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Biosystems & Biorobotics

Winnie Jensen
Ole Kæseler Andersen
Metin Akay Editors

Replace, Repair,
Restore, Relieve –
Bridging Clinical and
Engineering Solutions
in Neurorehabilitation
Proceedings of the 2nd International Conference
on NeuroRehabilitation (ICNR2014),
Aalborg, 24–26 June, 2014
Biosystems & Biorobotics

Volume 7

Series editor
Eugenio Guglielmelli, Campus Bio-Medico University of Rome, Rome, Italy
e-mail: [email protected]

Editorial Board
Dino Accoto, Campus Bio-Medico University of Rome, Rome, Italy
Sunil Agrawal, University of Delaware, Newark DE, USA
Fabio Babiloni, Sapienza University of Rome, Rome, Italy
Jose M. Carmena, University of California, Berkeley CA, USA
Maria Chiara Carrozza, Scuola Superiore Sant’Anna, Pisa, Italy
Paolo Dario, Scuola Superiore Sant’Anna, Pisa, Italy
Arturo Forner-Cordero, University of Sao Paolo, São Paulo, Brazil
Masakatsu G. Fujie, Waseda University, Tokyo, Japan
Nicolas Garcia, Miguel Hernández University of Elche, Elche, Spain
Neville Hogan, Massachusetts Institute of Technology, Cambridge MA, USA
Hermano Igo Krebs, Massachusetts Institute of Technology, Cambridge MA, USA
Dirk Lefeber, Vrije Universiteit Brussel, Brussels, Belgium
Rui Loureiro, Middlesex University, London, UK
Marko Munih, University of Ljubljana, Ljubljana, Slovenia
Paolo M. Rossini, University Cattolica del Sacro Cuore, Rome, Italy
Atsuo Takanishi, Waseda University, Tokyo, Japan
Russell H. Taylor, The Johns Hopkins University, Baltimore, MD, USA
David A. Weitz, Harvard University, Cambridge MA, USA
Loredana Zollo, Campus Bio-Medico University of Rome, Rome, Italy

For further volumes:

http://www.springer.com/series/10421
Aims & Scope

Biosystems & Biorobotics publishes the latest research developments in three main areas:
1) understanding biological systems from a bioengineering point of view, i.e. the study of
biosystems by exploiting engineering methods and tools to unveil their functioning principles
and unrivalled performance; 2) design and development of biologically inspired machines
and systems to be used for different purposes and in a variety of application contexts. The
series welcomes contributions on novel design approaches, methods and tools as well as
case studies on specific bioinspired systems; 3) design and developments of nano-, micro-,
macro- devices and systems for biomedical applications, i.e. technologies that can improve
modern healthcare and welfare by enabling novel solutions for prevention, diagnosis, surgery,
prosthetics, rehabilitation and independent living.
On one side, the series focuses on recent methods and technologies which allow multi-
scale, multi-physics, high-resolution analysis and modeling of biological systems. A special
emphasis on this side is given to the use of mechatronic and robotic systems as a tool for
basic research in biology. On the other side, the series authoritatively reports on current theo-
retical and experimental challenges and developments related to the “biomechatronic” design
of novel biorobotic machines. A special emphasis on this side is given to human-machine
interaction and interfacing, and also to the ethical and social implications of this emerging
research area, as key challenges for the acceptability and sustainability of biorobotics tech-
nology.
The main target of the series are engineers interested in biology and medicine, and specif-
ically bioengineers and bioroboticists. Volume published in the series comprise monographs,
edited volumes, lecture notes, as well as selected conference proceedings and PhD theses.
The series also publishes books purposely devoted to support education in bioengineering,
biomedical engineering, biomechatronics and biorobotics at graduate and post-graduate lev-
els.

About the Cover

The cover of the book series Biosystems & Biorobotics features a robotic hand prosthesis.
This looks like a natural hand and is ready to be implanted on a human amputee to help them
recover their physical capabilities. This picture was chosen to represent a variety of concepts
and disciplines: from the understanding of biological systems to biomechatronics, bioinspira-
tion and biomimetics; and from the concept of human-robot and human-machine interaction
to the use of robots and, more generally, of engineering techniques for biological research and
in healthcare. The picture also points to the social impact of bioengineering research and to its
potential for improving human health and the quality of life of all individuals, including those
with special needs. The picture was taken during the LIFEHAND experimental trials run at
Università Campus Bio-Medico of Rome (Italy) in 2008. The LIFEHAND project tested the
ability of an amputee patient to control the Cyberhand, a robotic prosthesis developed at
Scuola Superiore Sant’Anna in Pisa (Italy), using the tf-LIFE electrodes developed at the
Fraunhofer Institute for Biomedical Engineering (IBMT, Germany), which were implanted
in the patient’s arm. The implanted tf-LIFE electrodes were shown to enable bidirectional
communication (from brain to hand and vice versa) between the brain and the Cyberhand. As
a result, the patient was able to control complex movements of the prosthesis, while receiving
sensory feedback in the form of direct neurostimulation. For more information please visit
http://www.biorobotics.it or contact the Series Editor.
Winnie Jensen · Ole Kæseler Andersen
Metin Akay
Editors

Replace, Repair, Restore,

Relieve – Bridging Clinical
and Engineering Solutions
in Neurorehabilitation
Proceedings of the 2nd International
Conference on NeuroRehabilitation
(ICNR2014), Aalborg, 24–26 June, 2014

ABC
Editors
Winnie Jensen Metin Akay
Center for Sensory-Motor Interaction Biomedical Engineering Department
Aalborg University University of Houston
Aalborg Houston Texas
Denmark USA

Ole Kæseler Andersen

Center for Sensory-Motor Interaction
Aalborg University
Aalborg
Denmark

ISSN 2195-3562 ISSN 2195-3570 (electronic)

ISBN 978-3-319-08071-0 ISBN 978-3-319-08072-7 (eBook)
DOI 10.1007/978-3-319-08072-7
Springer Cham Heidelberg New York Dordrecht London

Library of Congress Control Number: 2014942266

c Springer International Publishing Switzerland 2014

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
While the advice and information in this book are believed to be true and accurate at the date of pub-
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errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect
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Springer is part of Springer Science+Business Media (www.springer.com)

Preface

Replace, Repair, Restore, Relieve – Bridging Clinical and Engineering Solutions in

Neurorehabilitation
Neural rehabilitation engineering is an emerging interdisciplinary research area
that aims to bridge neuroscience and engineering methods, and the present book fo-
cuses on developing novel solutions and therapies for people suffering from various
motor disabilities. Despite neural engineering is a relatively new research area, the
field is rapidly developing. This development requires continuously updated mate-
rial available for the increasing number of researchers and students in neural reha-
bilitation engineering.
The 2nd International Conference on NeuroRehabilitation took place on 24th -
th
26 June 2014 in Aalborg, Denmark, with participation of rehabilitation medicine
specialists, engineers, physiotherapists, exercise physiologists, neurophysiologists,
and other professionals involved in neuromuscular rehabilitation research.
The main themes of the conference were; neurorehabilitation applications and so-
lutions to restore or repair impaired neurological functions, techniques and methods
in neurorehabilitation, and translational challenges in neurorehabilitation. In addi-
tion, the conference hosted a commercially oriented track with emphasis on bringing
cutting-edge innovative technologies and research in neurorehabilitation from bench
to bedside.
This book contains the original conference contributions presented and discussed
at the conference.
The book is organized in four parts related to the main activities of the confer-
ence; 1) Plenary lectures, 2) Special sessions covering a range of specific topics
within neurorehabilitation, 3) Regular conference contributions, and 4) Innovation
session contributions. Each of the contribution parts are placed in alphabetical order
by the surname of the first author.
VI Preface

We would like to thank the scientific program committee for their invaluable
help to review the enclosed material and assist in securing high quality manuscripts.
We believe that this book presents the state-of-the-art within neurorehabilitation
research, and we do hope that many students and young researchers will find inspi-
ration within these pages.

Winnie Jensen
Ole Kæseler Andersen
Metin Akay
Contents

Keynote Papers
Role of Cortical Reorganization in the Rehabilitation of Chronic
Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Herta Flor
Induction of Cortical Plasticity: Clinical Applications . . . . . . . . . . . . . . . . 3
Min-Fang Kuo, Walter Paulus, Michael A. Nitsche
Miniaturized Neural Interfaces and Implants in Neurological
Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Thomas Stieglitz
Neuroprosthetics: Past, Present and Future . . . . . . . . . . . . . . . . . . . . . . . . . 15
Nitish V. Thakor

Special-Session Papers
Neuroplasticity in Constraint-Induced Movement Therapy . . . . . . . . . . . 23
Jakob Udby Blicher, Jamie Near, Erhard Næss-Schmidt, Leif Østergaard,
Heidi Johansen-Berg, Charlotte J. Stagg, Jørgen Feldbæk Nielsen,
Yi-Ching Lynn Ho
Advanced Prosthetic Control in Transhumeral Amputees Using
Osseointegration and Bidirectional Neuromuscular Interfaces . . . . . . . . . 25
Rickard Brånemark
The Control of Interlimb Coordination during Left-Right and
Transverse Split-Belt Locomotion in Intact and Spinal Cord-Injured
Cats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Alain Frigon, Yann Thibaudier, Marie-France Hurteau,
Alessandro Telonio, Charline Dambreville, Victoria Kuczynski
VIII Contents

Chiropractic Alters TMS Induced Motor Neuronal Excitability:

Preliminary Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Heidi Haavik, Imran Khan Niazi, Jens Duehr, Mat Kinget,
Paulius Ugincius, Oğuz Sebik, Gizem Yılmaz, Kemal S. Türker
Strength and Motor Function after Arm Training with an Exoskeleton
Robot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Verena Klamroth-Marganska, Georg Rauter, Robert Riener
Tongue Motor Training – Behavioral and Neurophysiological
Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
M. Kothari, P. Svensson, J. Jensen, A. Kjaersgaard, L. Baad-Hansen,
Jørgen Feldbæk Nielsen
Functional Electrical Stimulation, Clinical Perspective
and Implications for Future Neurorehabilitation . . . . . . . . . . . . . . . . . . . . 49
P.T. Birgit Larsen
Fully Implantable Multichannel EMG Measurement System:
First Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Sören Lewis, Michael Russold, Marie Hahn, Oskar C. Aszmann

Does Computerized Cognitive Rehabilitation Generalize? . . . . . . . . . . . . . 61

Jonas Lindeløv
Clinical Rationale and Guidelines for Rehabilitation at Home . . . . . . . . . 63
Andreas Luft
The Learning Benefits of Haptic Guidance Are Age-Dependent . . . . . . . . 65
Laura Marchal-Crespo, Mark van Raai, Georg Rauter, Peter Wolf,
Robert Riener
Robot Supported Gait Rehabilitation: Clinical Needs, Current State
of the Art and Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Zlatko Matjačić, Andrej Olenšek, Matjaž Zadravec
Spinal Cord Stimulation: Background and Clinical Application . . . . . . . . 81
Kaare Meier
Clinical Evaluation of Training System for Recovery of Motor
Function after Stroke in Patients with Hemiplegia . . . . . . . . . . . . . . . . . . . 83
Yoshifumi Morita, Noritaka Sato, Hiroyuki Ukai, Hirofumi Tanabe,
Toru Nagao, Rumi Tanemura, Yoshiaki Takagi, Yoshitaka Aoki
Exotendon Glove System for Finger Rehabilitation after Stroke . . . . . . . . 93
Shunji Moromugi, Toshio Higashi, Ryo Ishikawa, Seiya Kudo, Naoki Iso,
Shirou Ooso, Takeaki Shirotani, Murray J. Lawn, Takakazu Ishimatsu
Contents IX

Stretch Reflex Conditioning in Humans – Implications for Function . . . . 103

Natalie Mrachacz-Kersting, Priscila de Brito Silva, Yukiko Makihara,
Lars Arendt-Nielsen, Thomas Sinkjær, Uwe G. Kersting
The Role of Spinal Manipulation in Modulating Neuroplasticity
and Sensorimotor Integration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Bernadette Murphy, Heidi Haavik
Mathematical Modeling in Neuromodulation for Pain Relief . . . . . . . . . . 117
Carsten Dahl Mørch
Chiropractic, Cortical Excitability and BCI . . . . . . . . . . . . . . . . . . . . . . . . 121
Imran Khan Niazi, Mads Jochumsen, Jens Duehra, Mat Kingett,
Kim Dremstrup, Heidi Haavik
Abstract: Technical Device for Measurement of Spasticity, Developed
for Bedside Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Tue Hvass Petersen
Game Engines and Exergames to Guide Rehabilitation at Home . . . . . . . 129
Michele Pirovano, Renato Mainetti, Pier Luca Lanzi,
Nunzio Alberto Borghese
Mechanism of Spinal Cord and Peripheral Nerve Stimulation:
More than the Gate Control Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Louis Vera-Portocarrero
Lokomat: Clinical Training and Experience in a Neurorehabiltation
Hospital . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Christian Gunge Riberholt

CORBYS Project Overview: Approach and Achieved Results . . . . . . . . . 139

Danijela Ristić-Durrant, Siniša Slavnić, Cornelius Glackin
Rehabilitation Robot in Primary Walking Pattern Training for SCI
Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Taisuke Sakaki, Nobuhiro Ushimi, Koji Murakami,
Yong-Kwun Lee, Kazuhiro Tsuruta, Kanta Aoki, Kaoru Fujiie,
Ryuji Katamoto, Atsushi Sugyo, Yoshimitsu Kihara, Kenji Tateishi
Effect of Transcranial and Spinal Direct Current Stimulation on
Gait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Giorgio Sandrini, C. Mondino
Adaptive Behavior of the Spinal Cord in the Transition from Quiet
Stance to Walking: The Use of Widthrawal Reflexes to Support Gait
Initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Mariano Serrao
X Contents

Using Painful Sensory Stimulation to Improve the Hemiparetic Gait . . . . 165

Erika Geraldina Spaich, Ole Kæseler Andersen
Advanced Rehabilitation for Amputees after Selective Nerve
Transfers: EMG-Guided Training and Testing . . . . . . . . . . . . . . . . . . . . . . 169
Agnes Sturma, Peter Göbel, Malvina Herceg, Nan Gee, Aidan Roche,
Veronika Fialka-Moser, Oskar C. Aszmann
Learning to Change a Reflex to Improve Locomotion . . . . . . . . . . . . . . . . 179
Aiko K. Thompson
Advances in Robotic Gait Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Herman van der Kooij, Edwin H.F. van Asseldonk, Bram Koopman,
Gijs van Oort, Jos Meuleman, H. Carsten van Voort, S.M. Behrens
Assessing of Motor Performance in Stroke Using Body Worn Sensing . . . 191
Fokke B. van Meulen, Jasper Reenalda, Peter H. Veltink
Improving Interlimb Coordination Following Stroke: How Can We
Change How People Walk (and Why Should We)? . . . . . . . . . . . . . . . . . . . 195
Erin V. Vasudevan, Eileen M. Kirk
Exoskeletons Supporting Postural Balance – The BALANCE Project . . . 203
Jan F. Veneman
Spinal Reflex Conditioning: Mechanisms and Implications . . . . . . . . . . . . 209
Jonathan R. Wolpaw
Neuromechanical Interlimb Interactions and Rehabilitation of
Walking after Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
E. Paul Zehr, Trevor S. Barss, Chelsea Kaupp, Taryn Klarner,
Rinaldo A. Mezzarane, Tsuyoshi Nakajima, Yao Sun,
Tomoyoshi Komiyama

Conference Papers
Feature and Channel Selection Using Correlation Based Method for
Hand Posture Classification in Multiple Arm Positions . . . . . . . . . . . . . . . 227
Haitham M. Al-Angari, Gunter Kanitz, Sergio Tarantino, Jacopo Rigosa,
Christian Cipriani
Detection of Movement Intention from Movement-Related Cortical
Potentials with Different Paradigms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Susan Aliakbaryhosseinabadi, Ning Jiang, Aleksandra Vuckovic,
Romulus Lontis, Kim Dremstrup, Dario Farina,
Natalie Mrachacz-Kersting
Contents XI

