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THE UNIVERSITY OF EASTERN FINLAND Dissertations in Forestry and Natural Sciences
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DISSERTATIONS | ELISA KALLIONIEMI | ASSESSMENT OF MOTOR CORTICAL EXCITATION-... | No 219
ELISA KALLIONIEMI
ASSESSMENT OF MOTOR CORTICAL EXCITATION- INHIBITION BALANCE AND MICROSTRUCTURE PUBLICATIONS OF
THE UNIVERSITY OF EASTERN FINLAND
Functional and structural features of the nerves differentiate healthy brain from diseased. This thesis demonstrated that navigated transcranial
magnetic stimulation and magnetic resonance imaging can be used comprehensively to evaluate different functional and structural properties of the motor cortex. Furthermore,
it was shown that navigated transcranial magnetic stimulation is able to influence the function of the facial muscles indirectly via the
speech related cortical areas.
ELISA KALLIONIEMI
ELISA KALLIONIEMI
Assessment of motor
cortical excitation-inhibition balance and microstructure
Studies combining navigated transcranial magnetic stimulation and magnetic resonance imaging
Publications of the University of Eastern Finland Dissertations in Forestry and Natural Sciences
Number 219
Academic Dissertation
To be presented by permission of the Faculty of Science and Forestry for public examination in the Hall SN201 in Snellmania Building at the University of Eastern
Finland, Kuopio, on 29th April 2016, at 12 o’clock noon.
Grano Oy Jyväskylä, 2016 Editors: Prof. Pertti Pasanen,
Prof. Jukka Tuomela, Prof. Pekka Toivanen, Prof. Matti Vornanen Distribution:
Eastern Finland University Library / Sales of publications P.O.Box 107, FI-80101 Joensuu, Finland
tel. +358-50-3058396 http://www.uef.fi/kirjasto ISBN: 978-952-61-2076-8 (nid.) ISBN: 978-952-61-2077-5 (PDF)
ISSNL: 1798-5668 ISSN: 1798-5668 ISSN: 1798-5676 (PDF)
Author’s address: Kuopio University Hospital
Department of Clinical Neurophysiology KUOPIO, FINLAND
University of Eastern Finland Department of Applied Physics KUOPIO, FINLAND
email: elisa.kallioniemi@kuh.fi
Supervisors: Adjunct Professor Petro Julkunen, Ph.D.
Kuopio University Hospital
Department of Clinical Neurophysiology KUOPIO, FINLAND
University of Eastern Finland Department of Applied Physics KUOPIO, FINLAND
email: petro.julkunen@kuh.fi Laura Säisänen, Ph.D. University of Eastern Finland Institute of Clinical Medicine KUOPIO, FINLAND Kuopio University Hospital
Department of Clinical Neurophysiology KUOPIO, FINLAND
email: laura.saisanen@kuh.fi
Adjunct Professor Ari Pääkkönen, Ph.D. Kuopio University Hospital
Department of Clinical Neurophysiology KUOPIO, FINLAND
email: ari.paakkonen@kuh.fi Professor Pasi Karjalainen, Ph.D. University of Eastern Finland Department of Applied Physics KUOPIO, FINLAND
email: pasi.karjalainen@uef.fi
Grano Oy Jyväskylä, 2016 Editors: Prof. Pertti Pasanen,
Prof. Jukka Tuomela, Prof. Pekka Toivanen, Prof. Matti Vornanen Distribution:
Eastern Finland University Library / Sales of publications P.O.Box 107, FI-80101 Joensuu, Finland
tel. +358-50-3058396 http://www.uef.fi/kirjasto ISBN: 978-952-61-2076-8 (nid.) ISBN: 978-952-61-2077-5 (PDF)
ISSNL: 1798-5668 ISSN: 1798-5668 ISSN: 1798-5676 (PDF)
Author’s address: Kuopio University Hospital
Department of Clinical Neurophysiology KUOPIO, FINLAND
University of Eastern Finland Department of Applied Physics KUOPIO, FINLAND
email: elisa.kallioniemi@kuh.fi
Supervisors: Adjunct Professor Petro Julkunen, Ph.D.
Kuopio University Hospital
Department of Clinical Neurophysiology KUOPIO, FINLAND
University of Eastern Finland Department of Applied Physics KUOPIO, FINLAND
email: petro.julkunen@kuh.fi Laura Säisänen, Ph.D.
University of Eastern Finland Institute of Clinical Medicine KUOPIO, FINLAND Kuopio University Hospital
Department of Clinical Neurophysiology KUOPIO, FINLAND
email: laura.saisanen@kuh.fi
Adjunct Professor Ari Pääkkönen, Ph.D.
Kuopio University Hospital
Department of Clinical Neurophysiology KUOPIO, FINLAND
email: ari.paakkonen@kuh.fi Professor Pasi Karjalainen, Ph.D.
University of Eastern Finland Department of Applied Physics KUOPIO, FINLAND
email: pasi.karjalainen@uef.fi
Reviewers: Professor, Ulf Ziemann, M.D., Ph.D.
Eberhard Karls University Tübingen Department of Neurology and Stroke TÜBINGEN, GERMANY
email: ulf.ziemann@uni-tuebingen.de Associate Professor Angel Peterchev, Ph.D.
Duke University
Department of Psychiatry & Behavioral Sciences Department of Biomedical Engineering
Department of Electrical & Computer Engineering DURHAM, USA
email: angel.peterchev@duke.edu
Opponent: Associate Professor Pedro Michael Cavaleiro de Miranda, Ph.D.
University of Lisbon Faculty of Science LISBON, PORTUGAL email: pcmiranda@fc.ul.pt
ABSTRACT
When evaluating the state of the motor cortex it is essential to understand cortical structure and function. Unfortunately, complex interactions between motor function and cortical structure are still not fully understood. Thus, methods that can assess the cortical state and take account of these interactions are needed.
The overall goal of this thesis was to improve the measurement of the inhibitory state of the motor system and to gain more knowledge on the motor function by using navigated transcranial magnetic stimulation (nTMS). Furthermore, the potential of nTMS for measuring structural features was evaluated. As such, the use of nTMS as a structural tool has not yet been established. The newly developed methods were assessed by comparing the parameters extracted from the nTMS data with those obtained using magnetic resonance imaging.
By applying the silent period threshold measures developed in this thesis, it was found that there was a decrease in the between-subject variability in silent periods reflecting the inhibitory state of the motor cortex. In addition, the characteristics of a previously unrecognized inhibitory motor response, the late silent period, were examined; this will deepen our understanding of the inhibitory system. It was also demonstrated that although the functional areas are commonly mapped using excitatory responses, the inhibitory responses could also provide supplementary information in motor and speech mapping. Finally, a novel anisotropy index (AI) was developed. AI assesses concurrently the structure and function of the motor cortex and it is based on estimating nTMS induced motor responses at different coil angles. AI was found to be well repeatable within and between measuring sessions.
This thesis demonstrated that nTMS can be used to evaluate different aspects of the motor function in a comprehensive manner as well as clarifying the structural features of the motor cortex. These findings and the methods developed in this thesis
Reviewers: Professor, Ulf Ziemann, M.D., Ph.D.
