Preface

For centuries, electrical stimulation has been employed for treating neural disorders. As early as the Egyptian period, for example, medical records cite the use of electric eel shock therapy for pain, while during the eighteenth century it was used for treating paralysis and psychiatric symptoms. Enthusiasm for electrotherapy waned somewhat in the late 1800s and early 1900s as psychotherapies came to acquire greater prestige for treating psychiatric symptoms. In recent decades, however, interest in neurostimulation for therapy has again reignited, beginning chiefly with applications for motor disorders and pain treatment. High-frequency stimulation of the subthalamic nucleus or globus pallidus in patients with Parkinson's disease (PD) was notably found to produce clinical effects that were similar to surgical ablation, yet were reversible, unlike surgery, making them an appealing therapeutic strategy.

For the most part, the mechanisms elicited by neurostimulation are unknown. One widely acknowledged proposal is that neurostimulation somehow affects the electrical patterning that enables information transfer, since electrical activity is known to be fundamental to brain communication. The understanding of how patterning is structured, however, has been both evolving and vigorously debated, with the result that mechanisms of neurostimulation are themselves poorly understood. In the 1990s, though, Singer proposed a new thesis premised on the combinatorial properties of brain oscillations, which were intrinsic to neural operation. This provided for virtually unlimited freedom of expression in neural communication, unlike earlier models. Impelled in part by the prospect of an improved understanding of underlying mechanisms that may modulate, facilitate, or disrupt brain activity, as well as successes in symptomatic and long-term therapeutic relief, neurostimulatory and neuromodulatory protocols have since seen rapid growth in domains other than the motor diseases. Additionally fueling recent growth are the intrinsic advantages of neurostimulation over the more commonly used pharmaceutical agents. Unlike pharmacological approaches, which are difficult to target to specific brain regions and whose temporal distribution is usually prolonged, neurostimulation is inherently better suited to address the discrete spatial and temporal variation that characterizes individual dysfunctions.

The need for surgical intervention with its risk of secondary complications has spawned, moreover, an additional and equally broad group of non-invasive applications, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and repetitive TMS (rTMS), among others, which can be used both therapeutically as well as diagnostically. Diagnostically, for example, TMS can be a surrogate marker of recovery that is both sensitive and quantitative for cranial vascular disorders. TMS has also proven to be a useful tool for examining cortical and corticospinal physiology and enabling the understanding of motor dysfunction. When physiologic data are correlated with clinical function, they can assist diagnosis of underlying motor dysfunction. Operant conditioning with TMS, for instance, has been used both to assess the weakness of corticospinal connections and to promote targeted neuroplastic change.

**II**

**Section 3**

*by Sara Schatz*

**Section 4**

Neuromodulation for Neurodegenerative Disease **135**

**Chapter 7 137**

**Chapter 8 159**

and Spinal Dysfunction **175**

**Chapter 9 177**

**Chapter 10 191**

**Chapter 11 209**

**Chapter 12 245**

Intranasal Insulin as Promising Therapy for Preserving

Deep Brain Stimulation in Non-motor Symptoms of

*by Vladimira Vuletic, Valentino Racki, Darko Chudy* 

Neurostimulation and Neuromodulation for Pain

Cerebellar Transcranial Direct Current Stimulation (ctDCS) Effect in Perception and Modulation of Pain *by Tommaso Bocci, Roberta Ferrucci, Alberto Priori, Massimiliano Valeriani and Ferdinando Sartucci*

From Mechanisms to Analgesia: Towards the Use of

Non-Invasive Neuromodulation for Pain Relief in the Clinic

Neuromodulation in Urology: Current Trends and Future

Caudal Traction as a Pathogenetic Mechanism of Chiari

*by Miguel Bautista Royo-Salvador, Marco Fiallos-Rivera* 

*by Said M. Yaiesh, Abdullatif E. Al-Terki and Tariq F. Al-Shaiji*

Pragmatic Competence in MCI and AD

Neurodegenerative Diseases

*and Nenad Bogdanovic*

*by Alice G. Witney*

Malformation Type I

*and Horia Salca*

Applications

In view of the promise of these new methods, this book documents their expanding panorama, with particular emphasis on their evolution in medical care. The wide variety of medical applications presented in the text is intended not only to document the latest advances but also to evidence that their development is servicing more than the epiphenomenal; that is, neurostimulation and neuromodulation are not simply providing symptomatic care but involve substantive effects on dysfunctional physiology within the nervous system. Accordingly, the chapters illustrate the versatility of the technology and the generality of the physical and biological principles evoked in various treatments.