Muscle Synergy Features in Behavior Adaptation and Recovery . . . . . . . 245

Fady S. Alnajjar, Vincent Berenz, Ozaki Ken-ichi, Kensuke Ohno,
Hitoshi Yamada, Izumi Kondo, Shingo Shimoda
Human Cutaneous Reflexes Evoked with Simultaneous Multiple
Nerve Stimulation during Rhythmic Locomotor-Like Arm and Leg
Cycling in Stroke Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Ole Kæseler Andersen, Marc Klimstra, Evan Thomas,
Pamela M. Loadman, Sandra R. Hundza, E. Paul Zehr
Towards Establishing Clinical Guidelines for an Arm Rehabilitation
Virtual Reality System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Philippe S. Archambault, Nahid Gheidari Norouzi, Dahlia Kairy,
John M. Solomon, Mindy F. Levin
Modulatory Effect on Spinal and Supraspinal Responses during
Cognitive Attentional and Distraction Tasks . . . . . . . . . . . . . . . . . . . . . . . . 271
Federico Gabriel Arguissain, José Alberto Biurrun Manresa,
Carsten Dahl Mørch, Ole Kæseler Andersen
Equivalent Bilateral Early Latency Cutaneous Reflex Amplitudes
during Graded Contractions in Right Handers . . . . . . . . . . . . . . . . . . . . . . 279
Trevor S. Barss, Taryn Klarner, E. Paul Zehr
The Use of Ecological Sounds in Facilitation of Tool Use in Apraxia . . . . 289
Marta M.N. Bieńkiewicz, Philipp Gulde, Andrea Schlegel,
Joachim Hermsdörfer
Longitudinal Estimation of Intramuscular Tibialis Anterior
Coherence during Subacute Spinal Cord Injury: Relationship with
Neurophysiological, Clinical and Functional Measures . . . . . . . . . . . . . . . 295
Elisabeth Bravo-Esteban, Julian Taylor, Manuel Aleixandre,
Cristina Simon-Martínez, Diego Torricelli, José Luis Pons,
Julio Gómez-Soriano
Online Intramuscular EMG Decomposition with Varying Number of
Active Motor Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
Eric Le Carpentier, Yannick Aoustin, Jonathan Monsifrot, Dario Farina

Inter-session Reliability of Robot-Measured Parameters for the

Evaluation of Upper Limb Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Ivana Cusmano, Roberto Colombo, Irma Sterpi, Alessandra Mazzone,
Carmen Delconte, Fabrizio Pisano
Reducing the False Positives Rate in a BCI System to Detect
Error-Related EEG Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Álvaro Costa, Enrique Hortal, Andrés Úbeda, Eduardo Iáñez,
José María Azorín
XII Contents

A Tool to Address Movement Quality Outcomes of Post-stroke

Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Vincent Crocher, Justin Fong, Marlena Klaic, Denny Oetomo, Ying Tan
Characterization of a Dual PID-ILC FES Controller for FES-Robot
Control of Swing Phase of Walking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Antonio J. del-Ama, Ángel Gil-Agudo, José Luis Pons, Juan C. Moreno
Physiological Recruitment of Large Populations of Motor Units Using
Electrical Stimulation of Afferent Pathways . . . . . . . . . . . . . . . . . . . . . . . . 351
Jakob Lund Dideriksen, Silvia Muceli, Strahinja Dosen, Dario Farina
Extending a Dynamic Muscle Model for Usage with Amputees . . . . . . . . . 361
Stefan Erber, Markus Schachinger, Thomas Mandl, Peter Michael Goebel
Measuring the Effectiveness of an Intensive Rehabilitation Treatment
on Balance Parameters in Patients with Parkinson’s Disease through
a Stabilometric Platform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Davide Ferrazzoli, Rossana Bera, Roberto Maestri, Gloria Perini,
Letizia Spina, Roberto Gargantini, Gianni Pezzoli, Giuseppe Frazzitta
Detection of Common Synaptic Inputs Shared by Populations of
Motor Neurons Innervating Different Muscles: Methodology and
Considerations for Neuroprosthetic Treatment of Tremor . . . . . . . . . . . . . 373
Juan Álvaro Gallego, Jakob Lund Dideriksen, Ales Holobar,
Juan Pablo Romero, Julián Benito-León, Félix Bermejo-Pareja,
José Luis Pons, Eduardo Rocon, Dario Farina
A Novel Robot-Aided Therapy for Shoulder Rehabilitation after
Stroke: Active-Assisted Control of the RehaArm Robot Using
Electromyographic Signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Clara Genna, Strahinja Dosen, Liliana Paredes, Andrea Turolla,
Bernhard Graimann, Dario Farina
Analysis of Eye Movements, Kinematics and Dynamic Aspects of
Performance during Activities of Daily Living in Stroke Patients . . . . . . . 393
Philipp Gulde, Charmayne Hughes, Manish Parekh, Martin Russel,
Manuel Ferre, Alan Wing, Marta M.N. Bieńkiewicz, Joachim Hermsdörfer

Historical Background from 1986 – 2005 for the Development of the

ActiGait System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
Jens Peter Haase, Morten Haugland, Thomas Sinkjær
Impact of Problem Solving Therapy on Brain Networks Associated
with Depressive Symptoms in Poststroke Older Adults . . . . . . . . . . . . . . . 405
Niloufar Niakosari Hadidi, Leah Jappe, Kathryn Cullen, Kay Savik
Contents XIII

Improved Detection and Force Decoding through Combined

Near-Infrared Spectroscopy and Electroencephalographic
Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
Mia H. Hansen, Eric Kassebaum, Marlena A. Plocharska,
Mads Jochumsen, Ernest N. Kamavuako
Modeling the Functional Dependence of Stroke Patients:
The Outcome of an Improved Gait Training . . . . . . . . . . . . . . . . . . . . . . . . 421
Kristian Hennings, Sabata Gervasio, Ole Kæseler Andersen,
Erika Geraldina Spaich
Startling Acoustic Stimuli Elicit Rapid Hand Extension Following
Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Claire F. Honeycutt, Ursina A. Tresch, Eric J. Perreault
Detection of the Onset of Voluntary Movements Based on the
Combination of ERD and BP Cortical Patterns . . . . . . . . . . . . . . . . . . . . . 437
Jaime Ibáñez, J. Ignacio Serrano, M. Dolores del Castillo,
Esther Monge, Francisco Molina, Francisco Rivas, Isabela Alguacil,
J. Miangolarra-Page, José Luis Pons
Flexible Thread-like Electrical Stimulation Implants Based on
Rectification of Epidermically Applied Currents Which Perform
Charge Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Antoni Ivorra, Laura Becerra-Fajardo
High-Frequency Oscillations in Chemically Induced Spike-and-Wave
Epileptic Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
Jianhang Jiao, Cristian Sevcencu, Kristian Rauhe Harreby, Winnie Jensen
Detection of Movement Intentions through a Single Channel of
Electroencephalography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Mads Jochumsen, Imran Khan Niazi, Helene Rovsing,
Cecilie Rovsing, Gebbie A.R. Nielsen, Tina K. Andersen, Nhung P.T. Dong,
Marina E. Sørensen, Natalie Mrachacz-Kersting, Ning Jiang,
Dario Farina, Kim Dremstrup
A Standard Low-Cost Worldwide Accessible Nintendo Wii Balance
Test Can Differentiate Older Fallers from Non-fallers . . . . . . . . . . . . . . . . 473
Martin G. Jørgensen, Nicolas B. Hansen, Alberto L.R. Perez,
Erika Geraldina Spaich
Reliability of Multiple Baseline Measures for Locomotor Retraining
after Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Taryn Klarner, Trevor S. Barss, Yao Sun, Chelsea Kaupp, Simone Beattie,
E. Paul Zehr
XIV Contents

Continuous Monitoring of Respiration during Rehabilitation . . . . . . . . . . 487

Marketa Kotova, Ludek Zalud, Jana Kolarova, Petr Dobsak
The Effects of Neuromuscular Electrical Stimulation on
Corticomuscular Coherence in Patients with Stroke . . . . . . . . . . . . . . . . . . 493
Meei-I Lai, Li-Ling Pan, Chung-Lan Kao, Mei-Wun Tsai, Shun-Hwa Wei,
Li-Wei Chou
Exercising the Tibialis Anterior Muscle of Children with Cerebral
Palsy for Improved Neuroplasticity Using an Electrical Guitar . . . . . . . . . 501
Jeppe V. Larsen, Thomas B. Moeslund, Dan Overholt
Feedback Strategies for BCI Based Stroke Rehabilitation: Evaluation
of Different Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
Alexander Lechner, Rupert Ortner, Christoph Guger
A System for Real-Time Estimation of Joint Torque with Evoked
EMG under Electrical Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
Zhan Li, Mitsuhiro Hayashibe, David Andreu, David Guiraud
Wheelchair Control with the Tip of the Tongue . . . . . . . . . . . . . . . . . . . . . 521
Eugen Romulus Lontis, Bo Bentsen, Michael Gaihede,
Lotte N.S. Andreasen Struijk
Information on Ankle Angle from Intramuscular EMG Signals
during Development of Muscle Fatigue in an Open-Loop Functional
Electrical Stimulation System in Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
Line E. Lykholt, Sahana Ganeswarathas, Anil K. Thota,
Kristian Rauhe Harreby, Ranu Jung
Frailty Assessment Based on Trunk Accelerometry during Walking . . . . 537
Ion Martinikorena, Alicia Martínez-Ramírez, Pablo Lecumberri,
Nora Millor, Marisol Gómez, Mikel Izquierdo
Increasing Voltage Transients Using Implanted Titanium Nitride
Neural Stimulation Electrodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
Suzan Meijs, Morten Fjorback, Søren Sørensen, Kristian Rechendorff,
Nico J.M. Rijkhoff
Frailty Detection Using the Instrumented Version of the 30-s Chair
Stand Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
Nora Millor, Pablo Lecumberri, Marisol Gómez, Alicia Martínez-Ramírez,
Mikel Izquierdo
Contents XV

An EMG Pattern Comparison of Exoskeleton vs. End-Effector

Robotic Device for Assisted Walking Training . . . . . . . . . . . . . . . . . . . . . . . 563
Giovanni Morone, Marco Iosa, Federica Tamburella, Luca Muzzioli,
Iolanda Pisotta, Juan C. Moreno, José Luis Pons, Stefano Paolucci,
Febo Cincotti, Marco Molinari
Effectiveness of Robotic Assisted Walking Therapy: The Role of Age
and Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
Giovanni Morone, Marco Iosa, Franco Marinozzi, Erika D’Antonio,
Patrizia Poli, Stefano Masiero, Marco Molinari, Stefano Paolucci
Cortical Contribution to Crossed Reflexes in Walking Humans . . . . . . . . 575
Natalie Mrachacz-Kersting, Sabata Gervasio, Dario Farina,
Thomas Sinkjær
On Electrode Configuration for Low-Back Peripheral Nerve Field
Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
Carsten Dahl Mørch, Louis Vera-Portocarrero, Ken Steffen Frahm
Novel Approach for Investigation of Neuronal Alterations Following
Ischemic Stroke in a Rat Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
Rasmus Kragh Nielsen, Winnie Jensen
Modular Control of Gait in Incomplete Spinal Cord Injury:
Preliminary Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
Soraya Pérez-Nombela, Filipe Barroso, Diego Torricelli,
Julio Gómez Soriano, Ana de los Reyes-Guzmán,
Antonio J. del-Ama, José Luis Pons, Ángel Gil-Agudo
EEG-Based Classification of Imagined Arm Trajectories . . . . . . . . . . . . . 611
Patrick Ofner, Gernot R. Müller-Putz
Investigate the Changes of Motor Unit Recruitment Pattern after
Stroke Using Surface EMG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Pan Li-Ling, Lai Meei-I, Kao Chung-Lan, Tsai Mei-Wun, Wei Shun-Hwa,
Chou Li-Wei
Using Human-Computer Interface for Rehabilitation of Activities
of Daily Living (ADL) in Stroke Patients: Lessons from the First
Prototype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
Johannes Pflügler, Andrea Schlegel, Emilie Jean-Baptiste,
Pia Rotshtein, Matteo Pastorino, Javier Rojo, Jose Maria Cogollor,
Maria Teresa Arredondo, Marta M.N. Bieńkiewicz, Joachim Hermsdörfer
Evaluation of a New Exoskeleton for Upper Limb Post-stroke
Neuro-rehabilitation: Preliminary Results . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Elvira Pirondini, Martina Coscia, Simone Marcheschi, Gianluca Roas,
Fabio Salsedo, Antonio Frisoli, Massimo Bergamasco, Silvestro Micera
XVI Contents

Experimental Architecture to Analyse Brain Signals during Walking . . . 647

Daniel Planelles, Álvaro Costa, Andrés Úbeda, Eduardo Iáñez,
José María Azorín
Processing EEG Signals to Detect Intention of Upper Limb
Movement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
Daniel Planelles, Enrique Hortal, Eduardo Iáñez, Álvaro Costa,
José María Azorín
Preliminary Findings of Feasibility and Compliance of
Technology-Supported Distal Arm Training at Home after
Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
Gerdienke B. Prange, Sharon M. Nijenhuis, Patrizio Sale, Alfredo Cesario,
Nasrin Nasr, Gail Mountain, Farshid Amirabdollahian, Jaap H. Buurke
Exploring Relations between Functional Task Kinematics and Clinical
Assessment of Arm Function and Dexterity Post-stroke . . . . . . . . . . . . . . . 675
Gerdienke B. Prange, Sharon M. Nijenhuis, Stefanie M. Kersten,
Arno H.A. Stienen, J.S. Rietman
A Combined Interfascicular-Cuff Electrode (ICE) for Selective
Recruitment of Polyfascicular Peripheral Nerves Using Transversal
Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
Alessandro Ranieri, Rasmus Elbæk Andersen, Mette Vandborg Lauridsen,
Kristian Rauhe Harreby
Integration of Neurodynamics into Neurorehabilitation . . . . . . . . . . . . . . 695
Carlos Rodríguez-López, Bibiana Da Rocha-Souto, Nora Kern
Movement Related Cortical Potentials and Sensory Motor Rhythms
during Self Initiated and Cued Movements . . . . . . . . . . . . . . . . . . . . . . . . . 701
Andrej Savić, Romulus Lontis, Ning Jiang, Mirjana Popović,
Dario Farina, Kim Dremstrup, Natalie Mrachacz-Kersting
Use of Dynamic Movement Orthoses as Rehabilitative Method to
Improve Gait Stability in Ataxic Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
Mariano Serrao, Alberto Ranavolo, Carlo Casali, Silvia Mari,
Carmela Conte, Francesco Draicchio, Giorgio Sandrini,
Francesco Pierelli
A Blood Pressure-Related Profile Extracted from Pig Left Vagus
Nerves Using Cuff Electrodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
Cristian Sevcencu, Thomas Nørgaard Nielsen, Johannes J. Struijk
Patient Satisfaction of Using the ActiGaitR
Drop Foot Stimulator
System and Effect of Treatment on Walking . . . . . . . . . . . . . . . . . . . . . . . . 725
Kaare Severinsen, Kurt Grey, Anne Juhl, Preben Soerensen, L. Oppel,
P.T. Birgit Larsen
Contents XVII

Augmentative and Assistive Communication in Patients of Locked-In

Syndrome: A Case Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
F.A. Purva Sharma, S.B. Yash Jobanputra
Validation and Test of a Closed-Loop Tele-rehabilitation System
Based on Functional Electrical Stimulation and Computer Vision for
Analysing Facial Expressions in Stroke Patients . . . . . . . . . . . . . . . . . . . . . 741
Daniel Simonsen, Ramin Irani, Kamal Nasrollahi, John Hansen,
Erika Geraldina Spaich, Thomas B. Moeslund, Ole Kæseler Andersen
Gait Orthosis Lokomat Combined with Functional Electrical
Stimulation for Foot Drop Correction: A Feasibility Study . . . . . . . . . . . . 751
Erika Geraldina Spaich, Mette F. Bøg, Ema Erkocevic, Anne Smidstrup,
Ole Kæseler Andersen, Jørgen Feldbæk Nielsen
Learning Effect of the Nintendo Wii Agility Test in
Community-Dwelling Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759
Erika Geraldina Spaich, Nicolas B. Hansen, Alberto L.R. Perez,
Martin G. Jørgensen
Functionality of the Contralateral Biceps Femoris Reflex Response
during Human Walking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Andrew J.T. Stevenson, Svend S. Geertsen, Thomas Sinkjær,
Jens B. Nielsen, Natalie Mrachacz-Kersting
Rehabilitation Following Targeted Muscle Reinnervation in
Amputees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
Agnes Sturma, Malvina Herceg, Birgit Bischof, Veronika Fialka-Moser,
Oskar C. Aszmann
Centre of Pressure Assessment in Subjects with Incomplete
Spinal Cord Injury: Preliminary Data of Reliability, Validity and
Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
Federica Tamburella, Giorgio Scivoletto, Marco Iosa, Marco Molinari
A Functional Muscle Synergy for Forward Reaching . . . . . . . . . . . . . . . . . 789
Denise Taylor, J. Greg Anson
A Brain-Machine Interface Architecture to Control an Upper Limb
Rehabilitation Exoskeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
Andrés Úbeda, Daniel Planelles, Enrique Hortal, Francisco Resquín,
Aikaterini D. Koutsou, José María Azorín, José Luis Pons
Transcranial Direct Current Stimulation Enhances Propulsion during
Walking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
Edwin H.F. van Asseldonk
XVIII Contents