Eberhard Karls University Tübingen Department of Neurology and Stroke TÜBINGEN, GERMANY
email: ulf.ziemann@uni-tuebingen.de Associate Professor Angel Peterchev, Ph.D.
Duke University
Department of Psychiatry & Behavioral Sciences Department of Biomedical Engineering
Department of Electrical & Computer Engineering DURHAM, USA
email: angel.peterchev@duke.edu
Opponent: Associate Professor Pedro Michael Cavaleiro de Miranda, Ph.D.
University of Lisbon Faculty of Science LISBON, PORTUGAL email: pcmiranda@fc.ul.pt
ABSTRACT
When evaluating the state of the motor cortex it is essential to understand cortical structure and function. Unfortunately, complex interactions between motor function and cortical structure are still not fully understood. Thus, methods that can assess the cortical state and take account of these interactions are needed.
The overall goal of this thesis was to improve the measurement of the inhibitory state of the motor system and to gain more knowledge on the motor function by using navigated transcranial magnetic stimulation (nTMS). Furthermore, the potential of nTMS for measuring structural features was evaluated. As such, the use of nTMS as a structural tool has not yet been established. The newly developed methods were assessed by comparing the parameters extracted from the nTMS data with those obtained using magnetic resonance imaging.
By applying the silent period threshold measures developed in this thesis, it was found that there was a decrease in the between-subject variability in silent periods reflecting the inhibitory state of the motor cortex. In addition, the characteristics of a previously unrecognized inhibitory motor response, the late silent period, were examined; this will deepen our understanding of the inhibitory system. It was also demonstrated that although the functional areas are commonly mapped using excitatory responses, the inhibitory responses could also provide supplementary information in motor and speech mapping. Finally, a novel anisotropy index (AI) was developed. AI assesses concurrently the structure and function of the motor cortex and it is based on estimating nTMS induced motor responses at different coil angles. AI was found to be well repeatable within and between measuring sessions.
This thesis demonstrated that nTMS can be used to evaluate different aspects of the motor function in a comprehensive manner as well as clarifying the structural features of the motor cortex. These findings and the methods developed in this thesis
can be used as a basis for novel clinical applications when studying the motor cortical state.
National Library of Medicine Classification: WL 102, WL 141.5M2, WL 141.5.T7, WL 307
Medical Subject Headings: Transcranial Magnetic Stimulation Motor Cortex, Magnetic Resonance Imaging, Neurophysiology, Brain, Anisotropy, Functional Neuroimaging
Yleinen suomalainen asiasanasto: aivokuori, magneettitutkimus, aivot, motoriikka, neurofysiologia
Acknowledgements
The studies included in this thesis were conducted in the Department of Clinical Neurophysiology and in the Department of Clinical Radiology, Kuopio University Hospital during 2012- 2015. In addition, one study was carried out in the Center of Neurosurgery, University of Cologne, Germany in 2014. I would like to thank these departments for giving me the opportunity to conduct my research and to use their research facilities.
I express my deepest gratitude to my supervisors Adjunct Professor Petro Julkunen, Laura Säisänen, Ph.D., Adjunct Professor Ari Pääkkönen, and Professor Pasi Karjalainen for teaching me to become a researcher and providing valuable expertise and encouragement during the studies in this thesis. A very special thanks goes to my primary supervisor Petro. There is a quote by William Arthur Ward saying that “The mediocre teacher tells. The good teacher explains. The superior teacher demonstrates. The great teacher inspires.” For me, Petro has truly been a great teacher and I could not have imagined having a better mentor for my Ph.D. study.
In addition to my official supervisors, I warmly thank Mervi Könönen, Ph.D., who has shared her expertise in neuroimaging, supported me at every step in my research and offered her friendship. It has been a great pleasure to work with her.
I am very grateful to the pre-examiners of this thesis, Professor Ulf Ziemann, and Associate Professor Angel Peterchev for the encouraging words about my thesis. Further, I am grateful to Associate Professor Pedro Miranda, for accepting the role of my opponent at the defence of this thesis and thus being part in one of the most important events of my academic career.
My sincere thanks to my co-authors and collaborators Carolin Weiss Lucas, M.D., Professor Friedemann Awiszus, Adjunct Professor Jari Karhu, Professor Ritva Vanninen, Heidi Gröhn, Ph.D., and Minna Pitkänen, M.Sc., for their contribution in the
can be used as a basis for novel clinical applications when studying the motor cortical state.
National Library of Medicine Classification: WL 102, WL 141.5M2, WL 141.5.T7, WL 307
Medical Subject Headings: Transcranial Magnetic Stimulation Motor Cortex, Magnetic Resonance Imaging, Neurophysiology, Brain, Anisotropy, Functional Neuroimaging
Yleinen suomalainen asiasanasto: aivokuori, magneettitutkimus, aivot, motoriikka, neurofysiologia
Acknowledgements
The studies included in this thesis were conducted in the Department of Clinical Neurophysiology and in the Department of Clinical Radiology, Kuopio University Hospital during 2012- 2015. In addition, one study was carried out in the Center of Neurosurgery, University of Cologne, Germany in 2014. I would like to thank these departments for giving me the opportunity to conduct my research and to use their research facilities.
I express my deepest gratitude to my supervisors Adjunct Professor Petro Julkunen, Laura Säisänen, Ph.D., Adjunct Professor Ari Pääkkönen, and Professor Pasi Karjalainen for teaching me to become a researcher and providing valuable expertise and encouragement during the studies in this thesis. A very special thanks goes to my primary supervisor Petro. There is a quote by William Arthur Ward saying that “The mediocre teacher tells. The good teacher explains. The superior teacher demonstrates. The great teacher inspires.” For me, Petro has truly been a great teacher and I could not have imagined having a better mentor for my Ph.D. study.
In addition to my official supervisors, I warmly thank Mervi Könönen, Ph.D., who has shared her expertise in neuroimaging, supported me at every step in my research and offered her friendship. It has been a great pleasure to work with her.
I am very grateful to the pre-examiners of this thesis, Professor Ulf Ziemann, and Associate Professor Angel Peterchev for the encouraging words about my thesis. Further, I am grateful to Associate Professor Pedro Miranda, for accepting the role of my opponent at the defence of this thesis and thus being part in one of the most important events of my academic career.
My sincere thanks to my co-authors and collaborators Carolin Weiss Lucas, M.D., Professor Friedemann Awiszus, Adjunct Professor Jari Karhu, Professor Ritva Vanninen, Heidi Gröhn, Ph.D., and Minna Pitkänen, M.Sc., for their contribution in the
original publications. Hopefully we still have many fruitful projects ahead of us.
Further, I wish to thank the NBS staff, especially Meri, Sirpa, Taina and JP, who have supported me more than they might even realize and made special arrangements in their schedules to help me conduct TMS measurements.
I want to thank the present and former members of Team Nolla-Nolla, especially Heikki and Tuomas (equal contribution), Matti, Hanna, Alisa, Timo and Salla. You were always very supportive towards my research, listened my worries and provided fun and relaxed atmosphere in our underground office.
