James E. - UWA Research Repository · james e. stewart, bsc. (hons) school of psychology 2015 this...

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



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,


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.


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


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).


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


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.


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


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


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


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).


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).


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)


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.


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;


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


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


Peak

forc

e (%

MV

C)

HandLeftRight


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


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


Mea

n M

EP

am

plitu

de (m

V)

ResponseNo pinchIpsilateral onlyContralateral onlyBimanual equal forceBimanual unequal force


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.


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.


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.


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.


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


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.


0

10

20

30

10 30 10 30


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).


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


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


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


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.


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.


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


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,


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.


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.


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



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)


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).


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‐


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.


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.


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


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

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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,


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,


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.


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)


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)


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)


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.


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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