Design of a Subject-Specific EMG Model for Rehabilitation

Movement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813
Michele Vivian, Luca Tagliapietra, Monica Reggiani, Dario Farina,
Massimo Sartori
A Pilot Study on Clinical and Neurological Effects of Neurofeedback
Training for Treatment of Central Neuropathic Pain . . . . . . . . . . . . . . . . . 823
Aleksandra Vuckovic, Muhammad A. Hasan, Matthew Fraser,
Bernie Conway, David B. Allan
Parametrization of an Exoskeleton for Robotic Stroke Rehabilitation . . . 833
Patrick Weiss, Georg Männel, Thomas Münte, Achim Schweikard,
Erik Maehle
Pelvic Support Mechanism for Training Dynamic Balancing and
Turning during Treadmill-Based Walking: A Pilot Study . . . . . . . . . . . . . 845
Matjaž Zadravec, Andrej Olenšek, Zlatko Matjačić

Innovation Session Papers

Feature Extraction APP for Pain Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . 853
Shellie A. Boudreau, Richard Spence, Georgi Vasov, Line L. Egsgaard

Marsi Bionics’ Wearable Exoskeletons for the Daily Rehabilitation of

Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
Elena Garcia, Nacho Barraque
A Poly-fascicular, In Vitro Nerve Model for Development and
Optimization of Peripheral Nerve Interfaces . . . . . . . . . . . . . . . . . . . . . . . . 859
Kristian Rauhe Harreby
Control of Robotic and Prosthetic Arms Using an Inductive Tongue
Control System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
Daniel Johansen, Dejan B. Popovic, Lotte N.S. Andreasen Struijk
A New Device for Measuring Body Part Movements and Stretches . . . . . 867
Michael Skovdal Rathleff, Line Rode, Ole Simonsen
Smattress: A Smart Mattress Providing an Active Unobstructive
Bedding System Based on Musculoskeletal Modeling . . . . . . . . . . . . . . . . . 869
Afshin Samani
Kinect-Based Tele-rehabilitation System for Hand Function . . . . . . . . . . . 871
Daniel Simonsen, John Hansen, Erika Geraldina Spaich,
Ole Kæseler Andersen
A New Method to Diagnose Neuromuscular Disorders in the
Neck-Shoulder Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873
Steffen Vangsgaard, Ernst Albin Hansen, Pascal Madeleine
Contents XIX

Eir Innovation Sessions

How to Turn an Idea into a Commercial Success . . . . . . . . . . . . . . . . . . . . 877
Peter Mørch Eriksen
Industrial Perspectives on Innovation within Neurorehabilitation
between Private and Public Partners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
Bernhard Graimann
Reflex-Based Electrical Therapy: A Novel Method for Gait
Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
Kristian Hennings
The MedTech Industry at a Glance: Solving Tomorrow’s Healthcare
Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
Louise Feilberg
Transferring Rehabilitation Technology to Markets: Lessons Learned
in the Past Ten Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885
Zlatko Matjačić
Translational Research on Tongue Control Interface . . . . . . . . . . . . . . . . . 887
Gert Spender, Lotte N.S. Andreasen Struijk

Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889

Role of Cortical Reorganization in the
Rehabilitation of Chronic Pain

Herta Flor

Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health,

Medical Faculty Mannheim, Heidelberg University,
Mannheim, Germany

The role of cortical plasticity has been in focus for years as the target for
efficient rehabilitation. But how large a role does it play? And how is it most
efficiently targeted to obtain lasting changes. What are the neural mechanisms
and when is the most optimal time window after an injury to the nervous
system. What is the role of sensory feedback to the deafferented brain and is
multisensory input more efficient. These questions will be addressed mainly
from the perspective of chronic pain, but these findings may also be
interesting for other areas of rehabilitation.
Neuroscientific evidence has shown that the adult brain is plastic into high age
even in areas that were formerly thought to be hard-wired after an early
adaptive phase. Injury but also stimulation and learning, including social
factors, thus modify the maps in the sensorimotor areas but also lead to changes
in centers involved in the processing of emotion, motivation and cognition. Two
developments have greatly enhanced the interest in brain-based rehabilitation
methods in the area of chronic pain. First, it was shown that changes in the
representation of body maps in the brain are highly related to both the
intensity and the chronicity of chronic pain, both, injury-related neuropathic
and stimulation-related musculoskeletal pain. Second, there is accumulation
evidence that the representation of the body can modify pain perception. Thus,
that there are great similarities between phantom perceptions and bodily
illusions such as the rabbit or the rubber hand illusions and other body-related
somatosensory phenomena such as supernumerary limbs or out of body feelings.
This research has also shown that the brain does not process the physical but the
perceived reality, which opens the door to manipulations of the perceived reality,
for example via brain computer interfaces or virtual reality applications, in both
research on the basis of these phenomena as well as neurorehabilitation.

W. Jensen et al. (eds.), Replace, Repair, Restore, Relieve – Bridging Clinical 1

and Engineering Solutions in Neurorehabilitation, Biosystems & Biorobotics 7,
DOI: 10.1007/978-3-319-08072-7_1, © Springer International Publishing Switzerland 2014
2 H. Flor

Cortical plasticity related to chronic pain can thus be modified by

behavioral interventions that provide feedback to the brain areas that were
altered in a maladaptive manner. Interventions include behavioral extinction,
mirror training, sensory discrimination and prosthesis training. More recent
advances include training in augmented and virtual reality, prostheses with
sensory feedback as well as neurostimulation and neurofeedback applications. In
many instances preventive measures can be taken, e.g. in the pre- and
postoperative phases of a surgical intervention. In addition, pharmacological
interventions designed to alter neuroplasticity can be used alone or in
conjunction with training methods. Detailed studies comparing the efficacy of
these interventions are still lacking but we can provide some initial
evaluations on useful interventions and combinations as well as the optimal
modes of application, much of it derived from extinction learning theory. We
also need better biomarkers and predictors of treatment outcome.
These approaches open new avenues for both the prevention and treatment
of chronicity and physical impairment.

References
Flor, H.: Psychological pain interventions and neurophysiology: Implications for a
mechanism-based approach. American Psychologist 69, 188–196 (2014)
Moseley, G.L., Flor, H.: Targeting cortical representations in the treatment of chronic pain
– rationale and current state of the art. Neurorehabilitation and Neural Repair 26, 646–
652 (2012)
Flor, H., Turk, D.C.: Chronic pain. An integrated biobehavioral approach. IASP Press,
Seattle (2011)
Induction of Cortical Plasticity: Clinical
Applications

Min-Fang Kuo, Walter Paulus, and Michael A. Nitsche

University Medical Center, Dept. Clinical Neurophysiology,

Georg-August-University, Robert-Koch-Str. 40, 37099 Goettingen, Germany
[email protected]

Abstract. Many neurological diseases are associated with adaptations of

cortical plasticity, trying to compensate for functional loss. Transcranial
stimulation techniques allow to up- or downregulate excitability of cortical
areas. Thus the more focal and close to surface cortical deficits are the more
prone they are to transcranially induced induction of cortical excitability. A
summary of possibilities will be given using rehabilitation of stroke induced
dexterity loss and aphasia as examples.

Motor Function

Both repetitive Transcranial Magnetic Stimulation (rTMS) or Transcranial

Direct Current Stimulation (tDCS) can enhance activation of the
dysfunctional or reduce activation of the healthy hemisphere(Nitsche and
Paulus, 2000) and therefore re- establish a closer to normal interhemispheric
balance. In chronic subcortical stroke patients, one session of anodal
excitability-enhancing tDCS over the primary motor cortex of the lesioned
hemisphere can improve fine motor skills of the upper limb, as tested by the
Jebson-Taylor task, during, and also for some time after stimulation
(Hummel et al., 2005), confirmed by applying excitability-diminishing cathodal
tDCS of the contralateral non-lesioned motor cortex (Fregni et al., 2005).
The same procedure, a single session of cathodal tDCS of the unaffected
hemisphere, facilitated motor learning of the paretic hand in chronic stroke
patients (Zimerman et al., 2012). Pinch force, performance of simple
reaction time tasks, and selective muscle contraction can also be improved by
anodal tDCS of the affected or cathodal stimulation of the unaffected motor
cortex (Hummel and Cohen, 2006, Hesse et al., 2007, Bradnam et al., 2012).
A combination of anodal tDCS with peripheral nerve stimulation generates
superior functional effects compared to each stimulation tool applied alone
(Celnik et al., 2009). Moreover, repeated cathodal stimulation for 5
consecutive days resulted in cumulative effects, while stimulation once weekly
over 4 consecutive weeks did not (Boggio et al., 2007). Thus, in line with other

W. Jensen et al. (eds.), Replace, Repair, Restore, Relieve – Bridging Clinical 3

and Engineering Solutions in Neurorehabilitation, Biosystems & Biorobotics 7,
DOI: 10.1007/978-3-319-08072-7_2, © Springer International Publishing Switzerland 2014
4 M.-F. Kuo, W. Paulus, and M.A. Nitsche

data, a once daily session repeated at least over 3-5 days seems to be a
prerequisite for successful motor rehabilitation.
A whole group of studies was dedicated to the integration of tDCS into clinical
routine rehabilitation programs. Bilateral tDCS combining anodal tDCS of the
lesioned hemisphere with cathodal tDCS of the contralateral hemisphere during
physical/occupational therapy resulted in a better outcome of motor functions
than sham tDCS combined with therapy after 5 days of treatment. Interestingly,
only in the combined group functional magnetic resonance tomography
(fMRI) was increased after therapy. Prolongation of this regime to 10 days of
therapy resulted in stronger effects (Lindenberg et al., 2010, Lindenberg et al.,
2012).Later these findings were challenged(O'Shea et al., 2014). Similar effects
are described for bilateral and unilateral cathodal tDCS in combination with
constraint-induced movement therapy (Bolognini et al., 2011, Nair et al.,
2011). All of these studies were conducted in chronic stroke patients. In the
only study, in which the effects of anodal tDCS without combination with any
motor training, on motor functions in acute stroke patients was explored, tDCS
had no effects on motor outcome (Rossi et al., 2013).
With regard to lower limb function, increased force production during anodal
tDCS of the lesioned hemisphere (Tanaka et al., 2011), and improved
ankle control was described by anodal tDCS of the lesioned hemisphere
(Madhavan et al., 2011).
Taken together, these studies show a potential of tDCS to improve fine
motor skills, but also strength and selectivity of motor contraction, in chronic
stroke. This has been explored most extensively for upper limb functional
deficits, but also for lower limb and pharyngeal functions. Repetitive
application of stimulation results in cumulative effects, the effects can outlast
the therapeutic regimen for weeks, as far as explored, and can be associated
with enhanced activity and excitability of the lesioned hemispheres. So far it
is not clear which protocols are optimally suited to improve functions.
Approaches, such as combination of tDCS with peripheral nerve
stimulation, might enhance efficacy of stimulation further. Most of the studies
were conducted in small populations of selected patients, and larger studies are
needed to explore the relevance of the effects in more routine rehabilitation
settings.

Aphasia

Dependent on lesion location, i.e. involving Broca- and Wernicke areas, but also
temporal or parietal association cortices, and white matter, different kinds of aphasic
symptoms are discernible. During recovery rapid neuroplastic alterations of language-
related areas occur, which are associated with functional restitution (for reviews see
(Hamilton et al., 2011, Schlaug et al., 2011)). NIBS is an attractive approach to boost
the conventional rehabilitative approach of speech therapy (Ross et al., 2011, Holland
and Crinion, 2012). Similar to the motor system, an interhemispheric dysbalance
Induction of Cortical Plasticity: Clinical Applications 5

concept has been promoted for aphasia, beyond the rationale for direct plasticity
enhancement of the lesioned hemisphere. Therefore, reduction of excitability of the
healthy contralateral homolog area might indirectly enhance plasticity of the lesioned
one and thus improve regaining speech functions (Mylius et al., 2012).
In most of the studies conducted in aphasic stroke patients, anodal tDCS of
the left lesioned hemisphere was combined with speech therapy for up to 10
sessions. The anode was usually placed over the temporal or frontal cortex, and
the return electrode position was the contralateral supraorbital region (Baker et
al., 2010, Fiori et al., 2011, Fridriksson et al., 2011, Marangolo et al., 2011,
Vines et al., 2011). In general, stimulation improved speech function in these
patients. Moreover, the effects could remain stable for weeks or even
months. In the study of Monti and colleagues (Monti et al., 2008) only
cathodal tDCS of the lesioned hemisphere had a positive effect on picture
naming. The divergent result might be caused by specific stimulation protocol
differences as compared to the other studies, such as stimulation before therapy,
and return electrode position at the shoulder, which might have different
physiological effects due to different current flow direction (Moliadze et al.,
2010). Three studies following a different rationale, namely readjustment of
hemispheric dysbalance by cathodal tDCS of the healthy hemisphere,
demonstrated positive results (Jung et al., 2011, Kang et al., 2011, You et al.,
2011). Interestingly, it was most effective in patients with mild fluent
aphasia when the therapy started within 30 days after stroke (Jung et al.,
2011). In another positive study, anodal tDCS of the right frontal cortex was
combined with melodic intonation therapy, which involves activation of the
right prefrontal cortex (Vines et al., 2011). Taken together, these pilot studies
show that tDCS in combination with speech therapy is suited to enhance
speech function in aphasic patients. The most promising approaches encompass
excitability-enhancing stimulation of left-hemispheric language-related, and
excitability-reducing stimulation of the right hemispheric homolog areas
combined with speech therapy. However, systematic studies exploring
optimal stimulation protocols with regard to stimulation intensity, repetition
rate, electrode positions, which might differ also with regard to lesion location
and size, are needed as well as studies involving larger patient populations to
translate this approach into clinical practice.

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6 M.-F. Kuo, W. Paulus, and M.A. Nitsche

Bolognini, N., Vallar, G., Casati, C., Latif, L.A., El-Nazer, R., Williams, J., Banco, E.,
Macea, D.D., Tesio, L., Chessa, C., Fregni, F.: Neurophysiological and behavioral
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Fiori, V., Coccia, M., Marinelli, C.V., Vecchi, V., Bonifazi, S., Ceravolo, M.G.,
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Neuroscience 23, 2309–2323 (2011)
Fregni, F., Boggio, P.S., Mansur, C.G., Wagner, T., Ferreira, M.J., Lima, M.C., Rigonatti,
S.P., Marcolin, M.A., Freedman, S.D., Nitsche, M.A., Pascual-Leone, A.: Transcranial
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and the role of noninvasive brain stimulation. Brain and Language 118, 40–50 (2011)
Hesse, S., Werner, C., Schonhardt, E.M., Bardeleben, A., Jenrich, W., Kirker, S.G.:
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subacute stroke patients: a pilot study. Restorative Neurology and Neuroscience 25, 9–
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Aphasiology 26, 1169–1191 (2012)
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Induction of Cortical Plasticity: Clinical Applications 7

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effects of melodic intonation therapy. Front. Psychol. 2, 230 (2011)
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Miniaturized Neural Interfaces and Implants
in Neurological Rehabilitation

Thomas Stieglitz

Laboratory of Biomedical Microtechnology,

The Department of Microsystems Engineering-IMTEK,
The Bernstein Center Freiburg and the Cluster of Excellence
BrainLinks-BrainTools (ExC 1086),
Albert-Ludwig–University of Freiburg, Freiburg, Germany
[email protected]

Abstract. Restoration of functions after trauma or neurological diseases is the

major goal of rehabilitation. Technical aids complement remaining functions or
even try to replace them completely. Neural prostheses use electrical signals
from the nervous system as control signals or excite nerves by means of
electrical stimulation to elicit perceptions, induce movements or modulate neural
network behavior. Creating novel, neural prostheses applications for the
peripheral or central nervous system require neural interfaces and implants that
are biocompatible, long-term stable and highly robust. However, only few neural
interfaces have been tested or are routinely used in clinical applications today,
most of them made with "old-style" precision mechanics technologies. What are
the biological, tech- nological, electrical and material science challenges that must
be considered when designing an optimal neural interface? Do nano-, micro-
and biohybrid systems have a future in clinical applications of neural
implants? Design aspects and opportunities and challenges of miniaturization
technologies for neural implants will be presented and discussed for peripheral
and central nervous system applications. Devices will be introduced and
compared with respect to selectivity, long-term functionality and their
applicability in funda- mental and translational research as well as for clinical
applications.