The book is divided into four sections that sequentially cover theory and breadth, a focal exploration of neurostimulation in motor diseases, new and ancillary treatments for diseases of neural degeneration, and, finally, novel applications likely to see future growth.

Keeping in mind the factors propelling the evolution of these approaches, Section 1 considers a trio of topics, including theoretical issues governing neurostimulatory influence, ancillary methodological support for enhancing efficacy, and the range of circumstances encountered in application. Specifically, Chapter 1 speaks to how neurostimulation is likely to influence the structure of global brain activity in disease, with epilepsy used as a paradigmatic case. Chapter 2 features ancillary methodological issues involving the targeting of neurostimulation that are fundamental to therapeutic efficacy. Chapter 3 then surveys the diversity of neurological diseases and impairments for which neurostimulation has achieved therapeutic success, illustrating the common principles evoked in each treatment.

Section 2 explores how neurostimulation therapies evolve in medical management, with motor diseases as an exemplar, since these applications have had the longest interval within which to develop. Focusing on spasticity and dystonia, the section provides an in-depth examination of how neurostimulation can be merged successfully with pharmacological and rehabilitative methods in medical management regimes. Chapter 4 emphasizes the medical management of rehabilitation in spasticity and how adjunct treatments using neurostimulation or pharmacology can promote rehabilitative practices. Reversing this approach, Chapter 5 considers the now prevailing use of pharmacological intervention for spasticity and how approaches that rely primarily on pharmaceutical reagents can be enhanced through supplementary treatments that include neurostimulation. Chapter 6 closes this section with a review of the diagnostic tools needed for selecting among these options.

An especially significant new field for neurostimulation and neuromodulation is the neurodegenerative diseases, discussed in Section 3. Given the increased prevalence and chronic nature of cognitive diseases characterizing the elderly and a worldwide upward trend in elderly demographics, there is great need for new approaches to the treatment of these diseases. The chapters in this section discuss two strategies for approaching treatments of these diseases: the delay of their temporal progression and the mitigation of their effects on quality of life. Chapter 7 explores a novel neuromodulatory option for treating Alzheimer's dementia (AD) using improved long-term insulin delivery protocols that can delay neuron loss in degenerating brain tissue. Chapter 8 reviews how neurostimulation can overcome debilitating side effects like insomnia and somatosensory dysfunctions that greatly impact quality of life.

**V**

Finally, Section 4 explores the current diversity of applications for which

applications of neurostimulation in spinal dysfunctions.

can engage the brain in the brain's own language.

neurostimulation is increasingly resorted to. These applications target not only the brain but also major tracts that course through the spinal cord. Chapters 9 and 10 explore the use of non-invasive neurostimulation for pain. The significance of this work becomes apparent when one considers that chronic pain affects billions of people yearly. Chapter 9 reviews the clinical use of neurostimulation, often employed for intractable circumstances, while Chapter 10 explores potential mechanisms evoked by stimulation. Finally, Chapters 11 and 12 discuss therapeutic

This is an exciting time for therapies used to treat CNS disorders, when traditional rehabilitative and neurotransmitter-based pharmacological approaches are being supplemented or even supplanted by the new methods of neurostimulation and neuromodulation, which can intervene more precisely and on shorter time scales in regions specifically affected by the disorders. This book seeks to convey the therapeutic prospects of these new methods as well as the details of medical praxis. It is hoped that the excitement of these developments will induce their use in wider clinical settings and inspire the evolution of an even broader range of regimes that

> **Denis Larrivee** Professor,

> > Spain

USA

Tehran, Iran

Mind and Brain Institute,

Loyola University Chicago,

**Seyed Mansoor Rayegani, M.D**

Professor of Physical Medicine and Rehabilitation, Physical Medicine and Rehabilitation Research Center, Shahid Beheshti University of Medical Sciences,

University of Navarra Medical School,

Finally, Section 4 explores the current diversity of applications for which neurostimulation is increasingly resorted to. These applications target not only the brain but also major tracts that course through the spinal cord. Chapters 9 and 10 explore the use of non-invasive neurostimulation for pain. The significance of this work becomes apparent when one considers that chronic pain affects billions of people yearly. Chapter 9 reviews the clinical use of neurostimulation, often employed for intractable circumstances, while Chapter 10 explores potential mechanisms evoked by stimulation. Finally, Chapters 11 and 12 discuss therapeutic applications of neurostimulation in spinal dysfunctions.