I sincerely thank all the volunteers who participated in my research as study subjects and Ewen MacDonald, Ph.D., for language checking this thesis.
Special thanks to all my fellow neuroscientist in research laboratories in Finland and around the world, most importantly Tuomas, Jaakko, Lari, Julio, Selja, Johanna, Kaisu, Silvia, Elyana, Pantelis and Koos for all the friendship and support you have given me. I hope we don’t lose contact in the future although we might be scattered all around the world.
I wish to thank my friends and family, who have always been there for me and been an important part of my non-scientific life.
I heartily thank Jukka and my dogs Iia and Nella. Jukka has been very supportive towards my passion in research, even though sometimes it has meant that I have been very absent minded with some other aspects of my life. Iia and Nella have reminded me of the importance of having fun and are my partners in crime in long afternoon naps and lazy time.
I gratefully acknowledge the funding received towards my Ph.D. from the Doctoral programme in Medical Physics and Engineering at the Department of Applied Physics, The Paulo Foundation, Päivikki ja Sakari Sohlberg Foundation, Radiological Society of Finland, Suomen Neuroradiologit, The Finnish Society of Clinical Neurophysiology, The Finnish Concordia Fund, The Kaute Foundation, The Finnish Brain Research and Rehabilitation Center Neuron, Finnish Foundation for Technology Promotion, Cancer Society of Finland, State Research Funding (project
5041730), Orion-Farmos Research Foundation, Kuopio University Hospital (EVO 5041730 and 5041736), International Doctoral Programme in Biomedical Engineering and Medical Physics, and European Chapter of International Federation of Clinical Neurophysiology.
Finally, I wish to thank Philips for providing the ASL research licence to Kuopio University Hospital.
Kuopio, March 2016 Elisa Kallioniemi
original publications. Hopefully we still have many fruitful projects ahead of us.
Further, I wish to thank the NBS staff, especially Meri, Sirpa, Taina and JP, who have supported me more than they might even realize and made special arrangements in their schedules to help me conduct TMS measurements.
I want to thank the present and former members of Team Nolla-Nolla, especially Heikki and Tuomas (equal contribution), Matti, Hanna, Alisa, Timo and Salla. You were always very supportive towards my research, listened my worries and provided fun and relaxed atmosphere in our underground office.
I sincerely thank all the volunteers who participated in my research as study subjects and Ewen MacDonald, Ph.D., for language checking this thesis.
Special thanks to all my fellow neuroscientist in research laboratories in Finland and around the world, most importantly Tuomas, Jaakko, Lari, Julio, Selja, Johanna, Kaisu, Silvia, Elyana, Pantelis and Koos for all the friendship and support you have given me. I hope we don’t lose contact in the future although we might be scattered all around the world.
I wish to thank my friends and family, who have always been there for me and been an important part of my non-scientific life.
I heartily thank Jukka and my dogs Iia and Nella. Jukka has been very supportive towards my passion in research, even though sometimes it has meant that I have been very absent minded with some other aspects of my life. Iia and Nella have reminded me of the importance of having fun and are my partners in crime in long afternoon naps and lazy time.
I gratefully acknowledge the funding received towards my Ph.D. from the Doctoral programme in Medical Physics and Engineering at the Department of Applied Physics, The Paulo Foundation, Päivikki ja Sakari Sohlberg Foundation, Radiological Society of Finland, Suomen Neuroradiologit, The Finnish Society of Clinical Neurophysiology, The Finnish Concordia Fund, The Kaute Foundation, The Finnish Brain Research and Rehabilitation Center Neuron, Finnish Foundation for Technology Promotion, Cancer Society of Finland, State Research Funding (project
5041730), Orion-Farmos Research Foundation, Kuopio University Hospital (EVO 5041730 and 5041736), International Doctoral Programme in Biomedical Engineering and Medical Physics, and European Chapter of International Federation of Clinical Neurophysiology.
Finally, I wish to thank Philips for providing the ASL research licence to Kuopio University Hospital.
Kuopio, March 2016 Elisa Kallioniemi
LIST OF ABBREVIATIONS
ADM abductor digiti minimi AI anisotropy index
AI105 anisotropy index induced at a stimulation intensity of 105% of the resting motor threshold AI120 anisotropy index induced at a stimulation
intensity of 120% of the resting motor threshold aMT active motor threshold
APB abductor pollicis brevis ASL arterial spin labeling
ASLwiggle arterial spin labeling contrast for finger wiggle BOLD blood-oxygen-level dependent
BOLDsqueeze blood-oxygen-level dependent contrast for hand squeeze
BOLDwiggle blood-oxygen-level dependent contrast for finger wiggle
CoG center of gravity
CR coefficient of repeatability DTI diffusion tensor imaging D wave direct wave
EF electric field
EMG electromyography FA fractional anisotropy FDI first dorsal interosseus
fMRI functional magnetic resonance imaging FWHM full-width at half maximum
GABA gamma-aminobutyric acid ICC intraclass correlation coefficient ISI inter-stimulus interval
I wave indirect wave
LICI long interval intracortical inhibition MEP motor evoked potential
MIT motor inhibition threshold MR magnetic resonance
MRI magnetic resonance imaging MSO maximum stimulator output
LIST OF ABBREVIATIONS
ADM abductor digiti minimi AI anisotropy index
AI105 anisotropy index induced at a stimulation intensity of 105% of the resting motor threshold AI120 anisotropy index induced at a stimulation
intensity of 120% of the resting motor threshold aMT active motor threshold
APB abductor pollicis brevis ASL arterial spin labeling
ASLwiggle arterial spin labeling contrast for finger wiggle BOLD blood-oxygen-level dependent
BOLDsqueeze blood-oxygen-level dependent contrast for hand squeeze
BOLDwiggle blood-oxygen-level dependent contrast for finger wiggle
CoG center of gravity
CR coefficient of repeatability DTI diffusion tensor imaging D wave direct wave
EF electric field
EMG electromyography FA fractional anisotropy FDI first dorsal interosseus
fMRI functional magnetic resonance imaging FWHM full-width at half maximum
GABA gamma-aminobutyric acid ICC intraclass correlation coefficient ISI inter-stimulus interval
I wave indirect wave
LICI long interval intracortical inhibition MEP motor evoked potential
MIT motor inhibition threshold MR magnetic resonance
MRI magnetic resonance imaging MSO maximum stimulator output
MT motor threshold
NMR nuclear magnetic resonance
nTMS navigated transcranial magnetic stimulation rMT resting motor threshold
rMT50 resting motor threshold calculated from the threshold curves
rMTEF resting motor threshold expressed as the induced electric field
rTMS repetitive transcranial magnetic stimulation SICI short interval intracortical inhibition
SP silent period
SPT20 silent period threshold for a silent period duration of 20ms
SPT30 silent period threshold for a silent period duration of 30ms
SPT50 silent period threshold for a silent period duration of 50ms
TMS transcranial magnetic stimulation VOI volume of interest