Keywords: neural implant, rehabilitation, recording, stimulation, miniaturization.

1 Introduction

Neural prostheses aim to restore or replace lost functions due to trauma or

neurological diseases. Since all neural functions in the human body come along
with electrical activity of the nerve cells, the idea arose decades ago to take
advantage of this property. Technical devices were invented to interface
nervous structures to read out or to inscribe or even overwrite electrical
information. Adequate interfaces are needed for this endeavor. They must

W. Jensen et al. (eds.), Replace, Repair, Restore, Relieve – Bridging Clinical 9

and Engineering Solutions in Neurorehabilitation, Biosystems & Biorobotics 7,
DOI: 10.1007/978-3-319-08072-7_3, © Springer International Publishing Switzerland 2014
10 T. Stieglitz

neither harm the body nor lose their functionality over the course of the
application. The earliest clinical application that replaced lost neural activity
was the cardiac pacemaker. Its rise started in 1958 and it is the most
successful active implant nowadays with more than 350,000 new implantations
per year worldwide [1]. In neural prostheses or implants, only few success
stories have been written so far. Cochlear implants to restore hearing have been
implanted in about 250,000 patients worldwide. Deep brain stimulators to
treat symptoms of Parkinson’s (Lou Gehrig’s) disease symptoms as well as
vagal nerve and spinal cord stimulators modulate network activity by electrical
stimulation very successfully [1]. Implants to activate ankle flexion after brain
stroke, i.e. drop foot stimulators, and retinal vision prostheses have got
medical device approval in the EC and the USA but are still far from market
penetration. Recently, more applications have been developed in the field of
stroke rehabilitation, epilepsy diagnosis and treatment, psychia- tric disease
therapy, control of technical aids after para- lysis and artificial limbs after
amputation to list the main research lines. Some of them are on the way into
clinical practice, others still in different stages of fundamental research [1].
Further scientific findings are still needed to understand physiologic
function and pathophysiological changes in many diseases to develop an
“optimal” neural implant. On the other side, devices still look very “old-
fashioned” or “vintage-style” in most clinical applications. Which target
specifications have to be met to develop a new generation of neural interfaces
and implants with modern miniaturization technologies ? Starting with a
personal view on essential requirements of active implants, peripheral and
central nervous system interfaces will be introduced. Chemical and optical
interaction with the nervous system will be considered as alternative to
established electrical recording and stimulation techniques. System concepts
of implants that connect a kind of control center with its periphery conclude
the overview.

2 Essential Requirements

Implants must not harm the target tissue and need to establish a long-term
stable and functional interface. The technical term “biocompatibility”
summarizes the main requirements that a device shall meet [2]. The used
materials must not be toxic and shall interact with the tissue in a desired manner.
Shape and mechanical material properties determine the structural
biocompatibility that also influences the strength of the foreign body reaction.
Implants will be encapsulated by electrically insulating tissue (either glia or
fibroblasts) that deteriorates the recording and stimulation properties of the
interfaces. Safety of the implant also includes material stability, the absence of
eluates and debris and absence of tissue damage by (leakage) currents and
electrical shock beyond the intended use. All these aspects have to be
considered as fundament of application specific requirements.
Miniaturized Neural Interfaces and Implants in Neurological Rehabilitation 11

3 Interfaces to the Nervous System

The intended use as well as the implantation site determines the design of neural
interfaces. Invasiveness and selectivity in recording and stimulation have to be
well balanced [3]. Miniaturization helps to interface with few nerve cells or
axons but small electrode size results in increased noise and decreased charge
injection. A compromise has to be found for every application. Suitable materials
for implantable nerve interfaces include silicones, precious metals, polymers and
silicon [4-6].

3.1 Peripheral Nerve Interfaces

Electrode arrays have to interface the axons, arranged in fascicles in the
peripheral nervous system. For selective and graded recruitment, an electrode
array is mandatory to be able to address several subgroups of nerve fibers.
Electrodes can be wrapped around the nerve as cuff- electrodes or can be
inserted either between or inside the nerve fascicles [3-5]. Designs differ in
their designs according to electrode arrangement, shape, substrate and electrode
material [3-5]; polyimide, parylene C and silicone rubber have been established
as substrate materials while platinum, platinum iridium alloy, and iridium oxide
are common electrode materials. Precision mechanics, laser structuring and
microsystem technologies have been successfully applied to develop devices for
clinical trials and approved devices. Microsystem based intrafascicular
electrodes have shown highest selectivity in restoring natural sensory feedback
in hand prosthesis control [7]. Long-term stability of the thin-film-based
electrode contacts is of utmost importance [5] to transfer these promising
approaches in clinical practice.

3.2 Central Nervous System Interfaces

Electrode arrays are either placed inside the cortex or deeper structures of the
brain to record single unit activity or local field potentials or on or under the
meninges of the brain. Shaft-like electrode arrays are preferred for intra-
cortical implantations while planar arrays are suitable for epicortical application
[6]. While fundamental researchers prefer stiff silicon-based arrays to record
the activity of single nerve cells, chronic applications suffer from loss of active
channels and signal due to encapsulation of these devices [6]. Reasons of this
foreign body reaction include micromotions between the implant and the brain
tissue. Flexible probes could be a solution. Further investigations are needed to
prove reliability and long-term stability. In epicortical applications, increased
electrode densities and numbers help to better understand mechanisms in the
brain [8]. While polyimide-based microsystems [8] are success- ful in basic
research, silicone rubber is taken for clinical research because of experience
from other applications. Chronic stability and long-term functionality is the
12 T. Stieglitz

limiting factor from the technical side. More complex probes might lead to better
understanding of diseases and neural network activity that eventually leads to
better probes.

3.3 Non-electrical Interfaces

Electrical activity in the nervous system is not only based on distribution of
ions in the intra- and extracellular space but neurotransmitters influence nerve
cell activity and synaptic transmission. Therefore, monitoring of the chemical
environment, sometimes called metabolic monitoring, is of interest as well as
local drug delivery [9]. Integration of microfluidic channels can be done
technically but clogging due to protein and cell adhesion often limits the
usefulness in chronic applications as well as the size of pumps, valves and
reservoirs [9]. Opto- genetics takes advantage of the ability to genetically
modify nerve cells and to obtain light sensitive ion channels. It allows novel
investigation paradigms in basic research and needs adequate tools [10].
Microsystems engineering approaches are manifold to bring light to nerve cells
and record the electrical response. So far, all developments are more or less
in the prototype stage. Miniaturization, wireless communication and long-term
stability are still major tasks on the agenda.

3.4 Tailoring the Material-Tissue Interface

Tailoring the material-tissue interface to either mimic the biological
environment or to hide the technical substrate has a long history in implant
development. Basic research is done on nanostructuring the surface, biochemical
coatings, integration of cells onto or into coatings [11] and genetic engineering
of coatings [12] to influence the tissue reaction after implantation. Most
approaches, however, lack the ability to easily pass legal requirements in the
context of medical device approval, e.g. with respect to sterilization.

4 Implant Concepts

The cardiac pacemaker and the cochlea implant have set standards with respect
to reliability and robustness in (neural) implant concepts. They both protect
implant electronics in a hermetic package against water and ions. Energy
supply is either realized by a battery inside the package or a coil for wireless
electromagnetic energy transmission inside or outside the package [13-14].
Non- hermetic packaging of electronic components can be done for preclinical
studies or clinical studies with limited implantation time but might not be
stable over decades [13]. Hermetic packages include a (limited) number of
electrical feed-throughs that connect the electronic part inside with the electrodes
outside. In approved medical devices this number of feed-throughs is limited to
Miniaturized Neural Interfaces and Implants in Neurological Rehabilitation 13

about 20, so far. Current technology delivers packages at a certain size but has
been able to deliver long-term stable systems that survive about 10 years even in
parts of the body where motions are present [10]. Miniaturized implant
packages have to face the challenge of integrating hundreds of electrical feed-
throughs without deteriorating hermeticity. Ceramic-based packages in
combination with Laser- structuring and micromachining deliver solutions for
highly complex packages with predicted life-time exceed- ing human life
expectancy. In addition, novel measurement and validation techniques have to
be developed to over- come detection limits of established tests, e.g. the helium
leakage test, when certain package volumes are underrun. The major challenge
-according to the author’s personal opinion- lies in the development of high
channel-count connectors that allow reliable connection and detachment of the
different components of an implant. If multiple electrodes with cables and an
implant package with control electronics have to be implanted, detachable
connections might reduce implantation trauma due to smaller incisions and
tunnels. Single parts of an implant system might be replaced in case of failures
and variability of implant components, e.g. lengths of cables, can be better adapted
to the patient’s needs. Commercially available solutions are limited to one,
two, four and recently 8 channels for chronic implants. More sophisticated
solutions are needed to be able to take advantage of microsystems solutions, of
high channel count electrode arrays, and of complex system designs in chronic
applications. Instead of connec- tors, multiple distributed implants with body area
network communication to a central control implant can be envisioned as well as
extracorporal receivers in a distri- buted network integrated in clothes (i.e.
wearable elec- tronics). Intended use, application and patient numbers will
influence the final design while the benefit to the patients’ needs will determine
the success of the implant in neural rehabilitation applications.

5 Conclusions

Miniaturization technologies enable highly complex designs for interfaces and

implants in neural rehabilitation applications. Robustness and reliability of
devices are of utmost importance as well as the benefit for the patient to bring
exciting ideas into clinical applications. Long-term stability and functionality
of neural implants are still major challenges, especially in miniaturized devices,
that have to be solved before further success stories can be written.

Acknowledgment. Many parts of this work have been supported by German and
European grants: Bernstein Center Neuro-technology-The hybrid brain (BMBF-
01GQ0830), Cluster of Excellence BrainLinks-BrainTools (DFG, ExC 1086), Exist Go
Bio (BMBF-01GQ0420), FutureRet (BMBF--16SV3792), BrainCon (BMBF-0316064C),
NEURO- PROBES (FP 6, IST-027017), and TIME (FP 7, CP-FP-INFSO 224012). T.S.
thanks P. Fries for continuous support and discussion on central nervous system implants.
14 T. Stieglitz

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[10] Rubehn, B., et al.: A polymer-based microimplant for optogenetic applications:
design and first in vivo study. Lab on a chip 13(4), 579–588 (2013)
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Neuroprosthetics: Past, Present and Future

Nitish V. Thakor

Biomedical Engineering Department, Johns Hopkins University

Baltimore, USA
and
Singapore Institute for Neurotechnology (SINAPSE) National University of Singapore,
Singapore
[email protected], sinapseinstitute.org

Abstract. There has been a remarkable convergence in recent years between the
biomedical fields of neuroscience and rehabilitation and engineering fields of
robotics and prosthetics. This “union” of complementary disciplines has
resulted in rapid advances in the robotics and rehabilitation technologies on one
hand, and utilization of brain interfaces and brain signals for targeting suitable
clinical applications on the other hand. This review will address the slow
progress in past, explosive recent developments, and the pending major future
challenges to take the science and technology to the patient. I \ review the
broad field for neuroprosthesis, from sensory (e.g. tactile) to motor (upper and
lower limb) as well as rehabilitation technologies in these fields. I conclude
with recent remarkable developments in the field of brain machine interface,
how these are impacting the development of neutrally controlled prosthesis and
also discuss the challenges of taking the technology to the market and eventually
to the patient.

1 Introduction
The field of prosthesis, orthotics, and rehabilitation has always served great
human need, and has been of steady interest to inventors and scientists for
centuries. Despite the interest, technological progress has only been
incremental. This technology has taken a major leap forward, thanks to major
initiatives such as the “Revolutionizing Prosthesis” program by the Defense
Advanced Research Project Agency (DARPA) in the USA. Emergence of the
field of brain computer interface (BCI) and brain machine interface (BMI) has
further revolutionized the framework, greatly shifting the research focus from the
limbs to the brain and the nervous system. Indeed, the field of neuroengineering
in general, and neuroprosthesis in particular, has captured the interest and
imagination of students and serious researchers. This review presents the current
explosive developments, both in the technology as well as the neural interface
and control, and finally summarizes the challenges still being faced and the
future directions for the field.

W. Jensen et al. (eds.), Replace, Repair, Restore, Relieve – Bridging Clinical 15

and Engineering Solutions in Neurorehabilitation, Biosystems & Biorobotics 7,
DOI: 10.1007/978-3-319-08072-7_4, © Springer International Publishing Switzerland 2014
16 N.V. Thakor

2 Robotics, Prosthetics, Orthotics

2.1 Robotics
Robotics is a broad, interdisciplinary field, with applications to industry, as well
as to the medical centers and defense institutions. Overlap and synergy of the
robotics field with the fields of prosthetics and orthotics is quite great,
particularly in the areas of mechatronics, or design of mechanisms for upper
and lower limb prosthetics/orthotics. Both fields also rely on sensing and
actuation to provide that extra perception to the robotic mechanisms and the
rehabilitation devices. While the driver for the robotics field is mostly industry
(and to some extent military and health care), the driver for the field of
rehabilitation and prosthetics/orthotics is the health care services, although
defense establishment has lately taken an interest in providing the extra research
support to spur the technology for the benefit of soldiers and wounded
warriors.

2.2 Prosthetics and Orthotics

The fields of prosthetics and orthotics, and here we refer only to upper and
lower limb systems, have arguably remained stagnant for decades, indeed the
past century; during that period developments mainly comprised the mechanisms
that were predominantly passive or body powered. Constraints of cost, fitting to
the human body, ability to power the devices, and acceptance by the disabled
individuals, have all combined to hold back the field. A combination of recent
technological leaps as well as government investment have made the
prosthetic/orthotic devices significantly more functional, and to help overcome
the adoption issues and make them affordable as well. Among the major
technological developments have been anthropomorphic, or human inspired
prosthetic arms and legs, as well as advanced materials and power sources.
These technologies and synergies between the fields of robotics and
prosthetics/orthotics have now shifted the focus from the mechanisms to their
control. While autonomous or body powered control has been the common
approach for robotics and prosthetics, respectively, more intuitive or natural
would be the approaches of using signals and information from the body, indeed
the brain, to control the mechanisms. Even here, sensing the proprioceptive or
body motions and forces, and muscle activity (electromyogram) are more
common. Only over the past decade or so, the more intuitive and, inevitably,
neural interface and control has been considered and received a great surge in
research interest. This is the emerging field of neuroprosthetics.
Neuroprosthetics: Past, Present and Future 17

3 Neuroprosthetics

The concept of neuroprosthetics comes from the fundamental idea that it is the
brain, or the nervous system, that controls the limbs, and indeed also receives the
sensory input and feedback. Thus, direct interface to the nervous system,
particularly the brain, may eventually afford the best means to communicate to
the prosthetic or orthotic device. As such, considerable research is now underway
to develop technologies for interfacing to the nervous system, whether the brain,
spinal cord or the peripheral nerves. Further elements of this research include
a) microelectrodes and sensors that are implanted in the nervous system, b) high
density low power integrated circuits for amplification, filtering, data and power
harvesting, c) fully packaged hermetically sealed systems that are
biocompatible, d) signal analysis to interpret the information from the neurons,
spinal cord or the nerves, and e) control algorithm to bi-directionally interface to
the prosthetic/orthotic mechanism.
As such, this review will consider different ways to interface to the
nervous system and emerging approaches to interface and control the
prosthetic/orthotic devices by direct signals from the nervous system.

3.1 Neural Interface

The neural interface essentially means microelectrodes and microelectronics that
interfaces to the nervous system.

Microelectrodes – Microelectrode technology makes it possible to record from

individual or population of neurons. The resulting neural spike or local field
potential signals can be used to create a point process model or a population
model of neurons working together to achieve a coordinated control of the
prosthesis. Microelectrodes are made using modern silicon or MEMS technology
and are now commercially available. However, new generations of high density
electrodes, using nanotechnology or unconventional or biocompatible materials
such as polymers or carbon are under development. Spinal cord and nerves,
however, require different approaches, as the electrodes may be both penetrating
or non-penetrating, and may need considerable flexibility along with the ability
to interface to coarse (such as nerve) or fine (such as fascicles) structures.

