in
milliseconds. ʺLʺ and ʺRʺ denote the target force for the left and right hand. Target forces are
expressed as a percentage of MVC.
Response
condition
Force
condition
(% MVC)
No TMS Left M1 TMS Right M1 TMS
Left
hand
Right
hand
Left
hand
Right
hand
Left
hand
Right
hand
Unimanual L10 or R10 128 (16) 143 (12) 125 (13) 145 (14) 131 (11) 139 (15)
L30 or R30 166 (20) 178 (17) 161 (19) 180 (23) 159 (24) 172 (19)
Bimanual
Equal
L10 & R10 129 (12) 139 (14) 123 (13) 144 (18) 130 (17) 132 (15)
L30 & R30 168 (23) 175 (20) 161 (19) 181 (24) 165 (23) 166 (17)
Bimanual
Unequal
L10 & R30 154 (20) 178 (18) 148 (16) 185 (21) 148 (19) 164 (20)
L30 & R10 166 (17) 158 (14) 161 (19) 158 (16) 165 (27) 154 (20)
124 Appendix 2
Table 13 Means and standard deviations (in brackets) of peak forces in each condition, expressed
as a percentage of MVC. ʺLʺ and ʺRʺ denote the target force for the left and right hand.
Response
condition
Force
condition
(% MVC)
No TMS Left M1 TMS Right M1 TMS
Left
hand
Right
hand
Left
hand
Right
hand
Left
hand
Right
hand
Unimanual
L10 or R10 10.5
(1.4)
10.7
(1.5)
11.1
(1.1)
10.2
(1.3)
11.3
(1.9)
11.8
(2.0)
L30 or R30 26.4
(3.1)
26.1
(2.5)
27.1
(2.7)
25.2
(5.2)
26.7
(4.1)
26.4
(4.3)
Bimanual
Equal
L10 & R10 11.0
(1.7)
10.3
(1.2)
10.9
(0.8)
10.0
(1.5)
11.7
(3.6)
10.8
(2.7)
L30 & R30 25.8
(3.3)
24.8
(2.6)
26.9
(3.4)
24.3
(3.7)
26.7
(3.7)
26.1
(3.9)
Bimanual
Unequal
L10 & R30 15.3
(3.9)
24.9
(4.8)
16.0
(4.2)
23.6
(5.7)
15.3
(4.8)
23.6
(4.5)
L30 & R10 24.9
(3.5)
13.3
(2.2)
24.4
(4.9)
13.5
(2.0)
25.0
(3.3)
14.3
(3.2)
Table 14 Means and standard deviations (in brackets) of the coefficient of variation of peak forces
in each condition. ʺLʺ and ʺRʺ denote the target force for the left and right hand. Target forces are
expressed as a percentage of MVC.
Force
condition
(% MVC)
No TMS Left M1 TMS Right M1 TMS
Response
condition
Left
hand
Right
hand
Left
hand
Right
hand
Left
hand
Right
hand
Unimanual
L10 or R10 0.28
(0.07)
0.28
(0.07)
0.21
(0.05)
0.24
(0.09)
0.28
(0.11)
0.25
(0.08)
L30 or R30 0.20
(0.04)
0.20
(0.04)
0.22
(0.07)
0.21
(0.08)
0.23
(0.07)
0.21
(0.07)
Bimanual
Equal
L10 & R10 0.24
(0.06)
0.23
(0.04)
0.24
(0.07)
0.29
(0.10)
0.26
(0.06)
0.22
(0.06)
L30 & R30 0.20
(0.04)
0.20
(0.05)
0.18
(0.05)
0.19
(0.05)
0.20
(0.06)
0.18
(0.05)
Bimanual
Unequal
L10 & R30 0.28
(0.08)
0.24
(0.06)
0.27
(0.09)
0.28
(0.09)
0.27
(0.11)
0.24
(0.10)
L30 & R10 0.22
(0.05)
0.29
(0.08)
0.21
(0.07)
0.26
(0.08)
0.22
(0.06)
0.23
(0.09)
125
Appendix 3.
Supplementary statistics for Experiment 3
Summary statistics, describing characteristics of the pinch responses recorded
Experiment 3 (presented in Chapter 6), are shown below.
Table 15 Means and standard deviations (in brackets) of pinch rise times in each condition, in
milliseconds. Target forces are expressed as a percentage of MVC.
TMS Target force
(% MVC)
Left hand
rise time (ms)
Right hand
rise time (ms)
None 10 121 (21) 122 (24)
30 173 (23) 178 (31)
M1 10 119 (22) 119 (25)
30 171 (27) 179 (35)
Occipital 10 119 (26) 121 (24)
30 175 (26) 180 (35)
Table 16 Means and standard deviations (in brackets) of total pinch durations in each condition,
in milliseconds. Target forces are expressed as a percentage of MVC.
TMS Target force
(% MVC)
Left hand
duration (ms)
Right hand
duration (ms)
None 10 323 (52) 351 (67)
30 494 (51) 544 (56)
M1 10 326 (51) 348 (74)
30 498 (62) 554 (71)
Occipital 10 326 (60) 358 (70)
30 501 (50) 546 (62)
126 Appendix 3
Table 17 Means and standard deviations (in brackets) of peak forces in each condition, as a
percentage of MVC.
TMS Target force
(% MVC)
Left hand
force (% MVC)
Right hand
force (% MVC)
None 10 9.1 (3.2) 8.2 (3.0)
30 22.6 (6.6) 21.0 (6.4)
M1 10 9.6 (3.1) 8.2 (3.1)
30 22.9 (6.9) 21.2 (6.2)
Occipital 10 9.6 (3.4) 8.8 (3.0)
30 24.1 (6.5) 22.0 (7.8)
Table 18 Means and standard deviations (in brackets) of the coefficients of variation of peak
forces in each condition. Target forces are expressed as a percentage of MVC.
TMS Target force
(% MVC)
Left hand
coef. variation
Right hand
coef. variation
None 10 0.29 (0.05) 0.28 (0.06)
30 0.22 (0.06) 0.20 (0.05)
M1 10 0.26 (0.07) 0.31 (0.06)
30 0.23 (0.07) 0.22 (0.06)
Occipital 10 0.28 (0.06) 0.28 (0.08)
30 0.19 (0.05) 0.20 (0.07)
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