LIST OF SYMBOLS
B magnetic field strength
B0 external magnetic field strength C TMS coil windings
dl vector along the TMS coil windings γ gyromagnetic ratio
I electric current
Mi t-value in fMRI statistics / MEP amplitude / SP duration at a certain location
M0 net magnetization
Mxy transverse plane to the net magnetization Mx net magnetization in x-direction
My net magnetization in y-direction Mz net magnetization in z-direction µ0 permeability of free space
/r-r’/ distance from the windings to the point where the electric field is calculated
t time / t-value in fMRI statistics T1 longitudinal relaxation time T2 transverse relaxation time
T2* relaxation time component in the presence of magnetic field distortions
xCoG x-coordinate of the CoG
xi x-coordinates (lateral-medial direction) yCoG y-coordinate of the CoG
yi y-coordinates (anterior-posterior direction) ω0 Larmor frequency
zCoG z-coordinate of the CoG
zi z-coordinates (inferior-superior direction)
MT motor threshold
NMR nuclear magnetic resonance
nTMS navigated transcranial magnetic stimulation rMT resting motor threshold
rMT50 resting motor threshold calculated from the threshold curves
rMTEF resting motor threshold expressed as the induced electric field
rTMS repetitive transcranial magnetic stimulation SICI short interval intracortical inhibition
SP silent period
SPT20 silent period threshold for a silent period duration of 20ms
SPT30 silent period threshold for a silent period duration of 30ms
SPT50 silent period threshold for a silent period duration of 50ms
TMS transcranial magnetic stimulation VOI volume of interest
LIST OF SYMBOLS
B magnetic field strength
B0 external magnetic field strength C TMS coil windings
dl vector along the TMS coil windings γ gyromagnetic ratio
I electric current
Mi t-value in fMRI statistics / MEP amplitude / SP duration at a certain location
M0 net magnetization
Mxy transverse plane to the net magnetization Mx net magnetization in x-direction
My net magnetization in y-direction Mz net magnetization in z-direction µ0 permeability of free space
/r-r’/ distance from the windings to the point where the electric field is calculated
t time / t-value in fMRI statistics T1 longitudinal relaxation time T2 transverse relaxation time
T2* relaxation time component in the presence of magnetic field distortions
xCoG x-coordinate of the CoG
xi x-coordinates (lateral-medial direction) yCoG y-coordinate of the CoG
yi y-coordinates (anterior-posterior direction) ω0 Larmor frequency
zCoG z-coordinate of the CoG
zi z-coordinates (inferior-superior direction)
LIST OF ORIGINAL PUBLICATIONS
This thesis is based on data presented in the following articles, referred to by the Roman numerals I-VI.
I Kallioniemi E, Säisänen L, Könönen M, Awiszus F and Julkunen P. On the estimation of silent period thresholds in transcranial magnetic stimulation. Clinical Neurophysiology 125: 2247-2252, 2014.
II *Weiss Lucas C, *Kallioniemi E, Neuschmelting V, Nettekoven C, Reck N, Goldbrunner R, Karhu J, Grefkes C and Julkunen P. Tolerability and inhibitory effects of high- frequency rTMS during speech task: Characteristics and topographic representation of cortical silent periods evoked in facial and jaw muscles. Submitted for publication.
III Kallioniemi E, Pitkänen M, Könönen M, Vanninen R and Julkunen P. Localization of cortical primary motor area of the hand using navigated transcranial magnetic stimulation, BOLD and arterial spin labeling fMRI. Submitted for publication.
IV Kallioniemi E, Säisänen L, Pitkänen M, Könönen M, Karhu J and Julkunen P. Input-output characteristics of late corticospinal silent period induced by transcranial magnetic stimulation. Journal of Clinical Neurophysiology 32:346-351, 2015.
V Kallioniemi E, Könönen M, Säisänen L, Gröhn H and Julkunen P. Functional neuronal anisotropy assessed with neuronavigated transcranial magnetic stimulation. Journal of Neuroscience Methods 256:82-90, 2015.
VI Kallioniemi E, Könönen M and Julkunen P. Repeatability of functional anisotropy in navigated transcranial magnetic
LIST OF ORIGINAL PUBLICATIONS
This thesis is based on data presented in the following articles, referred to by the Roman numerals I-VI.
I Kallioniemi E, Säisänen L, Könönen M, Awiszus F and Julkunen P. On the estimation of silent period thresholds in transcranial magnetic stimulation. Clinical Neurophysiology 125: 2247-2252, 2014.
II *Weiss Lucas C, *Kallioniemi E, Neuschmelting V, Nettekoven C, Reck N, Goldbrunner R, Karhu J, Grefkes C and Julkunen P. Tolerability and inhibitory effects of high- frequency rTMS during speech task: Characteristics and topographic representation of cortical silent periods evoked in facial and jaw muscles. Submitted for publication.
III Kallioniemi E, Pitkänen M, Könönen M, Vanninen R and Julkunen P. Localization of cortical primary motor area of the hand using navigated transcranial magnetic stimulation, BOLD and arterial spin labeling fMRI. Submitted for publication.
IV Kallioniemi E, Säisänen L, Pitkänen M, Könönen M, Karhu J and Julkunen P. Input-output characteristics of late corticospinal silent period induced by transcranial magnetic stimulation. Journal of Clinical Neurophysiology 32:346-351, 2015.
V Kallioniemi E, Könönen M, Säisänen L, Gröhn H and Julkunen P. Functional neuronal anisotropy assessed with neuronavigated transcranial magnetic stimulation. Journal of Neuroscience Methods 256:82-90, 2015.
VI Kallioniemi E, Könönen M and Julkunen P. Repeatability of functional anisotropy in navigated transcranial magnetic
stimulation – coil-orientation versus response. NeuroReport 26:515-521, 2015.
*Carolin Weiss Lucas and Elisa Kallioniemi contributed equally to this study.
This thesis also contains some unpublished data.
AUTHOR’S CONTRIBUTION
I The author designed the study with the co-authors, conducted the measurements with the second and last author, did the data analyses, interpreted the results with the co- authors, and prepared the manuscript.
II The author conducted the data analyses, interpreted the results with co-authors, and prepared the manuscript with C.
Weiss Lucas.
III The author designed the study with the co-authors, conducted the measurements and analyses, interpreted the results with the co-authors, and prepared the manuscript.
IV The author designed the study with the co-authors, conducted the measurements with the second and the last author, conducted the majority of the data analyses, interpreted the results with the co-authors, and prepared the manuscript.
V The author designed the study with the co-authors, conducted the measurements with the third and the last author, did the data analyses and interpreted the results with the co-authors, and prepared the manuscript.
VI The author designed the study with the co-authors, conducted the measurements and data analyses, interpreted the results with the co-authors, and prepared the manuscript.
stimulation – coil-orientation versus response. NeuroReport 26:515-521, 2015.
*Carolin Weiss Lucas and Elisa Kallioniemi contributed equally to this study.
This thesis also contains some unpublished data.
AUTHOR’S CONTRIBUTION
I The author designed the study with the co-authors, conducted the measurements with the second and last author, did the data analyses, interpreted the results with the co- authors, and prepared the manuscript.