Sensors – With the recent interest in providing sensory feedback to the nervous
system, the need to develop sensors for prostheses has become all the more
relevant. Human limbs benefit from tactile, proprioception, pressure/force,
temperature, and pain. Modern prostheses are incredibly limited in all these areas,
adopting only some modest research ideas and commercial tactile sensor
technologies. Even greater problem and concern is how to interface these
sensors, or sensory signals to the nervous system. Indeed, the most common
18 N.V. Thakor

and highly limited approach is to sensory feedback is through electrical

stimulation to the nerves or the sensory cortex.

VLSI circuits – Very large scale integrated (VLSI) are highly integrated circuits
that incorporate a large number of amplifier and interface electronics on single or
few chips. These chips interface to microelectrode arrays to transduce the
electrical signals. Critical circuit components include amplifiers interfacing to
electrodes to capture neural spike activity or to brain tissue to capture the local
field potentials. To provide feedback, electrical stimulation is given to
peripheral nerves or directly to the sensory cortex, resulting in a sensory percept.
This requires multi-channel stimulator with biphasic pulse output and high
voltage compliance if interfaced to muscles.
Power and data transfer – Implanted systems need their own power for
considerable lengths of time that the implant might last (indeed, prostheses may
last decades). Traditional option for powering is to use implanted Lithium-
based batteries which can last several years. But for even more extended
periods lasting decades, or when size is of serious concern, wireless power
transfer or continuous power harvesting may be needed. Various radio-
frequency and inductive powering approaches are therefore used. When the
neural interface is implanted chronically, it also captures a great deal of data
continuously. These data (from neuronal spike activity to nerve signals) must be
processed continuously and in real- time, a capability that stretches the current
implantable signal processing technology. Therefore, another option is to
wirelessly transfer data from within the cortex to outside, or bidirectionally, that is
if stimulation is also provided by the signal processor.

System integration – Last but not the least, this hardware must be fully integrated
into an implantable package. Key features of the implanted system are to
provide hermetically sealed package (providing protection to the sensors and
electronics) and biocompatibility (to make the implant acceptable to the body).
Very few materials, such as Platinum metal for electrodes, silicones and
ceramics, and Titanium can for hermetically sealing, have proven track record
and regulatory approval. Therefore, full system integration and packaging
remains a major barrier to taking various research products to commercial and
clinical practice.

3.2 Neural Signal Analysis and Control

Signals from brain – Neural signals, as eluded to earlier, include neuronal spike
activity (single or multiunit) recorded by an array of microelectrodes. Thus,
the signal processing involves detection and sorting of neural spikes as well as
building a model of the inter-spike interval distributions. From this
distribution, or a point-process model of the spiking activity, a generalized
model is created to determine what the neural activities code for, e.g. movement,
Neuroprosthetics: Past, Present and Future 19

direction, velocity or force of the intended limb movement. It is also possible to

work with local field potentials to achieve the same goal, although not as
effectively (these potentials, though, may be more robust over long term).

Signals from nerves and spinal cord – While cortical prostheses have
garnered a great deal of attention, prostheses controlled by signals from nerves or
the spinal cord also serve special needs. Nerve interfaces are arguably less
traumatic or invasive, e.g. nerve prostheses would not require brain surgery, and
may be used to decode the target signals carried to the muscles. Nerves also
carry sensory signals back and thus decoding signals from the nerve or its
fascicles can provide an indicator of tactile or other sensory information. Spinal
signals are arguably much more difficult to tap into, not only because they are
difficult to access through the vertebra but also due to the very complex
organization of the spinal cord. Tapping into ganglia out of the spinal cord may
be an option.

3.3 Applications
Cortical control: motor prosthesis and sensory feedback – Building motor
prostheses is the most popular, vibrant area of research. Application of neural
interface and signals to control prosthetic limbs has now been demonstrated
in animal models and human subjects. Microelectrodes are implanted (most
commonly this research is done on non- human primates) in the motor and the
premotor cortex and neural spikes or local field potential signals are decoded to
predict the end point or the trajectory of the movement. Neural decoding and
algorithms are trained or adapted, but it has also been shown that neurons
adapt their output under reinforced learning to achieve the desired end point or
trajectory. In nonhuman primates as well as human subjects, different
decoding results such as reach and grasp of objects has been demonstrated.
Researchers continue to enhance the degrees of freedom, i.e. complexity of
movements (such as different grasps) and increasing the speed and precision.
Research on sensory prosthesis, i.e. getting the sensory information back to
brain is less well advanced but preliminary work indicates that
microstimulation of the cortex may provide some sensory percepts and may be
used to provide feedback for object reach and grasp. Much additional work is
needed to provide high-resolution sensory feedback of object shape or texture,
or other senses such as proprioception (instantaneous positional feedback).

Spinal interface for prosthetic or assistive locomotion – Spinal cord injury

results in devastating consequences potentially resulting in paralysis and life
long impairment of limb function - most vivid is the paralysis that impairs
locomotion. To restore locomotion, it would be necessary to provide some motor
command pertaining to the intended movement from the brain to the limb
muscles. These signals may be tapped directly from the cortex (motor
20 N.V. Thakor

command signals encoded by neurons) or from the spinal cord (such as the
central pattern generator oscillator signals pertaining to locomotion). Using
microstimulation, it has been shown in rodent and cat models that such
locomotion signals can also be activated. Very early, preliminary evidence of
the beneficial effects microstiulation on restoring some degree of locomotion
has also been demonstrated.

Peripheral nerve interface: motor and sensory– Peripheral never injury commonly
results from accidents and once the nerve is severed, corresponding muscle
atrophies and despite the limb being intact loss of limb function occurs.
Interfacing to the intact end of the peripheral nerve may allow us to tap into
the neural signals coding for the intended movement. Microelectrodes may be
inserted longitudinally or transversely into the nerve to capture the signals from
the nerve fascicles. A less invasive, although less specific, approach is to put
an electrode cuff around the nerve to be monitored. Although the nerve interface
is may appear to be less invasive than the cortex, that connection is also
harder to maintain and decode due to small nerve fiber size, its movement
along with the limb, and the complex nature of nerve fascicles and axons.
Nevertheless, some degree of decoding may be possible to elicit a command
signals to use for functional electrical stimulation of the limb and achieve
some level of functional response. Sensory feedback requires a reversal of the
process; seeking input from sensors on the limb (such as tactile sensors
mounted on the hand) and stimulating the nerve to provide some degree of
sensory perception. This type of sensory feedback, as of now, is quite
experimental and only some crude mapping of perception of touch on the hand
has been demonstrated.
Nerve signals are quite small and are difficult to get capture and decode.
However, when nerves innervate muscles, that interface results in an
amplification of the nerve signals when the muscle contracts producing the
electromyogram. Thus, artificial peripheral nerve innervation may provide an
indirect means of tapping into the nerve signals, i.e. by interpreting the innervated
muscle an estimate of the motor command carried by the nerve can be obtained
from the muscle contracture. Put it other way, when there is a loss of limb, the
reinnervated muscle provides the signature of the intended motor function,
which can then be relayed to the prosthetic limb. This approach, called
targeted muscle reinnervation, has been a very successful, rapidly gaining
clinical acceptance due to its effectiveness, despite the rather invasive and
complex nature of the interface and the overall technology.

4 Discussion and Conclusion

Prosthetics and orthotics technologies substitute for or augment the natural

human limb function. To function as a natural extension of the human body,
these devices need an intuitive and naturalistic human-like – meaning cortical or
Neuroprosthetics: Past, Present and Future 21

cognitive - interface. This need has spawned the field of neuroprosthesis and
neuroorthosis. Current research is at the demonstrative phase, suggesting
through work in rodent or nonhuman primate models that neural control of an
arm or a leg is possible by tapping into the cortical neurons, spinal cord, or
peripheral nerve. Pioneering studies in humans have also been carried out,
demonstrating the feasibility of this approach.
The technology of neural interface, from microelectrode arrays to VLSI
circuits is advancing rapidly. Higher density recording, coupled with better
decoding algorithms may provide better signature of the brain’s intent and
correspondingly control of the prosthesis. These technologies need further
refinement and integration in chronically implanted systems so that long
term performance, both recording and stimulation can be demonstrated. For
long term implantation, the electrode- brain tissue interface needs to be
improved. Major barriers that remain, including demonstrating chronic
reliability and biocompatibility, demonstrating safety and efficacy, and
obtaining regulatory approvals, ethical considerations of carrying out clinical
trials and balancing the risk and reward, and formulating a suitable business
model including scale up, cost effectiveness and reimbursement.
Future research should focus on greatly enhancing the functionality and
bidirectional intuitive interface that restores limb function over the life-time
of the subject. Motor prostheses need to be more continuous and show higher
level of functionality, such as for dexterous manipulation. Sensory prostheses
need to carry information other than tactile to include other sensory percepts.
Fully integrated bidirectional prosthesis is close to demonstrability but far from
ubiquitous use by amputees and disabled. Some of the challenges are
technical, however greater challenge is to carry out quality experimental studies
and clinical trials to demonstrate the feasibility and performance pertaining to
the use of neuroprosthesis by the disable in their daily living.
Continuing research, technological refinement, and extended experimental
and clinical validation, including patient safety and effectiveness will be
needed to brain neural prosthesis to wide spread clinical realization. High level
of interest and creativity shown by researchers, and considerable progress over
the past decade, however, bodes well for the field.

Acknowledgment. My research over the past decade has been funded by the
U.S. Defense Advanced Research Project Agency, the National Institutes of
Health, the National Science Foundation, and presently the Singapore Institute
for Neurotechnology and the National Research Foundation of Singapore.
Neuroplasticity in Constraint-Induced
Movement Therapy

Jakob Udby Blicher1,2, Jamie Near3, Erhard Næss-Schmidt2, Leif Østergaard1,

Heidi Johansen-Berg4, Charlotte J. Stagg4, Jørgen Feldbæk Nielsen2,
and Yi-Ching Lynn Ho1
1
Center for Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark
2
Hammel Neurorehabilitation & Research Centre, Aarhus University Hospital,
Hammel, Denmark
3
Dept. of Psychiatry, McGill University, Montreal, QC, Canada
4
Oxford Centre for Functional MRI of the Brain (FMRIB), Nuffield Department of
Clinical Neurosciences, University of Oxford, UK

Background: In healthy subjects, decreasing GABA facilitates motor learning[1].

Recent studies, using PET[2], TMS[3-5], and pharmacological challenges[6], have
pointed indirectly to a decrease in neuronal inhibitory activity after stroke.
Therefore, we hypothesize that a suppression of GABA levels post stroke might
be beneficial to motor recovery during Constraint-Induced Movement Therapy
(CIMT).

Objective: To relate GABA changes to motor relearning after stroke through the
use of j-difference edited Magnetic Resonance Spectroscopy (MRS).

Methods: 21 patients (3-12 months post stroke) and 21 healthy, age-matched

subjects were recruited. Patients had mild to moderate hand impairment, with at
least 10° of active wrist extension, at least 10° of thumb abduction/extension, and
at least 10° of extension in at least two additional digits. Patients were examined
by a medical doctor and a physiotherapist prior to enrollment in the study. Patients
completed two weeks of CIMT, and were scanned before and after training.
For MRS a 2x2x2 cm voxel was placed on the “hand knob” (hand area located in
the primary motor cortex[7]) in the affected hemisphere of the patients and in the
dominant hemisphere of the healthy subjects. GABA was expressed as a ratio to
Creatine (Cr). Motor function was measured using the Wolf Motor Function Test
(WMFT)[8].

Results: GABA/Cr was significantly lower (p< 0.001) in patients (0.33) at

baseline compared to healthy subjects (0.42). After therapy, patients showed a
significant improvement in hand function (p< 0.001), which was negatively
correlated with GABA/Cr changes (R=-0.57 , p=0.015) – larger improvements in
patients were associated with greater reductions in GABA/Cr. Results were also
significant after correcting for changes in intracortical grey matter volume.

W. Jensen et al. (eds.), Replace, Repair, Restore, Relieve – Bridging Clinical 23

and Engineering Solutions in Neurorehabilitation, Biosystems & Biorobotics 7,
DOI: 10.1007/978-3-319-08072-7_5, © Springer International Publishing Switzerland 2014
24 J.U. Blicher et al.

Conclusion: A decrease in GABA levels appears to facilitate motor recovery after

stroke. GABA, as measured non-invasively with MRS, could be a biomarker for
neuronal plasticity during post stroke recovery and guide rehabilitation
interventions as transcranial direct current stimulation[9].

References
1. Stagg, C.J., Bachtiar, V., Johansen-Berg, H.: The role of GABA in human motor
learning. Curr. Biol. 21, 480–484 (2011)
2. Heiss, W.D., Grond, M., Thiel, A., et al.: Permanent cortical damage detected by
flumazenil positron emission tomography in acute stroke. Stroke 29, 454–461 (1998)
3. Liepert, J., Storch, P., Fritsch, A., Weiller, C.: Motor cortex disinhibition in acute
stroke. Clin. Neurophysiol. 111, 671–676 (2000)
4. Swayne, O.B., Rothwell, J.C., Ward, N.S., Greenwood, R.J.: Stages of motor output
reorganization after hemispheric stroke suggested by longitudinal studies of cortical
physiology. Cereb Cortex 18, 1909–1922 (2008)
5. Blicher, J.U., Jakobsen, J., Andersen, G., Nielsen, J.F.: Cortical Excitability in Chronic
Stroke and Modulation by Training: A TMS Study. Neurorehabil. Neural Repair 23,
486–493 (2009)
6. Lazar, R.M., Berman, M.F., Festa, J.R., Geller, A.E., Matejovsky, T.G., Marshall, R.S.:
GABAergic but not anti-cholinergic agents re-induce clinical deficits after stroke. J.
Neurol. Sci. 292, 72–76 (2010)
7. Yousry, T.A., Schmid, U.D., Alkadhi, H., et al.: Localization of the motor hand area to
a knob on the precentral gyrus. A new landmark. Brain 120(Pt. 1), 141–157 (1997)
8. Wolf, S.L., Lecraw, D.E., Barton, L.A., Jann, B.B.: Forced use of hemiplegic upper
extremities to reverse the effect of learned nonuse among chronic stroke and head-
injured patients. Exp. Neurol. 104, 125–132 (1989)
9. O’Shea, J., Boudrias, M.H., Stagg, C.J., et al.: Predicting behavioural response to TDCS
in chronic motor stroke. Neuroimage (2013)
Advanced Prosthetic Control in Transhumeral
Amputees Using Osseointegration and
Bidirectional Neuromuscular Interfaces

Rickard Brånemark

Integrum Company,
Gothenburg, Sweden

Abstract. Bidirectional neuromuscular interfaces have been permanently

implemented in a patient using an osseointegrated percutaneous implant system.
Preliminary results from the first year of use will be presented.

1 Introduction

Although myoelectric prostheses have been clinically implemented since the

1960’s, they are still far from the functionality of their biological counterpart. It is
a widely known fact that the lack and instability of physiologically appropriate
control signals are the bottleneck of the field. Implantable neuromuscular
interfaces could provide enough and long-term stable signals [1], however, the
permanent communication with implanted devices is a major constraint that has
hindered this solution for decades. In order to overcome this problem, we have
developed a permanent bidirectional interface into the human body, the
Osseointegrated Human-Machine Gateway (OHMG).

2 Method

The OHMG is an enhancement of the OPRA Implant System [2], which is a

percutaneous osseointegrated implant for treatment of amputees. It has a modular
design that allows customization of the neuromuscular interfaces according to the
patient’s anatomy and prosthetic needs (Figure 1). It initially comprises epimysial
and cuff electrodes combinations, which account for up to 12 contacts. The
recording features of the cuff electrodes have been optimized in a frog sciatic
nerve model [3]. Furthermore, analog electronics and advanced control strategies
based in pattern recognition have been developed (BioPatRec) [4].

W. Jensen et al. (eds.), Replace, Repair, Restore, Relieve – Bridging Clinical 25

and Engineering Solutions in Neurorehabilitation, Biosystems & Biorobotics 7,
DOI: 10.1007/978-3-319-08072-7_6, © Springer International Publishing Switzerland 2014
26 R. Brånemark

Fig. 1 The Osseointegrated Human-Machine Gateway (OHMG), an enhancement of the

OPRA Implant system [2]. Animation to illustrate the concept at:
http://youtu.be/w8hlziytLkM.