This is an exciting time for therapies used to treat CNS disorders, when traditional rehabilitative and neurotransmitter-based pharmacological approaches are being supplemented or even supplanted by the new methods of neurostimulation and neuromodulation, which can intervene more precisely and on shorter time scales in regions specifically affected by the disorders. This book seeks to convey the therapeutic prospects of these new methods as well as the details of medical praxis. It is hoped that the excitement of these developments will induce their use in wider clinical settings and inspire the evolution of an even broader range of regimes that can engage the brain in the brain's own language.

> **Denis Larrivee** Professor, Mind and Brain Institute, University of Navarra Medical School, Spain

> > Loyola University Chicago, USA

## **Seyed Mansoor Rayegani, M.D**

Professor of Physical Medicine and Rehabilitation, Physical Medicine and Rehabilitation Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

**IV**

impact quality of life.

In view of the promise of these new methods, this book documents their expanding panorama, with particular emphasis on their evolution in medical care. The wide variety of medical applications presented in the text is intended

not only to document the latest advances but also to evidence that their

likely to see future growth.

selecting among these options.

development is servicing more than the epiphenomenal; that is, neurostimulation and neuromodulation are not simply providing symptomatic care but involve substantive effects on dysfunctional physiology within the nervous system. Accordingly, the chapters illustrate the versatility of the technology and the generality of the physical and biological principles evoked in various treatments.

The book is divided into four sections that sequentially cover theory and breadth, a focal exploration of neurostimulation in motor diseases, new and ancillary treatments for diseases of neural degeneration, and, finally, novel applications

Keeping in mind the factors propelling the evolution of these approaches, Section 1 considers a trio of topics, including theoretical issues governing neurostimulatory influence, ancillary methodological support for enhancing efficacy, and the range of circumstances encountered in application. Specifically, Chapter 1 speaks to how neurostimulation is likely to influence the structure of global brain activity in disease, with epilepsy used as a paradigmatic case. Chapter 2 features ancillary methodological issues involving the targeting of neurostimulation that are fundamental to therapeutic efficacy. Chapter 3 then surveys the diversity of neurological diseases and impairments for which neurostimulation has achieved therapeutic success, illustrating the common principles evoked in each treatment.

Section 2 explores how neurostimulation therapies evolve in medical management,

with motor diseases as an exemplar, since these applications have had the longest interval within which to develop. Focusing on spasticity and dystonia, the section provides an in-depth examination of how neurostimulation can be merged successfully with pharmacological and rehabilitative methods in medical management regimes. Chapter 4 emphasizes the medical management of rehabilitation in spasticity and how adjunct treatments using neurostimulation or pharmacology can promote rehabilitative practices. Reversing this approach, Chapter 5 considers the now prevailing use of pharmacological intervention for spasticity and how approaches that rely primarily on pharmaceutical reagents can be enhanced through supplementary treatments that include neurostimulation. Chapter 6 closes this section with a review of the diagnostic tools needed for

An especially significant new field for neurostimulation and neuromodulation is the neurodegenerative diseases, discussed in Section 3. Given the increased prevalence and chronic nature of cognitive diseases characterizing the elderly and a worldwide upward trend in elderly demographics, there is great need for new approaches to the treatment of these diseases. The chapters in this section discuss two strategies for approaching treatments of these diseases: the delay of their temporal progression and the mitigation of their effects on quality of life. Chapter 7 explores a novel neuromodulatory option for treating Alzheimer's dementia (AD) using improved long-term insulin delivery protocols that can delay neuron loss in degenerating brain tissue. Chapter 8 reviews how neurostimulation can overcome debilitating side effects like insomnia and somatosensory dysfunctions that greatly

**1**

Section 1

Neurostimulation in

Theory and Practice

Section 1