II The author conducted the data analyses, interpreted the results with co-authors, and prepared the manuscript with C.
Weiss Lucas.
III The author designed the study with the co-authors, conducted the measurements and analyses, interpreted the results with the co-authors, and prepared the manuscript.
IV The author designed the study with the co-authors, conducted the measurements with the second and the last author, conducted the majority of the data analyses, interpreted the results with the co-authors, and prepared the manuscript.
V The author designed the study with the co-authors, conducted the measurements with the third and the last author, did the data analyses and interpreted the results with the co-authors, and prepared the manuscript.
VI The author designed the study with the co-authors, conducted the measurements and data analyses, interpreted the results with the co-authors, and prepared the manuscript.
Contents
Acknowledgements ... 7
1 Introduction ... 23
2 Structure and function of the cortical motor areas ... 25
2.1 Motor cortex and cortical layers ... 25
2.2 Blood circulation and vasculature ... 27
2.3 Balance of excitation and inhibition ... 29
2.4 Motor function impairment ... 29
3 Transcranial magnetic stimulation ... 31
3.1 Principles ... 31
3.2 Stimulation coils ... 32
3.3 Waveforms ... 33
3.4 Pulse sequences ... 34
3.5 Navigated transcranial magnetic stimulation ... 34
3.6 Physiological basis ... 36
3.6.1 Motor evoked potential ... 38
3.6.2 Silent period ... 39
3.6.3 Motor threshold ... 40
4 Magnetic resonance imaging ... 41
4.1 Principles ... 41
4.2 Diffusion tensor imaging ... 43
4.3 Functional magnetic resonance imaging ... 44
4.3.1 Blood-oxygen-level dependent ... 44
4.3.2 Arterial spin labeling ... 46
5 Aims of the thesis ... 49
6 Methods ... 51
6.1 Subjects ... 51
6.2 Devices and data acquisition ... 52
Contents
Acknowledgements ... 7
1 Introduction ... 23
2 Structure and function of the cortical motor areas ... 25
2.1 Motor cortex and cortical layers ... 25
2.2 Blood circulation and vasculature ... 27
2.3 Balance of excitation and inhibition ... 29
2.4 Motor function impairment ... 29
3 Transcranial magnetic stimulation ... 31
3.1 Principles ... 31
3.2 Stimulation coils ... 32
3.3 Waveforms ... 33
3.4 Pulse sequences ... 34
3.5 Navigated transcranial magnetic stimulation ... 34
3.6 Physiological basis ... 36
3.6.1 Motor evoked potential ... 38
3.6.2 Silent period ... 39
3.6.3 Motor threshold ... 40
4 Magnetic resonance imaging ... 41
4.1 Principles ... 41
4.2 Diffusion tensor imaging ... 43
4.3 Functional magnetic resonance imaging ... 44
4.3.1 Blood-oxygen-level dependent ... 44
4.3.2 Arterial spin labeling ... 46
5 Aims of the thesis ... 49
6 Methods ... 51
6.1 Subjects ... 51
6.2 Devices and data acquisition ... 52
6.2.1 Magnetic resonance imaging ... 52 6.2.2 Navigated transcranial magnetic stimulation ... 52 6.2.3 Electromyography ... 52 6.3 Measurements ... 53 6.3.1 Locating the cortical motor representation with nTMS ... 53 6.3.2 Determining motor threshold ... 54 6.3.3 Silent period thresholds and late silent period (Studies I and IV) ... 55 6.3.4 Silent period during a speech task (Study II) ... 55 6.3.5 Motor mapping with nTMS and fMRI (Study III) ... 56 6.3.6 Anisotropy index (Studies V and VI) ... 56 6.4 Data analyses ... 57 6.4.1 Pre-processing the electromyography ... 57 6.4.2 Study I ... 57 6.4.3 Study II ... 58 6.4.4 Study III ... 58 6.4.5 Study IV... 59 6.4.6 Studies V and VI ... 60 6.5 Statistical analyses ... 61 6.5.1 Study I ... 61 6.5.2 Study II ... 61 6.5.3 Study III ... 62 6.5.4 Study IV... 62 6.5.5 Study V ... 62 6.5.6 Study VI... 62 6.6 Ethical considerations ... 63 7 Results ... 65 7.1 Silent period thresholds (Study I) ... 65 7.1.1 Threshold curves and calculated thresholds ... 65 7.1.2 Between-subject variability in SP duration ... 66 7.2 Silent period during a speech task (Study II) ... 67 7.2.1 Resting motor threshold and motor inhibition threshold ... 67 7.2.2 Silent period characteristics ... 68 7.2.3 Tolerability of different speech mapping protocols ... 69 7.3 Motor mapping with nTMS and fMRI (Study III)... 69 7.3.1 Motor representations mapped with different methods ... 69
7.4 Late silent period (Study IV) ... 71 7.5 Anisotropy index (Studies V and VI) ... 72 7.5.1 MEP-amplitude–coil angle curves and AI ... 72 7.5.2 Cortical excitability and fractional anisotropy ... 72 7.5.3 Comparison between biphasic and monophasic waveforms ... 73 7.5.4 Influence of applied smoothing window on AI ... 74 7.5.5 Repeatability of AI and coil angle ... 75 8 Discussion ... 77 8.1 Silent period thresholds ... 77 8.2 Late silent period ... 79 8.3 Silent period during speech mapping... 81 8.4 Motor mapping with nTMS and fMRI ... 82 8.5 Anisotropy index ... 83 8.6 Future considerations ... 86 9 Summary and conclusions ... 89 10 References ... 91
6.2.1 Magnetic resonance imaging ... 52 6.2.2 Navigated transcranial magnetic stimulation ... 52 6.2.3 Electromyography ... 52 6.3 Measurements ... 53 6.3.1 Locating the cortical motor representation with nTMS ... 53 6.3.2 Determining motor threshold ... 54 6.3.3 Silent period thresholds and late silent period (Studies I and IV) ... 55 6.3.4 Silent period during a speech task (Study II) ... 55 6.3.5 Motor mapping with nTMS and fMRI (Study III) ... 56 6.3.6 Anisotropy index (Studies V and VI) ... 56 6.4 Data analyses ... 57 6.4.1 Pre-processing the electromyography ... 57 6.4.2 Study I ... 57 6.4.3 Study II ... 58 6.4.4 Study III ... 58 6.4.5 Study IV... 59 6.4.6 Studies V and VI ... 60 6.5 Statistical analyses ... 61 6.5.1 Study I ... 61 6.5.2 Study II ... 61 6.5.3 Study III ... 62 6.5.4 Study IV... 62 6.5.5 Study V ... 62 6.5.6 Study VI... 62 6.6 Ethical considerations ... 63 7 Results ... 65 7.1 Silent period thresholds (Study I) ... 65 7.1.1 Threshold curves and calculated thresholds ... 65 7.1.2 Between-subject variability in SP duration ... 66 7.2 Silent period during a speech task (Study II) ... 67 7.2.1 Resting motor threshold and motor inhibition threshold ... 67 7.2.2 Silent period characteristics ... 68 7.2.3 Tolerability of different speech mapping protocols ... 69 7.3 Motor mapping with nTMS and fMRI (Study III)... 69 7.3.1 Motor representations mapped with different methods ... 69
7.4 Late silent period (Study IV) ... 71 7.5 Anisotropy index (Studies V and VI) ... 72 7.5.1 MEP-amplitude–coil angle curves and AI ... 72 7.5.2 Cortical excitability and fractional anisotropy ... 72 7.5.3 Comparison between biphasic and monophasic waveforms ... 73 7.5.4 Influence of applied smoothing window on AI ... 74 7.5.5 Repeatability of AI and coil angle ... 75 8 Discussion ... 77 8.1 Silent period thresholds ... 77 8.2 Late silent period ... 79 8.3 Silent period during speech mapping... 81 8.4 Motor mapping with nTMS and fMRI ... 82 8.5 Anisotropy index ... 83 8.6 Future considerations ... 86 9 Summary and conclusions ... 89 10 References ... 91
1 Introduction
Navigated transcranial magnetic stimulation (nTMS) is a non- invasive brain stimulation method [1] suitable for evaluating the cortical neurophysiology and characteristics of motor pathways [2–10]. nTMS is widely used as a pre-surgical tool in the evaluation of functional motor cortical representations [11–16]
and it has several applications in rehabilitative therapy of neuronal disorders and brain traumas [17–20]. nTMS can also be applied to study the characteristics of the excitatory and the inhibitory motor systems separately [21–24]. The interrelation between these systems constitutes the basis for the operation of a healthy brain [8, 25].