3 Results

Preliminary clinical results show that the OHMG has the potential to allow
permanent access to implanted electrodes, and once validated, it will open new
possibilities for more advanced and natural prosthetic control. Long-term clinical
studies are required to prove the benefits of implantable interfaces in prosthetic
control. The early clinical results from the OHMG study will be reported.

4 Conclusion

For the first time bidirectional neuromuscular interfaces have been implemented in
a patient for the daily control of the arm prosthesis in activities of the daily living;
that is without being confined inside a research laboratory. The patient has been
using the system for over one year without complications, thus demonstrating the
potential of this novel technology to improve rehabilitation of individuals with arm
amputations.

Acknowledgment. This project was funded by ALF, Vinnova, Västra Gotalandsregionen,

Connacyt, Integrum, and Promobilia.
Advanced Prosthetic Control in Transhumeral Amputees 27

References
[1] Ortiz-Catalan, M., Brånemark, R., Håkansson, B., Delbeke, J.: On the viability of
implantable electrodes for the natural control of artificial limbs: Review and
discussion. Biomed. Eng. Online 11, 33 (2012)
[2] Brånemark, R., Berlin, Ö., Hagberg, K., Bergh, P., Gunterberg, B., Rydevik, B.: A
novel osseointegrated, percutaneous prosthetic system for treatment of patients with
transfemoral amputation: A prospective study of 51 patients. Bone Jt. J. 96-B(1), 106–
113 (2014)
[3] Ortiz-Catalan, M., Marin-Millan, J., Delbeke, J., Håkansson, B., Brånemark, R.: Effect
on signal-to-noise ratio of splitting the continuous contacts of cuff electrodes into
smaller recording areas. J. Neuroengineering Rehabil. 10, 22 (2013)
[4] Ortiz-Catalan, M., Brånemark, R., Håkansson, B.: BioPatRec: A modular research
platform for the control of artificial limbs based on pattern recognition algorithms.
Source Code Biol. Med. 8, 11 (2013)
The Control of Interlimb Coordination during
Left-Right and Transverse Split-Belt
Locomotion in Intact and Spinal
Cord-Injured Cats

Alain Frigon, Yann Thibaudier, Marie-France Hurteau, Alessandro Telonio,

Charline Dambreville, and Victoria Kuczynski

Université de Sherbrooke, Sherbrooke, Qc J1H 5N4 Canada

{alain.frigon,marie-france.hurteau,alessandro.telonio,
charline.dambreville}@usherbrooke.ca,
[email protected], [email protected]

Abstract. Proper coordination of the four limbs, or interlimb coordination, is a

fundamental requirement for locomotion in terrestrial mammals. The control of
interlimb coordination during quadrupedal locomotion was studied in adult cats by
independently controlling the speed of the left and right sides, or of the fore- and
hindlimbs, using a treadmill with four independent running surfaces. Here, we
briefly present some of our recent findings pertaining to the control of interlimb
coordination during quadrupedal locomotion in intact and spinal cord-injured
adult cats.

1 Introduction
Precise and flexible coordination of the four limbs (i.e. interlimb coordination) is a
fundamental requirement for quadrupedal or bipedal locomotion. Maintaining
dynamic stability in a changing environment requires constant adjustments in
interlimb coordination. Despite its importance, the neural control of interlimb
coordination in mammalian systems is largely unknown, although genetic
manipulations in mice have begun to identify some of the neuronal populations
involved [1,2]. It has been well documented that humans have conserved a
quadrupedal-like control of interlimb coordination during bipedal walking [3,4].
As such, studies in quadrupedal terrestrial mammals that walk on all four limbs,
such as the cat, are appropriate and useful translational models to uncover
neurophysiological and biomechanical mechanisms involved in the control of
interlimb coordination during human locomotion. To study interlimb coordination
during locomotion, we recently devised a series of experimental paradigms
whereby the speeds of the left and right sides [5] or of the fore- and hindlimbs [6]
were independently controlled, respectively. Here, we briefly review recent
findings during left-right (i.e. unequal speeds for the left and right sides) and
transverse (i.e. unequal speeds for the fore- and hindlimbs) split-belt locomotion
paradigms in intact and spinal cord-injured cats.

W. Jensen et al. (eds.), Replace, Repair, Restore, Relieve – Bridging Clinical 29

and Engineering Solutions in Neurorehabilitation, Biosystems & Biorobotics 7,
DOI: 10.1007/978-3-319-08072-7_7, © Springer International Publishing Switzerland 2014
30 A. Frigon et al.

2 Methods

2.1 Animals and Surgical Procedures

All procedures were approved by the Animal Care Committee of the Université de
Sherbrooke and were in accordance with policies and directives of the Canadian
Council on Animal Care. Before and after experiments, animals were housed and
fed within designated areas. Five adult cats (1 male, 4 females) weighing between
3.5 and 7.7 kg were used. Cats were trained to walk on an animal treadmill with
four independently controlled running surfaces 120 cm long and 30 cm wide
(Bertec Corporation, Columbus, Ohio). A Plexiglas separator (120 cm long, 3 cm
high, 0.5 cm wide) was placed between the left and right belts for left-right split-
belt locomotion. Two Plexiglas separators (120 cm long, 50 cm high) were also
placed 30 cm apart to constrain the animal to walk with the left and right sides
separately on the two belts during left-right split-belt locomotion or at the midline
between the front and rear belts on the left side of the treadmill for transverse split-
belt locomotion. Cats were given food and affection as reward.
Implantation and spinal transection surgeries were performed under aseptic
conditions in an operating room with sterilized equipment. Prior to surgery, the cat
was sedated with an intramuscular (i.m) injection of Butorphanol (0.4 mg/kg),
Acepromazine (0.1 mg/kg), and Glycopyrrolate (0.01 mg/kg). Induction was done
with Ketamine/Diazepam (0.11 ml/kg in a 1:1 ratio, i.m.). Once anesthetized, the
cat was quickly intubated with a flexible endotracheal tube and anesthesia was
maintained by adjusting isoflurane concentration as needed (1.5 - 3%). The fur
overlying the back, stomach, and hindlimbs was shaved with electric clippers and
loose hair was vacuumed. The level of anesthesia was confirmed and adjusted
throughout the surgery by monitoring cardiac and respiratory rates, by applying
pressure to the paw to detect limb withdrawal, and by assessing jaw tone. Body
temperature was monitored using a rectal thermometer. In two cats (2 females), the
spinal cord was completely transected (i.e. spinalized) at low thoracic levels. A
small laminectomy was performed between the junction of the 12th and 13th
vertebrae, the dura was removed, and after local lidocaine application (Xylocaine,
2%), the spinal cord was transected with surgical scissors. Hemostatic material
(Surgicel) was inserted within the gap, and muscles and skin were sewn back to
close the opening in anatomic layers.
For electromyography (EMG), pairs of Teflon insulated multistrain fine wires
(AS633; Cooner wire, Chatsworth, CA, USA) were directed subcutaneously from a
head-mounted 24 pin connector (Hirose Electric Co Ltd) and sewn into the belly of
selected hindlimb and forelimb muscles for bipolar recordings. During surgery an
antibiotic (Convenia, 0.1 ml/kg) was injected subcutaneously and a transdermal
fentanyl patch (25 mcg/hr) was taped to the back of the animal 2-3 cm from the
base of the tail. During surgery and approximately seven hours later, another
analgesic (Buprenorphine 0.01 mg/kg) was administered subcutaneously. After
surgery, cats were placed in an incubator and closely monitored until they regained
consciousness.
The Control of Interlimb Coordination during Left-Right and Transverse Split-Belt 31

For the spinalized cats, the bladder was manually emptied 1–2 times each day.
The hindlimbs were frequently cleaned by placing the lower half of the body in a
warm soapy bath. After a few days, cats were trained 5 times a week to walk on the
treadmill. Early after spinalization, training consisted of two experimenters moving
the hindlimbs over the moving treadmill belt to simulate locomotion with similar
joint kinematics and paw contacts while the forelimbs were positioned on a fixed
platform located ∼1 cm above the belt. After a few days, the skin of the perineal
region was stimulated to evoke stepping movements. A Plexiglas separator was
placed between the hindlimbs to prevent them from impeding each other because of
increased adductor activity. Initially, the experimenter supported the hindquarters
by lifting the tail. Recording sessions started once the animals attained a stable
locomotor pattern with full weight bearing and consistent plantar foot placement.
The experimenter provided equilibrium by holding the tail.

2.2 Experimental Paradigms

Left-right split-belt locomotion: Each cat performed two sessions that consisted of
several episodes of tied-belt (i.e. equal speeds for the left and right sides) and left-
right split-belt locomotion. In spinalized cats only the hindlimbs moved, with the
forelimbs on a fixed platform. During tied-belt locomotion, speeds ranged from 0.3
to 1.0 m/s in 0.1-m/s increments. During left-right split-belt locomotion, one side
walked at a constant speed of 0.4 m/s, 0.5 m/s or 0.6 m/s while the other side varied
its speed from 0.3 to 1.0 m/s in 0.1-m/s increments. Episodes of tied-belt or left-
right split-belt locomotion at the different speeds were presented randomly from
one session to another and approximately 30 seconds of rest were given between
episodes. Each episode lasted approximately 20 s to obtain 10-15 cycles. Left and
right treadmill speeds were increased with an acceleration of 0.1 m/s and data
collection started when the desired speeds were attained.

Transverse split-belt locomotion: Each cat performed five sessions of several

locomotor episodes in five conditions: (1) fore- and hindlimbs walking at equal
speeds (i.e. tied-belt locomotion) from 0.4 m/s to 0.8 m/s in 0.1-m/s increments; (2,
3) forelimbs walking at a constant speed of 0.4 m/s or 0.8 m/s with the speed of the
hindlimbs increasing from 0.4 to 0.8 m/s in 0.1-m/s increments; (4, 5) hindlimbs
walking at a constant speed of 0.4 m/s or 0.8 m/s with the speed of the forelimbs
increasing from 0.4 to 0.8 m/s in 0.1-m/s increments. In a few sessions, faster
speeds (up to 1.4 m/s) were used to evaluate the effects of increasing the speed
difference between the front and rear belts. Only episodes where the animal had its
forelimbs and hindlimbs on their respective belts were retained for analysis. Each
episode lasted approximately 20 s to obtain 10-15 cycles. Front and rear treadmill
speeds were increased with an acceleration of 0.1 m/s and data collection started
when the desired speeds were attained.
32 A. Frigon et al.

2.3 Data Acquisition and Analysis

Videos of the left and right sides were captured with two cameras (Basler AG) at
60 frames per second. A custom-made Labview program acquired the images and
synchronized the cameras. Videos were analyzed off-line. Cycle duration was
measured from successive paw contacts. Paw contact was defined as the first frame
where the paw made visible contact with the treadmill surface. Stance duration
corresponded to the interval of time from paw contact to the most caudal
displacement of the paw relative to the hip or the shoulder, while swing duration
was measured as cycle duration minus stance duration.

3 Results

3.1 Left-Right Split-Belt Locomotion

One form of adjustment in interlimb coordination occurs when walking along a
circular path, where the outer leg must walk faster than the inner leg [7]. One way
to simulate some features of circular path walking is by independently controlling
the speed of the left and right sides (i.e. left-right split-belt locomotion). During
left-right split-belt locomotion, the stance and swing phases on the slow side are
increased and decreased, respectively, while the stance and swing phases on the
fast side are decreased and increased, respectively [5,8,9]. We recently studied
bilateral changes in hindlimb stance and swing phases by measuring the slopes of
the linear regressions between stance duration and cycle duration (rSTA) and
between swing duration and cycle duration (rSW) during left-right split-belt and
tied-belt (i.e. equal speeds on left and right sides) locomotion in intact and chronic
spinalized adult cats [5]. The slopes of the regressions between the phases and
cycle duration quantify how the stance and swing phases vary as a function of cycle
duration. During tied-belt locomotion, rSTA was significantly greater than rSW
bilaterally, as shown previously [10,11]. During left-right split-belt locomotion,
rSTA and rSW were respectively decreased and increased on the constant side,
compared to values obtained during tied-belt locomotion, whereas on the varying
side, rSTA and rSW were respectively increased and decreased. Thus, phase variations
were differentially modulated in both hindlimbs concurrently. Results were similar
in intact and chronic spinalized cats, indicating that the bilateral control of phase
variations is mediated at the level of the spinal cord, most likely by a sensory
mechanism.

3.2 Transverse Split-Belt Locomotion

While left-right split-belt locomotion alters some features of interlimb coordination,
independently controlling the speed of the fore- and hindlimbs primarily alters
inter-girdle coordination. The adaptation to transverse split-belt locomotion is
The Control of Interlimb Coordination during Left-Right and Transverse Split-Belt 33

strikingly different if it is the forelimbs or the hindlimbs that are walking faster [6].
If the forelimbs walk faster than the hindlimbs, there is often an uncoupling of the
forelimb and hindlimb rhythms (i.e. unequal cycle durations) with the forelimbs
taking two or more steps for every hindlimb cycle. As a result, the sequence of limb
contacts (i.e. footfall patterns) that normally proceeds with a hindlimb contact
followed by contact of the homolateral forelimb, termed a lateral sequence [12], is
altered. When the forelimbs walk faster than the hindlimbs, a diagonal sequence
can emerge whereby contact of the hindlimb is followed by contact of the
contralateral forelimb. In contrast, if the hindlimbs walk faster than the forelimbs,
cycle duration is equal at both girdles, even with hindlimb speeds up to 1.4 m/s.
The footfall pattern also maintains a normal lateral sequence. From these results, it
is clear that inter-girdle coordination is organized asymmetrically in quadrupeds.

4 Conclusion

Left-right and transverse split-belt locomotion are useful tools to study interlimb
coordination during quadrupedal locomotion. We recently showed that phase
variations are bilaterally altered during left-right split-belt locomotion and that a
spinal mechanism is involved [5]. We have also shown that inter-girdle
coordination is organized asymmetrically and that an uncoupling of the forelimb
and hindlimb rhythms occurs when the forelimbs are made to walk at a faster
speed than the hindlimbs [6]. An uncoupling of the forelimb and hindlimb
rhythms also occurs following incomplete thoracic [13] or cervical [14] spinal
cord injuries and it is always the forelimbs that take extra steps, similar to what
occurs with transverse split-belt locomotion with the forelimbs walking faster.
Transverse split-belt locomotion could help elucidate the mechanisms involved in
this uncoupling and its potential role in adapting interlimb coordination to certain
environmental demands. In coming years, we will determine how the control
systems regulating interlimb coordination are modified and adapt following
incomplete spinal cord injuries and other types of injuries or diseases that disrupt
the control of locomotion.

Acknowledgment. The present research was funded by a Discovery Grant and by a

Research Tools and Infrastructure Grant from the Natural Sciences and Engineering
Research Council of Canada to Alain Frigon.

References
[1] Talpalar, A.E., Bouvier, J., Borgius, L., Fortin, G., Pierani, A., Kiehn, O.: Dual-mode
operation of neuronal networks involved in left-right alternation. Nature 500(7460),
85–88 (2013)
[2] Kiehn, O.: Development and functional organization of spinal locomotor circuits.
Curr. Opin. Neurobiol. 21(1), 100–109 (2011)
 Another Random Document on
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He paused and looked down at her in passionate wrath while he
wondered what she would say to all this; but she was silent.
"Again I ask you why should I spare you?" he repeated; "are you not
afraid of my vengeance, Xenie St. John?"
"No, I am not afraid," she repeated, defiantly, yet even as she spoke
he saw that a shudder that was not of the morning's cold shook her
graceful form. A sudden consciousness of the truth that lurked in his
words had rushed over her.
"Yes, we are deadly foes," she repeated to herself, with a deeper
consciousness of the meaning of those words than she had ever had
before. "Why should he spare me, since I am wholly in his power?"
His voice broke in suddenly on her swift, tumultuous thoughts,
making her start with its cold abruptness.
"Ah, I see that you begin to realize your position," he said, icily.
"What is your revenge worth now in this moment of your deadly
peril? Is it dearer to you than your life?"
"Yes, it is dearer to me than my life," she answered, steadily. "If
nothing but my life would buy revenge for me I would give it freely!"
He regarded her a moment with a proud, silent scorn. She returned
the gaze with interest, but even in her passionate anger and hatred
she could not help owning to her secret heart that she had never
seen him looking so handsome as he did just then in the rough but
well-fitting tweed suit, with the glow of the morning on his fair face,
and that light of scorn in his dark-blue eyes.
Suddenly he spoke:
"Well, go your way, Xenie St. John. You are in my way, but it is not
by this means I will remove you from it. I am not a murderer—your
life is safe from my vengeance. Yet I warn you not to go further in
your wild scheme of vengeance against me. It can only result in
disaster to yourself. I am forewarned of your intentions and your
wicked plot. You can never wrest from me the inheritance that Uncle
John intended for me!"
"We shall see!" she answered, with bold defiance, undaunted by his
threatening words.
Then, as the little babe in her arms began to moan pitifully again,
she remembered the dreadful trouble that had sent her out into the
rain, and turning from him with a sudden wail of grief, she began to
run along the shore, looking wildly around for some trace of the lost
one.
She heard Howard's footsteps behind her, and redoubled her speed,
but in a minute his hand fell on her shoulder, arresting her flight. He
spoke hastily:
"I heard you calling for Lora before I met you—speak, tell me if she
also is wandering out here like a madwoman, and why?"
She turned on him fiercely.
"What does it matter to you, Howard Templeton?"
"If she is lost I can help you to find her," he retorted. "What can you
do? A frail woman wandering in the rain with a helpless babe in your
arms!"
Bitterly as she hated him, an overpowering sense of the truth of his
words rushed over her.
She hated that he should help her and yet she could not let her own
angry scruples stand in the way of finding Lora.
She looked up at him and the hot tears brimmed over in her black
eyes and splashed upon her white cheeks.
"Lora is missing," she answered, in a broken voice. "She has been ill,
and last night she wandered in her mind. This morning while
mamma and I slept she must have stolen away in her delirium.
Mamma was prostrated by the shock, and I came out alone to find
her."
"You should have left the child at home. It will perish in the rain and
cold," he said, looking at her keenly.
She shivered and grew white as death, but pressed the babe closer
to her breast that the warmth of her own heart might protect its
tender life.
"Why did you bring the child?" he persisted, still watching her
keenly.
"I will not tell you," she answered, defiantly, but with a little shiver
of dread. What if he had seen her when she found it on the sands?
"Very well; you shall not stay out longer with it, at least. Granted
that we are deadly foes—still I have a man's heart in my breast. I
would not willingly see a woman perish. Go home, Xenie, and care
for your mother. I will undertake the search for Lora. If I find her
you shall know it immediately. I promise you."
He took the heavy cloak from his own shoulders and fastened it
around her shivering form.
She did not seem to notice the action, but stood still mechanically,
her dark, tearful eyes fixed on the mist-crowned sea. He followed
her gaze, and said in a quick tone of horror:
"You do not believe she is in there? It would be too horrible!"
"Oh, my God!" Mrs. St. John groaned, with a quiver of awful dread
in her voice.
He shivered through all his strong, lithe young frame. The thought of
such a death was terrible to him.
"You said she was ill and delirious?" he said, abruptly.
"Yes," she wailed.
"Poor Lora—poor little Lora!" he exclaimed, with a sudden tone of
pity. "Alas! is it not too probable that she has met her death in those
fatal waves?"
"Oh, she could not, she could not," Xenie moaned, wildly. "She hated
the sea. Her lover was drowned in it. She could not bear the sight or
the sound of it."
He did not answer for a moment. He was looking away from her
with a great, solemn dread and pity in his beautiful, blue eyes.
Suddenly he said, abruptly:
"Go home, Mrs. St. John, and stay there until you hear news. I will
go and arouse the village. I will have help in the search, and if she is
found we will bring her home. If she is not, God help you, for I fear
she has drowned herself in the sea."
With a long, moaning cry of anguish, Xenie turned from him and
sped along the wet sand back to her mother. Howard Templeton
watched the flying figure on its way with a grave trouble in his
handsome face, and when she was out of sight, he turned in an
opposite direction and walked briskly along the sand, looking
carefully in every direction.
"They talk of judgment," he muttered. "Has God sent this dreadful
thing upon Xenie St. John for her sinful plans? If it is so, surely it will
bring her to repentance. In the face of such a terrible affliction, she
must surely be afraid to persist in attempting such a stupendous
fraud."
 CHAPTER XVI.
Half dead with weariness and sorrow, Mrs. St. John staggered into
her mother's presence with the wailing infant in her arms.
She sank down upon the floor by the side of the couch and laid the
child on her mother's breast, moaning out:
"I found him down there, lying on the wet sand all alone, mamma—
all alone! Oh! Lora, Lora!"
A heart-rending moan broke from Mrs. Carroll's lips. Her face was
gray and death-like in the chill morning light.
She closed her arms around the babe and strained it fondly to her
breast.
"Mamma, are you better? Can you speak yet? I have much to tell
you," said Xenie, anxiously.
Mrs. Carroll made a violent effort at articulation, then shook her
head, despairingly.
"I will send for the doctor as soon as the maid returns. She cannot
be long now—it is almost broad daylight," said Xenie, with a heavy
sigh. "And in the meantime I will feed the babe. It is cold and
hungry. Mamma, shall I give it a little milk and water, warmed and
sweetened?"
Mrs. Carroll assented, and Xenie went out into the little kitchen,
lighted a fire and prepared the infant's simple nourishment.
Returning to Lora's room, she sat down in a low rocker, took the
child in her arms, and carefully fed it from a teaspoon, first removing
the cold blanket from around it, and wrapping it in warm, dry
flannels.
Its fretful wails soon ceased under her tender care, and it fell into a
gentle slumber on her breast.
"Now, mamma," she said, as she rocked the little sleeper gently to
and fro, "I will tell you what happened to me while I was searching
for my sister."
In as few words as possible, she narrated her meeting with Howard
Templeton.
Mrs. Carroll greeted the information with a groan. She was both
astonished and frightened at his appearance in France, when they
had supposed him safe in America.
She struggled for speech so violently that the dreadful hysteric
constriction in her throat gave way before her mental anguish, and
incoherent words burst from her lips.
"Oh, Xenie, he will know all now, and Lora's good name and your
own scheme of revenge will be equally and forever blasted! All is
lost!"
"No, no, mamma, that shall never be! He shall not find us out. I
swear it!" exclaimed her daughter passionately. "Let him peep and
pry as he will, he shall not learn anything that he could prove. We
have managed too cleverly for that."
And then the next moment she cried out:
"But, oh, mamma, you are better—you can speak again!"
"Yes, thank Heaven!" breathed Mrs. Carroll, though she articulated
with difficulty, and her voice was hoarse and indistinct. "But, Xenie,
what could have brought Howard Templeton here? Can he suspect
anything? Did he know that we were here?"
Xenie was silent for a moment, then she said, thoughtfully:
"It may be that he vaguely suspects something wrong. Indeed, from
some words he used to me, I believe he did. But what then? It is
perfectly impossible that he could prove any charge he might make,
so it matters little what he suspects. Oh, mamma, you should have
seen how black, how stormy he looked when I showed him the
child, and told him it was mine. I should have felt so happy then had
it not been for my fear and dread over Lora."
"My poor girl—my poor Lora!" wailed the stricken mother. "Oh,
Xenie, I am afraid she has cast herself into the sea."
"Oh, no, do not believe it. She did not, she could not! You know how
she hated the sea. She has but wandered away, following her wild
fancy of finding her husband. She was too weak to go far. They will
soon find her and bring her back," said Xenie, trying to whisper
comfort to the bereaved heart of the mother, though her own lay
heavy as lead in her breast.
She rose after a moment and went to the window.
"It is strange that Ninon does not return to get the breakfast," she
said, looking out. "Can her mother be worse, do you think,
mamma?"
"She may be, but I hardly think it likely. She was better of the fever
the last time Ninon went to see her. It is likely that the foggy, rainy
morning has deceived her as to the lateness of the hour. She will be
along presently, no doubt," said Mrs. Carroll, carelessly; for her
trouble rendered her quite indifferent to her bodily comfort.
Xenie sat down again, and rocked the babe silently for a little while.
"Oh, mamma, how impatient I grow!" she said, at length. "It seems
to me I cannot wait longer. I must put the child down and go out
again. I cannot bear this dreadful suspense."
"No, no; I will go myself," said Mrs. Carroll, struggling up feebly from
the lounge. "You are cold and wet now, my darling. You will get your
death out there in the rain. I must not lose both my darlings at
once."
But Xenie pushed her back again with gentle force.
"No, mamma, you shall not go—you are already ill," she said. "Let
the child lie in your arms, and I will go to the door and see if anyone
is coming."
Filled with alternate dread and hope, she went to the door and
looked out.
No, there was naught to be seen but the rain and the mist—nothing
to be heard but the hollow moan of the ocean, or the shrill, piping
voice of the sea birds skimming across the waves.
"It is strange that the maid does not come," she said again,
oppressed with the loneliness and brooding terror around her.
She sat down again, and waited impatiently for what seemed a
considerable time; then she sprang up restlessly.
"Mamma, I will just walk out a very little way," she said. "I must see
if anyone is coming yet."
"You must not go far, then, Xenie." Mrs. Carroll remonstrated.
Xenie dashed out into the rain again, and ran recklessly along the
path, looking far ahead of her as if to pierce the mystery that lay
beyond her.
Presently she saw a young French girl plodding along toward her.
It was Ninon, the belated maid. Over her arm she carried a dripping-
wet shawl.
It was a pretty shawl, of warm woolen, finely woven, and striped
with broad bars of white and red.
Xenie knew it instantly, and a cry of terror broke from her lips. It
belonged to Lora.
She had seen it lying around her sister's shoulders when she kissed
her good-night; yet here it hung on Ninon's arms, wet and dripping,
the thick, rich fringes all matted with seaweed.
 CHAPTER XVII.
Xenie's heart beat so fast at the sight of what Ninon was carrying
that she could not move another step.
She had to stand still with her hands clasped over her throbbing side
and wait till the girl came up to her. Then:
"Oh, Heaven, Ninon, where did you get that?" she gasped, looking at
the shawl with eyes full of horror, yet afraid to touch it, for it seemed
like some dead thing.
"Oh, ma'amselle," faltered the girl stopping short and looking at
Xenie's anguished face. "Oh, ma'amselle," she faltered again, and
her pretty, piquant face grew white and her black eyes sought the
ground, for Ninon, although poor and lowly, had a very tender heart,
and she could not bear to see the anguish in the eyes of her young
mistress.
"I asked you where did you get that shawl?" Xenie repeated. "It was
my sister's shawl. She wore it last night, and now, to-day, she is
missing. Did you know that, Ninon?"
"Yes," the girl answered, in her pretty, broken English. She had
heard it. A gentleman, a tourist, had brought the news to the village,
and the men were all out looking for her.
Would her mistress come to the house? She had something to tell
her, but not out there in the cold and wet. She looked fit to drop,
indeed she did, declared the voluble, young French girl.
So she half-led, half-dragged Mrs. St. John back to the cottage and
into the room where the stricken mother was waiting for tidings of
her lost one.
The maid had a sorrowful story to tell.
The waves had cast a dead body up on the beach an hour ago—the
corpse of a woman, thinly dressed in white, with long, beautiful
black hair flowing loosely and tangled with seaweed.
They could not tell who she was, for—and here Ninon shuddered
visibly—the rough waves had battered and swollen her features
utterly beyond recognition.
But they thought that she was young, for her limbs were white and
round, and beautifully moulded, and this shawl which Ninon carried
had been tightly fastened about her shoulders.
The maid had recognized it and brought it with her to show the
bereaved mother and sister, and to ask if they wished to go and view
the body and try to identify it.
All this the maid told sorrowfully and hesitatingly, while the two
women sat like statues and listened to her, every vestige of hope
dying out of their hearts at the pitiful story, and at length Xenie cast
herself down upon the wet shawl and wept and wailed over it as
though it had been the dead body of poor Lora herself lying there all
wet and dripping with the ocean spray before her anguished sight.
Then Ninon begged her to listen to what she had to say further.
"The gentleman is going to send a vehicle for you that you may go
and see the body, if you wish—I can hear the roll of the wheels now!
Shall I help you to get ready?"
Xenie looked at her mother with a dumb inquiry on her beautiful,
pallid features.
"Yes, go, dear, if you can bear it. Perhaps, after all, it may not be our
darling," said Mrs. Carroll, with a heavy sigh, even while she tried to
cheat her heart by the doubt which she felt to be a vain one.
So, with Ninon's aid, Xenie changed her wet and drabbled garments
for a plain, black silk dress, and a black hat and thick veil.
Then, leaving the maid to take care of her mother, Mrs. St. John
entered the vehicle and was driven to the place where a group of
excited villagers kept watch over a ghastly something upon the sand
—the mutilated semblance of a human being that the cruel sea had
beaten and buffeted beyond recognition.
It was a terrible ordeal for that young, beautiful, and loving sister to
pass alone.
As she stepped from the vehicle with a wildly-beating heart before
the curious scrutiny of the strangers around her, she involuntarily
cast a glance around her in the vague, scarce-defined belief that
Howard Templeton would be upon the scene. But, no, there was no
sign of his presence.
Strangers advanced to lead her forward; strangers questioned her;
strangers drew back the sheet that had been reverently folded over
the dead, and showed her that ghastly form that all believed must
have been her sister.
She knelt down, trying to keep back her sobs, and looked at the
form lying there in the awful majesty of death, with the cold,
drizzling rain beating down on its swollen, discolored features.
How could that awful thing be Lora—her own, beautiful, tender
Lora?
And yet, and yet, that beautiful, long, black hair—that fine,
embroidered night-robe, hanging in tattered remnants now where
the sea had rent it—did they not belong to her sister? Sickening with
an awful dread, she touched one of the cold, white hands.
It was a ghastly object now, swollen and livid, yet you could see that
once it had been a beautiful hand, delicate, dimpled, tapering.
And on the slender, third finger, deeply imbedded in the swollen
flesh, were two rings—plain, broad, gold bands. Xenie's eyes fell
upon them, and with a wild, despairing cry, "Oh, Lora, my sister!"
she fell upon the wet sand, in a deep and death-like swoon.
 CHAPTER XVIII.
After leaving Xenie on the seashore, Howard Templeton walked away
hurriedly to the little fishing village, a mile distant, and gave the
alarm of Lora's disappearance.
By a promise of large rewards, he speedily induced a party of men
to set out in separate directions to scour the adjacent country for
the wanderer.
But scarcely had they set out on their mission when someone
brought to Howard the news of the corpse that old ocean had cast
upon the sands.
Dreading, yet fully expecting to behold the dead body of Lora
Carroll, Howard Templeton turned back and accompanied the man to
the scene.
They found a group of excited men and women gathered, on the
shore, drawn thither by that nameless fascination which the dreadful
and mysterious always possesses for every class of minds whether
high or low.
Conspicuous in the group was Ninon, the pretty young maid-servant,
and, as Howard came upon the scene, she was volubly explaining to
the bystanders that the shawl which was tightly pinned about the
shoulders of the dead woman belonged to the missing girl for whom
the men had gone out to search.
Was she quite sure of it, they asked her. Yes, she was quite sure.
She had seen it night after night lying across the bed in the young
lady's sleeping-apartment.
When she was ill and restless, as often happened, she would put it
around her shoulders and walk up and down the room for hours,
weeping and wringing her hands like one in sore distress.
"Yes," Ninon said, she could swear to the shawl. She would take it
home with her and show it to her mistress, and they would see that
she was right.
No one interfered to prevent her.
With an irrepressible shudder at touching the dead, the girl drew out
the pins and took the wet shawl.
Then, as she started on her homeward way, Howard Templeton, who
had stood still like one in a dream of horror, started forward and told
her that he himself would send a vehicle for the ladies, that they
might come if they wished to identify the body.
For himself, he had no idea whether or not that the poor, bruised
and battered corpse could be Lora Carroll.
He could see nothing that reminded him of her except the beautiful,
black hair lying about her head in heavy, clinging masses, sodden
with water and tangled with seaweed.
He longed, yet dreaded, for Mrs. Carroll and her daughter to arrive
and confirm or dissipate his fears and end the dreadful suspense.
And yet, with the rumble of the departing wheels of the conveyance
he had sent for them, a sudden cowardice stole over the young
man's heart.
He could not bear the thought of the anguish of which he might
soon be the witness.
Obeying a sudden, inexplicable impulse, he turned from the little
company of watchers by the dead and walked off from them, taking
the course along the shore that led away from the little village.
Oftentimes those simple little impulses that seem to us mere
accidental happenings, would appear in reality to be the actual
fulfillment of some divine design.
Howard little dreamed, as he turned away with a kind of sick horror,
that was no shame to his manhood, from the sight of so much
misery, that "a spirit in his feet" was guiding him straight to the
living Lora, even while his heart foreboded that it was she who lay
cold and lifeless on the ocean shore.
Yet so it was. True it is, as the great bard expresses it, that "there's
a divinity that shapes our ends, rough-hew them as we will."
Howard hurried along aimlessly, his thoughts so busy on one painful
theme that he took no note of where he was going, or how fast he
went.
He was a rapid walker usually, and when he at length brought
himself to a sudden abrupt stop he realized with a start that he had
come several miles at least.
The rain had ceased, the sun had come out in all its majestic glory,
and beneath its fervid kisses the mist that hid the ocean was melting
into thin air.
It bade fair to be a beautiful day, after all.
The pearly rain-drops sparkled like diamonds on the leaves and
flowers, the sky was blue and beautiful, with here and there a little
white cloud sailing softly past.
The day had began like many a life, in clouds and tears, but it
promised to close in as fair and sweet a serenity as many an early-
shadowed life has done.
Howard involuntarily thought of the poet's beautiful lines:
 "Be still, sad heart, and cease repining,
Behind the clouds is the sun still shining!
Days of sunshine are given to all,
Though into each life some rain must fall."