The use of nTMS to study subtle variations in the excitatory motor system has been relatively well standardized and it is now an accepted part of diagnostics [2, 25, 26], but the clinical applications related to the inhibitory system have been limited [27]. This poor exploitation of the nTMS induced inhibitory responses stems from the fact that no consensus exists on how to measure reliably the inhibitory state, which makes it difficult to interpret and to compare the results between studies.
The nTMS evoked neural responses, both excitatory and inhibitory, are highly dependent on the direction of the induced current with respect to the stimulated neuronal structure [7, 28–
33]. Thus, in addition to detecting functional characteristics, nTMS could at least in theory, measure structural features from the stimulated neuronal area. The use of nTMS for this purpose, however, has not progressed very far, although some studies have found a relationship between the nTMS evoked responses and the underlying neuronal microstructure [34]. These results, however, could not be confirmed in subsequent studies [35–37].
Several neurological disorders and brain traumas induce variations in the functional state of the neurons and disturb the excitatory-inhibitory equilibrium in the cortex [38–43]. These
1 Introduction
Navigated transcranial magnetic stimulation (nTMS) is a non- invasive brain stimulation method [1] suitable for evaluating the cortical neurophysiology and characteristics of motor pathways [2–10]. nTMS is widely used as a pre-surgical tool in the evaluation of functional motor cortical representations [11–16]
and it has several applications in rehabilitative therapy of neuronal disorders and brain traumas [17–20]. nTMS can also be applied to study the characteristics of the excitatory and the inhibitory motor systems separately [21–24]. The interrelation between these systems constitutes the basis for the operation of a healthy brain [8, 25].
The use of nTMS to study subtle variations in the excitatory motor system has been relatively well standardized and it is now an accepted part of diagnostics [2, 25, 26], but the clinical applications related to the inhibitory system have been limited [27]. This poor exploitation of the nTMS induced inhibitory responses stems from the fact that no consensus exists on how to measure reliably the inhibitory state, which makes it difficult to interpret and to compare the results between studies.
The nTMS evoked neural responses, both excitatory and inhibitory, are highly dependent on the direction of the induced current with respect to the stimulated neuronal structure [7, 28–
33]. Thus, in addition to detecting functional characteristics, nTMS could at least in theory, measure structural features from the stimulated neuronal area. The use of nTMS for this purpose, however, has not progressed very far, although some studies have found a relationship between the nTMS evoked responses and the underlying neuronal microstructure [34]. These results, however, could not be confirmed in subsequent studies [35–37].
Several neurological disorders and brain traumas induce variations in the functional state of the neurons and disturb the excitatory-inhibitory equilibrium in the cortex [38–43]. These
Kallioniemi E: Function and structure of the motor cortex assessed with navigated TMS and MRI
complex functional changes may be accompanied by structural changes in the affected brain area [44–47]. It is important to clarify the interactions between cortical excitation and inhibition in order to develop clinically feasible methods, to create prognostic measures, and to individualize rehabilitative therapies.
Furthermore, knowledge on how the functional states interact with the neuronal structure would provide a wider perspective in understanding the symptoms and effects of neural diseases affecting the motor function.
This thesis was undertaken to broaden and enhance the applicability of nTMS to study motor cortical neurophysiology by applying the aforementioned principles of nTMS. The following sections will provide the necessary background, study-specific aims and methods, in order that the main results can be understood and discussed.
2 Structure and function of the cortical motor areas
2.1 MOTOR CORTEX AND CORTICAL LAYERS
The motor areas are located near the central sulcus and include primary motor cortex, supplementary motor cortex, premotor cortex and posterior parietal cortex [48]. Of these, the primary motor cortex is situated in the precentral gyrus. This cortical site is responsible for the execution of motor functions and includes the muscle representations (Fig. 2.1) [48, 49]. The primary motor cortex can be considered as the most fundamental motor area.
The supplementary motor cortex contributes to the control of movements, and the premotor and the posterior parietal cortices take part in planning movements, although they also have other functions [48, 49]. In addition to these cortical areas, motor functions are controlled to some extent by the prefrontal cortex [48, 50] and other non-cortical brain regions, such as basal ganglia and thalamus, the cerebellum and the areas connecting the brain with the spinal cord [51].
The primary motor cortex consists mainly of excitatory pyramidal neurons and inhibitory interneurons [52–57]. The role of the pyramidal neurons is to operate as primary excitatory units and they can alter their receptive fields rapidly as a function of the behavioural state and previous activities [58]. In contrast, the interneurons regulate the function of the pyramidal neurons [53, 59, 60]. In the motor cortex, the gamma-aminobutyric acid (GABA) interneurons are considered to be the most important inhibitory elements [60–62].
Kallioniemi E: Function and structure of the motor cortex assessed with navigated TMS and MRI
complex functional changes may be accompanied by structural changes in the affected brain area [44–47]. It is important to clarify the interactions between cortical excitation and inhibition in order to develop clinically feasible methods, to create prognostic measures, and to individualize rehabilitative therapies.
Furthermore, knowledge on how the functional states interact with the neuronal structure would provide a wider perspective in understanding the symptoms and effects of neural diseases affecting the motor function.
This thesis was undertaken to broaden and enhance the applicability of nTMS to study motor cortical neurophysiology by applying the aforementioned principles of nTMS. The following sections will provide the necessary background, study-specific aims and methods, in order that the main results can be understood and discussed.
2 Structure and function of the cortical motor areas
2.1 MOTOR CORTEX AND CORTICAL LAYERS
The motor areas are located near the central sulcus and include primary motor cortex, supplementary motor cortex, premotor cortex and posterior parietal cortex [48]. Of these, the primary motor cortex is situated in the precentral gyrus. This cortical site is responsible for the execution of motor functions and includes the muscle representations (Fig. 2.1) [48, 49]. The primary motor cortex can be considered as the most fundamental motor area.
The supplementary motor cortex contributes to the control of movements, and the premotor and the posterior parietal cortices take part in planning movements, although they also have other functions [48, 49]. In addition to these cortical areas, motor functions are controlled to some extent by the prefrontal cortex [48, 50] and other non-cortical brain regions, such as basal ganglia and thalamus, the cerebellum and the areas connecting the brain with the spinal cord [51].
The primary motor cortex consists mainly of excitatory pyramidal neurons and inhibitory interneurons [52–57]. The role of the pyramidal neurons is to operate as primary excitatory units and they can alter their receptive fields rapidly as a function of the behavioural state and previous activities [58]. In contrast, the interneurons regulate the function of the pyramidal neurons [53, 59, 60]. In the motor cortex, the gamma-aminobutyric acid (GABA) interneurons are considered to be the most important inhibitory elements [60–62].
Kallioniemi E: Function and structure of the motor cortex assessed with navigated TMS and MRI
Figure 2.1. The primary motor cortex is situated in the precentral gyrus. The functional muscle representations are located according to a certain order in the primary motor cortex, in which the leg and hand representations are more medial than the facial muscle representations. Furthermore, two motor tracts leave the primary motor cortex, i.e. the corticospinal tract and the corticobulbar tract.
The cerebral cortex generally comprises of six distinct layers numbered from superficial to deep (Fig. 2.2). Layer IV, however, is absent in the motor cortex [63]. From the existing layers, layer I contains only a few neurons whereas layers II and III include excitatory pyramidal neurons which are connected to large pyramidal tract neurons, also called the Betz cells, in layer V [63, 64]. The lowermost cortical layer, layer VI, has mainly small spindle-like pyramidal neurons and multiform neurons, and only a few large pyramidal neurons [63, 65]. The axons leaving from layer VI terminate in other cortical areas and in thalamus [63, 65].
The large pyramidal cells in layer V are the upper motor neurons in the corticospinal and the corticobulbar tracts. The axons of the pyramidal cells descend to brainstem through the internal capsule and cerebral peduncle. From the brainstem, the corticospinal tract continues to the spinal cord and synapses with the lower motor neurons controlling the movement of the torso, as well as the upper and lower limbs. In addition to axons originating from the primary motor cortex, the corticospinal tract also receives axons from the premotor and sensory cortex. The corticobulbar tract axons, in contrast, descend only to brainstem and synapse there with the lower motor neurons of the cranial nerves. They are involved in controlling, for example, the facial musculature. Overall, the motor function is organized in such a
Structure and function of the cortical motor areas
way that the left hemisphere controls the movements of the right- hand side and vice versa. [48, 49]
Figure 2.2. The motor cortex is composed of five distinct layers, namely I, II, III, V and VI. Layer I contains only a few neurons and layer II and III include small excitatory pyramidal neurons. Large excitatory pyramidal neurons are mainly located in layer V and only a few are situated in layer VI. The inhibitory interneurons controlling the excitatory neurons are intermingled among the pyramidal neurons.
2.2BLOOD CIRCULATION AND VASCULATURE
In order that the brain can function properly, the neurons require a constant flow of glucose and oxygen. The neurons differ from other body cells in that they will not survive for long without oxygen and a lack of oxygenized blood may result in necrosis (infarct) of neural tissue. The oxygen and glucose are distributed to the brain via the vascular system (Fig. 2.3) in which the oxygen is bound to hemoglobin molecules. The blood enters the brain through the internal carotid arteries and the vertebral arteries.
From these sites, the blood moves through the small arterioles to even smaller capillaries within the neural tissue in which the oxygen is extracted from the hemoglobin. The deoxygenated hemoglobin carries waste carbon dioxide resulting from the
Kallioniemi E: Function and structure of the motor cortex assessed with navigated TMS and MRI
Figure 2.1. The primary motor cortex is situated in the precentral gyrus. The functional muscle representations are located according to a certain order in the primary motor cortex, in which the leg and hand representations are more medial than the facial muscle representations. Furthermore, two motor tracts leave the primary motor cortex, i.e. the corticospinal tract and the corticobulbar tract.
The cerebral cortex generally comprises of six distinct layers numbered from superficial to deep (Fig. 2.2). Layer IV, however, is absent in the motor cortex [63]. From the existing layers, layer I contains only a few neurons whereas layers II and III include excitatory pyramidal neurons which are connected to large pyramidal tract neurons, also called the Betz cells, in layer V [63, 64]. The lowermost cortical layer, layer VI, has mainly small spindle-like pyramidal neurons and multiform neurons, and only a few large pyramidal neurons [63, 65]. The axons leaving from layer VI terminate in other cortical areas and in thalamus [63, 65].
The large pyramidal cells in layer V are the upper motor neurons in the corticospinal and the corticobulbar tracts. The axons of the pyramidal cells descend to brainstem through the internal capsule and cerebral peduncle. From the brainstem, the corticospinal tract continues to the spinal cord and synapses with the lower motor neurons controlling the movement of the torso, as well as the upper and lower limbs. In addition to axons originating from the primary motor cortex, the corticospinal tract also receives axons from the premotor and sensory cortex. The corticobulbar tract axons, in contrast, descend only to brainstem and synapse there with the lower motor neurons of the cranial nerves. They are involved in controlling, for example, the facial musculature. Overall, the motor function is organized in such a
Structure and function of the cortical motor areas
way that the left hemisphere controls the movements of the right- hand side and vice versa. [48, 49]
Figure 2.2. The motor cortex is composed of five distinct layers, namely I, II, III, V and VI. Layer I contains only a few neurons and layer II and III include small excitatory pyramidal neurons. Large excitatory pyramidal neurons are mainly located in layer V and only a few are situated in layer VI. The inhibitory interneurons controlling the excitatory neurons are intermingled among the pyramidal neurons.
2.2BLOOD CIRCULATION AND VASCULATURE
In order that the brain can function properly, the neurons require a constant flow of glucose and oxygen. The neurons differ from other body cells in that they will not survive for long without oxygen and a lack of oxygenized blood may result in necrosis (infarct) of neural tissue. The oxygen and glucose are distributed to the brain via the vascular system (Fig. 2.3) in which the oxygen is bound to hemoglobin molecules. The blood enters the brain through the internal carotid arteries and the vertebral arteries.
From these sites, the blood moves through the small arterioles to even smaller capillaries within the neural tissue in which the oxygen is extracted from the hemoglobin. The deoxygenated hemoglobin carries waste carbon dioxide resulting from the
Kallioniemi E: Function and structure of the motor cortex assessed with navigated TMS and MRI
breakdown of glucose from capillaries into small venules which drain into the large veins and exit the brain. [66, 67]
The cortex receives its blood supply via the meningeal arteries that pass through the pia matter on the surface of the cortex and branch into small arterioles [68]. The vascularization of the subcortical white matter structures is substantially less dense than those of cortical grey matter [66]. Furthermore, the vascular density is not consistent across the cortical layers, but clearly denser vascularization exists in those layers with higher concentration of neurons [66].