He paused and looked around him. He found that he had come into
the outskirts of another rude, little fishing village.
A little ahead of him he could see the fishers bustling about on the
shore.
"I have come four miles, at least," he said to himself. "What a great,
hulking, cowardly fellow I am to run that far from a woman's tears.
Far better have stayed and tried to dry them. Um! She wouldn't have
let me," he added, with a rueful second thought.
Then, after a moment's idle gazing out at sea, aimlessly noting the
flash of a sea-gull's wing as it wheeled in the blue air above him, he
said, resolutely:
"I'll go back, anyhow. Perhaps I can do something to help them.
They are but women—my countrywomen, too, and I'll not desert
them in their trouble, even though she does hate me."
He turned around suddenly to return, and the fate that was
watching him to prevent such a thing, placed a simple stone in the
way. He stepped upon it heedlessly, his ankle turned, and, with a
sharp cry of pain, Howard fell to the ground.
He made an effort to rise, but the acute pains that suddenly darted
through his ankle caused him to fall back upon the wet sand in a
hurry.
"Umph! my ankle is evidently master of the situation," he thought,
with an expression of comical distress.
Raising himself on his elbow, he shouted aloud to the men in the
distance, and presently two of them came running to his assistance.
"I have sprained my ankle," he explained to them in their native
tongue. "Please assist me to rise, and I will try to walk."
But when they took him by the arms and raised him up, they found
that it was impossible for him to walk.
"This is a deuced bore at the present time, certainly," complained
the sufferer. "Can you get me any kind of a trap to drive me back to
the village yonder?"
The peasants looked at him stupidly, and informed him carelessly
that there was nothing of the kind available. Only one man in the
vicinity owned a horse, and it had sickened and died a week before.
Howard felt a great and exceeding temptation to swear a very small
oath at this crisis, but being too much of a gentleman to yield to this
wicked whisper of the evil one, groaned very loudly instead.
"Then what the deuce am I to do?" he inquired, as much of himself
as of the two fishermen. "How am I to get away from this spot of
wet sand? Where am I to go?"
The peasants scrutinized him as stupidly as before, and to all of
these questions answered flatly that they did not know, indeed.
Howard thought within himself that the proverbial politeness of the
French was greatly tempered by stupidity in this case.
"Well, then," he inquired next, "is there any kind of a hotel around
here?"
"Yes, there was such a place," they informed him, readily; and
Howard at once begged them to summon aid and construct a litter
for him, promising to reward them liberally if they would carry him
to the hotel.
Gold—that magic "open sesame" to every heart—procured him ready
and willing attention.
It was but a short while before he found himself in tolerably
comfortable quarters at the rude hotel of the fishing village, and
obsequiously waited upon by the single Esculapius the place
afforded.
Howard's sprain was pronounced very severe indeed. It was so
painful that he could not walk upon it at all, and was ordered to
strict confinement to his couch for three days.
"A fine prospect, by Jove!" Howard commented, discontentedly.
"What am I to do shut up here three days in solitary confinement?
and what will those poor women do over yonder with not a single
masculine soul to turn to in their helplessness? Not that they wish
my help, of course, but I had meant to offer it to them all the same
if there was anything I could have done," he added, grimly, to his
own self.
The three days dragged away very drearily. On the fourth day
Howard availed himself of the aid of a crutch and got into the little
public room of the hotel.
Among the few idlers that were gathered about in little friendly
groups, he saw a rather intelligent-looking fisherman going from one
to another with a small slip of paper in his hand.
As they read it some shook their heads, and some dived into their
pockets and brought forth a few pence, which they dropped into the
fisherman's extended palm.
Howard was quite curious by the time his turn came. He took the
paper in his hand and found it to be an humble petition for charity,
which duly set forth:
"Whereas, an unknown woman lies ill of a fever at a house of one
Fanchette Videlet, a poor widow, almost without the necessaries of
life, it is here begged by the said widow that all Christian souls will
contribute a mite to the end of securing medical attendance and
comforts for the poor unknown wayfarer."
This petition, which was written in excellent French, and duly signed
Fanchette Videlet, had a strange effect upon Howard Templeton. His
face grew pale as death; his eyes stared at the poor fisherman in
perplexed thought, while he absently plunged his hand into his
pocket and drew it out full of gold pieces.
 CHAPTER XIX.
"Here, my man, take this," he said, putting the coins into the man's
hand.
"Why, this is too much, sir," said the honest fisherman, holding his
hand out and looking at the gold in surprise. "You will rob yourself,
sir."
"No, no; keep it. It is but a trifle," said Howard, pushing his hand
back. "But, pray, will you answer a few questions for me?"
"As many as you like, sir—and thank you for your generosity,"
answered the fisherman, politely.
"I am very much interested in the sad story written here," said
Howard, glancing at the paper which he still held in his hand.
"Yes, sir, it is very sad," assented the fisherman.
"How came this unknown sick woman at the Widow Videlet's
house?" inquired Howard.
"The poor soul came there a few days ago, sir. She was ill and quite
out of her head—could give no account of herself."
"Can you tell me what day she came there?"
"This makes the fourth day since she came, sir. I remember it was
the same day you were brought to the hotel."
The young man started. It was the same day that Lora Carroll had
disappeared.
Could it be Lora? Had it been some other waif the great sea had cast
up from its deep?
"Did you see this woman? Could you describe her to me?" asked
Howard, eagerly.
"I saw her the day she came wandering into Dame Videlet's
cottage," was the answer.
"You can tell me how she looked then," said Howard, restraining his
impatience by a great effort.
"Yes, sir. She was a mere girl in appearance—very young and very
beautiful, with black eyes and long, black hair. She was thinly clad in
a fine night-dress," answered the fisherman.
"Did you say she was out of her mind?" asked Howard.
"Yes, sir; she raved continually."
"What form did her delirium take?"
"Oh, sir," cried the fisherman, in a tone of pity and sympathy for the
wretched unknown, "it seemed like she had lost her baby. She was
going around from one to the other in the place asking, asking
everyone, for her baby. She said she was so tired and she had lost it
out of her arms in the rain and the darkness, and could not find it
again."
Howard's heart gave a great, tumultuous bound of surprise, then
almost stopped beating with the suddenness of the shock.
It all rushed over him with the suddenness of a revelation.
It had seemed so strange to him that Mrs. St. John should have
taken the tender little babe with her in the rain and wind when she
went to search for Lora.
The truth flashed over him like lightning now.
Xenie had found the babe upon the sand where Lora had dropped it
in her fevered flight.
No wonder she had been so angry and defiant when he had
questioned her about it.
He felt sure now, beyond the shadow of a doubt, that the unknown
sick woman in the poor widow's cottage could be none other than
Lora herself.
"Poor, unhappy creature," he thought, with a thrill of commiseration.
"It must be that God himself has sent me here to succor and
befriend her."
He rose hurriedly and took up his crutch.
"How far is Dame Videlet's cottage from here?" he inquired.
"But a few rods, sir—a little further on toward the beach," said the
fisherman, regarding him in some surprise.
"I will go down there and see that unfortunate woman, if you will
guide me," said Howard. "I believe that she is a friend of mine. You
may return their pence to those poor fishermen, who can ill spare it,
perhaps. I will charge myself with her expenses even if she should
not prove to be the person I think she is."
The fisherman looked at him admiringly and hastened to do his
bidding.
Then they walked along to the widow's cottage very slowly, for
Howard found himself exceedingly awkward in the use of his crutch.
But after all it seemed but a very few minutes before they stood in
the one poor little room of Dame Videlet's dilapidated cot bowing to
the kind old soul who had taken the poor wayfarer in beneath the
shelter of her lowly roof, shared her simple crust with her, and
tended her with kindly, Christian hands.
"How is your patient to-day, my kind woman?" inquired the young
man.
"Ah, sir, ah, sir, you may even see for yourself," she answered sadly,
as she turned toward the bed.
Howard went forward with a quickened heart-beat, and stood by her
side looking down at the sufferer.
Yes there she lay—poor little Lora—with wide, unrecognizing, black
eyes, with cheeks crimson with fever and parted lips through which
the breath came pantingly. A heavy sigh broke unconsciously from
Howard's lips.
"Good sir, do you know her?" asked the woman, regarding him
anxiously.
"Yes, I know her," he answered; "she is a friend of mine and has
wandered away from her home in the delirium of fever. You shall be
richly rewarded for your noble care of her."
"I ask no reward but the blessing of Heaven, sir," said the good old
woman, piously; "I have done the best I could for her ever since she
staggered into the door and asked me for her lost baby."
As if the word struck some sensitive chord in her consciousness,
Lora turned her wild, bright eyes upon Howard's face, and
murmured in a pathetic whisper:
"Have you found my baby—Jack's baby and mine?"
Alas for Xenie's secret, guarded with such patient care and sleepless
vigilance.
Howard looked down upon her with a mist of tears before his sight—
she looked so fair, and young, and sorrowful, lying there calling for
her lost little child.
"I have lost my baby, I have lost my baby!" she wailed aloud,
throwing her arms wildly over her head and tangling her fingers in
the long, dark tresses floating over the pillow in their beautiful
luxuriance. "It is lost, lost, lost, my darling little one! It will perish in
the rain and the cold!"
Involuntarily Howard reached out and took one of the restless white
hands in his, and held it in a firm and tender clasp.
"Lora, Lora," he said, in a gentle, persuasive voice, "listen to me.
The baby is found. Xenie found it on the shore where you lost it out
of your arms. It is safe—it is well, with Xenie."
Lora turned her hollow glance upon his face, and though no gleam
of recognition shone in her eyes, his impressive words penetrated
her soul. She threw out her arms yearningly.
"It is found, it is found! Oh, thank God!" she murmured, happily.
"Bring him to me, for the love of Heaven! Lay him here upon my
breast, my precious little son!"
"Oh, sir, then it is true she had a child; and it is living. I thought
perhaps it was dead," said the poor widow.
"She has a child, indeed, and she lost it in her delirious flight; but
her sister found it soon afterward. It is at this moment not more
than four miles from here," answered the young man, without
reflecting that many things might have happened during his long
imprisonment of four days in the lonely little fishing village.
"Then, if you will take my advice, sir, as she is a friend of yours, you
will try to get that child here as soon as possible. I will do the best I
can for her, and the doctor has promised to do all in his power; but I
believe that the child is the only thing that will save her life," said
Dame Videlet, gravely shaking her head in its homely white cap.
"It shall be brought," said Howard, earnestly, and without a doubt
but that he could keep the promise thus made.
Dame Videlet thanked God aloud, then added that the sooner it
were brought the better it would be for the mother.
All the while poor Lora lay tossing in restless pain, and begging
piteously for her little child to be laid upon her breast.
Howard bent over her as tenderly and gently as a brother.
"Lora, my poor child, try to be patient," he said. "I will bring the
child to you; only be patient a little while."
But it was all in vain to preach patience to that racked heart and
weary, fevered brain.
He stole away, followed by despairing cries for the little child—cries
that echoed in his heart and brain many days afterward, when his
warm heart was half-broken because he could not keep the promise
he had made in such perfect confidence and hope.
"How shall I get back to the village four miles away from here?" he
asked of the man who had accompanied him and was still waiting
for him.
"I can take you in my fishing-boat and row you there, and welcome,
sir," was the hearty response. "It's a wee bit leaky, but as good as
any other craft about, and there's no conveyance to be had by land."
"What a great simpleton I have been, by George, never to have
thought of a boat before," said Howard, looking vexed at himself.
"Here I have been four days, and wanting to get back to the village
badly, and never thought of all the little boats and the great, wide
ocean."
"Mayhap it's all for the best, sir," said the fisherman. "If you had
gone back sooner, you might never have found the sick lady, your
friend. You should see the hand of the Lord in it, my young sir."
"It looks like it," admitted Howard, "though, truth to tell, mon ami, I
do not usually look for such intervention in my affairs. His Satanic
Majesty is at present controlling my mundane affairs."
"The Lord rules, sir," answered the man, launching his little boat,
and trying to make a comfortable and dry seat for his crippled young
passenger.
The little boat shot out into the blue and sparkling waves, and
danced along like a thing of life in the beautiful spring sunshine.
"We must go a mile below the village to the home of my friend's
mother," Howard explained, as they went along.
Then he fell to wondering how Xenie would receive him when he
came to her with the glad tidings of Lora's discovery.
"How strange that I should carry her glad tidings," he thought. "I am
afraid I do not keep to the letter of my vow of hatred as firmly as
she does. Would she bring me good news as willingly?"
His heart answered no.
The keel grated on the shore, and springing out, they went up to the
pretty cottage were Mrs. Carroll had lived in strict retirement for
several months with her two daughters.
But there a terrible disappointment awaited Howard.
The cottage was untenanted.
They knocked several times, eliciting no response, and finally
opening the doors, they found that the occupants had moved out.
All was still and silent, and Howard's heart sank heavily as he
thought of poor Lora lying in the widow's cot and moaning for the
child he had promised to bring her.
"They are gone away," said Howard in a more hopeless voice than
he knew himself. "We must return to the village. We may hear news
from them there."
And in his heart he was fervently praying that he would, for how
could he return to Lora without the child?
They went to the little village where the dead body had been
washed upon the sands, and he asked everyone he met if they knew
where the occupants of the little cottage had gone.
No one could tell him anything of their whereabouts. They had
identified the drowned woman as their relative, had buried her, and
then quietly left the place, taking Ninon, the little maid, with them.
He could not obtain the least clew by which he might follow them
and bring them back to the sick girl whom they mourned as dead.
Howard did not know what to do now, for he remembered that
Dame Videlet had said that the child was the only thing that could
save Lora's life.
He went into the churchyard and looked at the new-made grave with
the cross of white marble, and the simple inscription "Lora, ætat
18."
"Perhaps the inscription might come true after all in a few—a very
few days," he thought, sadly.
 CHAPTER XX.
Howard did not know what to do: it seemed such a terrible thing to
go back to Lora with bad tidings. Perhaps the shock would kill her.
Oh, if Mrs. St. John had but waited a little longer! Why need she
have hurried away so precipitately?
Well, there was no help for it.
He must go back and tell her how inopportunely things had turned
out, and how sorry he was that he could not keep his promise.
He would get Dame Videlet to break it to her very gently.
She would not bungle over it like a great, awkward fellow like
himself.
The good old woman was waiting for him outside the door.
Her face was radiant, but it changed and grew very anxious as he
came up to her, and she saw that his arms were empty.
"Where is the child?" she whispered.
Briefly and sadly he told the story of his disappointment, and the
widow wiped the tears of sorrow from her eyes as he concluded.
"How is she now?" he inquired, anxiously.
"She has been better, much better, since you told her the child was
found. Her reason has returned to her, and she has wept tears of
joy. She is impatiently waiting for you now, for I told her just now
that you were returning. Alas, alas!" groaned Dame Videlet, her
tender heart quite melted by the thought of Lora's disappointment.
Howard groaned in unison with her.
"Will it go hard with her?" he asked, sorrowfully.
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