Figure 2.3. The vasculature system of the brain visualized with magnetic resonance imaging. The system comprises of arteries bringing blood into the brain and of veins transporting blood out of the brain. In the figure, only the largest arteries and veins are visible.
Although the blood volume entering the brain is relatively constant over time, neuronal activity induces alterations in local blood flow and thus, in the local concentrations of oxygen and glucose [66]. When neural activity is initiated, it triggers the blood vessels to dilate [66]. This relationship between neural activity and the vascular system is called neurovascular coupling [66].
There is a short time delay before the vessels are able to dilate to meet the increased demand [66]. Due to this delay, the concentration of deoxygenated hemoglobin in the veins increases at first for a brief period, which is followed by an over- compensation in blood flow of oxygenated hemoglobin [66].
Hence, the so-called hemodynamic response caused by the neural activity is delayed [69–71]. After the initiation, the hemodynamic response reaches a maximum 5–8s after the onset and finally returns to baseline after about 10s from the maximum [71, 72].
Structure and function of the cortical motor areas
2.3BALANCE OF EXCITATION AND INHIBITION
The balance between excitation and inhibition relates to the specific contributions of excitatory and inhibitory synaptic inputs to neural activity. In a healthy brain, excitation is commonly followed by inhibition after a brief delay and the amount of inhibition generated is proportional to the level of excitation. In the motor cortex, this leads to a rather stable ratio between excitation and inhibition in different motor actions over time. The cooperation between excitation and inhibition permits the gradual recruitment of firing neurons, enabling fine-tuning of the neural activity. Furthermore, the counterbalanced inhibition restrains the temporal and spatial spread of neuronal activity, and plays a major role in neuronal plasticity. Neural plasticity describes the ability of neurons to reorganize with respect to function and structure in response to external changes. [73–76]
2.4 MOTOR FUNCTION IMPAIRMENT
In a dynamic structure such as the brain, even a slight imbalance in network functions, for example a sudden brain trauma, may produce severe disturbances of information flow, behaviour and neural structure. These changes may impair the motor function either permanently or temporarily and generate muscle weakness, spasticity, loss of sensation, lack of muscle control, or even a total paralysis [49, 77]. These disturbances may lead to functional or structural reorganization of the motor areas [15, 78], an imbalance between the excitatory and inhibitory systems [39–
41, 79–81], limited neural plasticity [82] or disturbed blood flow [83, 84]. These perturbations may further be associated with different neurological or neuropsychiatric diseases [85–87].
Kallioniemi E: Function and structure of the motor cortex assessed with navigated TMS and MRI
breakdown of glucose from capillaries into small venules which drain into the large veins and exit the brain. [66, 67]
The cortex receives its blood supply via the meningeal arteries that pass through the pia matter on the surface of the cortex and branch into small arterioles [68]. The vascularization of the subcortical white matter structures is substantially less dense than those of cortical grey matter [66]. Furthermore, the vascular density is not consistent across the cortical layers, but clearly denser vascularization exists in those layers with higher concentration of neurons [66].
Figure 2.3. The vasculature system of the brain visualized with magnetic resonance imaging. The system comprises of arteries bringing blood into the brain and of veins transporting blood out of the brain. In the figure, only the largest arteries and veins are visible.
Although the blood volume entering the brain is relatively constant over time, neuronal activity induces alterations in local blood flow and thus, in the local concentrations of oxygen and glucose [66]. When neural activity is initiated, it triggers the blood vessels to dilate [66]. This relationship between neural activity and the vascular system is called neurovascular coupling [66].
There is a short time delay before the vessels are able to dilate to meet the increased demand [66]. Due to this delay, the concentration of deoxygenated hemoglobin in the veins increases at first for a brief period, which is followed by an over- compensation in blood flow of oxygenated hemoglobin [66].
Hence, the so-called hemodynamic response caused by the neural activity is delayed [69–71]. After the initiation, the hemodynamic response reaches a maximum 5–8s after the onset and finally returns to baseline after about 10s from the maximum [71, 72].
Structure and function of the cortical motor areas
2.3BALANCE OF EXCITATION AND INHIBITION
The balance between excitation and inhibition relates to the specific contributions of excitatory and inhibitory synaptic inputs to neural activity. In a healthy brain, excitation is commonly followed by inhibition after a brief delay and the amount of inhibition generated is proportional to the level of excitation. In the motor cortex, this leads to a rather stable ratio between excitation and inhibition in different motor actions over time. The cooperation between excitation and inhibition permits the gradual recruitment of firing neurons, enabling fine-tuning of the neural activity. Furthermore, the counterbalanced inhibition restrains the temporal and spatial spread of neuronal activity, and plays a major role in neuronal plasticity. Neural plasticity describes the ability of neurons to reorganize with respect to function and structure in response to external changes. [73–76]
2.4 MOTOR FUNCTION IMPAIRMENT
In a dynamic structure such as the brain, even a slight imbalance in network functions, for example a sudden brain trauma, may produce severe disturbances of information flow, behaviour and neural structure. These changes may impair the motor function either permanently or temporarily and generate muscle weakness, spasticity, loss of sensation, lack of muscle control, or even a total paralysis [49, 77]. These disturbances may lead to functional or structural reorganization of the motor areas [15, 78], an imbalance between the excitatory and inhibitory systems [39–
41, 79–81], limited neural plasticity [82] or disturbed blood flow [83, 84]. These perturbations may further be associated with different neurological or neuropsychiatric diseases [85–87].
Kallioniemi E: Function and structure of the motor cortex assessed with navigated TMS and MRI
3 Transcranial magnetic stimulation
3.1 PRINCIPLES
Transcranial magnetic stimulation (TMS) is a brain stimulation technique that can be applied to modulate neural tissue in a non- invasive manner. TMS is based on the principles of electromagnetic induction discovered by Faraday already in 1831. In 1985, Barker et al. [1] introduced the method as it is currently used. TMS is suitable for application in the primary motor cortex, since the effects of stimulation can be readily and objectively quantified through the TMS evoked muscle responses [2, 4–6, 27].
The stimulating pulse in TMS is generated by applying a brief pulse of electric current to a coil [28] placed on the head above the cortical target area. The current in the coil produces an orthogonal magnetic field [88, 89] which penetrates the skull and induces a transient electric field (EF) on the cortex [28]. The magnetic field itself has no direct effect on neural tissue, it is the induced EF that is the factor which actually activates the neurons in TMS [28]. The penetrating depth of the pulse is limited, and thus TMS mainly stimulates cortical structures rather than subcortical white matter [90]. The induced EF in the cortex follows the Faraday’s law:
∇ × 𝑬𝑬𝑬𝑬 = −𝜕𝜕𝑩𝑩(𝑡𝑡)𝜕𝜕𝑡𝑡 , (3.1)
where t is the time and B is the magnetic field generated by the TMS coil which can be calculated using the Biot–Savart law:
