Innovative Neuromodulation

Jeffrey Arle, Jay L. Shils

• Publisher: Academic Press
• Year: 2017
• Print ISBN: 9780128004548
• eBook ISBN: 9780128005965
• Topic: Scienze biologiche
• Subtopic: Biotecnologia in medicina

Innovative Neuromodulation serves as an extensive reference that includes a basic introduction to the relevant aspects of clinical neuromodulation that is followed by an in-depth discussion of the innovative surgical and therapeutic applications that currently exist or are in development.This information is critical for neurosurgeons, neurophysiologists, bioengineers, and other proceduralists, providing a clear presentation of the frontiers of this exciting and medically important area of physiology. As neuromodulation remains an exciting and rapidly advancing field—appealing to many disciplines—the editors' initial work (Essential Neuromodulation, 2011) is well complemented by this companion volume.- Presents a comprehensive reference on the emerging field of neuromodulation that features chapters from leading physicians and researchers in the field- Provides commentary for perspectives on different technologies and interventions to heal and improve neurological deficits- Contains 300 full-color pages that begin with an overview of the clinical phases involved in neuromodulation, the challenges facing therapies and intraoperative procedures, and innovative solutions for better patient care

Section II

New Modes of Therapy

Outline

Chapter 5 Ultrasound Neuromodulation: A Chapter for Innovative Neuromodulation

Chapter 6 Optogenetics

Chapter 7 Introduction to Basic Mechanisms of Transcranial Magnetic Stimulation

Chapter 8 Transcranial Direct Current Stimulation: From Historical Foundations to Future Directions

Chapter 9 Viral Vectors and Other Modulatory Biologics

Chapter 5

Ultrasound Neuromodulation

A Chapter for Innovative Neuromodulation

R.F. Dallapiazza, K. Timbie and W.J. Elias, University of Virginia, Charlottesville, VA, United States

Abstract

Neuromodulation with ultrasound was first described more than 50 years ago. Recent developments in transcranial ultrasound delivery have renewed interest in applying ultrasound in neurosurgery and neuroscience. Since focused ultrasound is able to penetrate the skull to target deep cerebral structures without damaging intervening tissues, it has been hailed as a potential tool for noninvasive brain mapping and treatment in humans. This review discusses the fundamental mechanisms, historical and contemporary studies, and the potential clinical applications of ultrasound neuromodulation.

Keywords

Ultrasound; neuromodulation; high-intensity ultrasound; low-intensity ultrasound; mechanical neuromodulation; cavitation; noninvasive brain mapping; lesional neurosurgery

Outline

Introduction 102

Physics of Ultrasound 102

Historical Perspective of Ultrasonic Neuromodulation 106

Experimental Cortical Neuromodulation 108

Neuromodulation of Visual-Evoked Potentials 111

Experimental Neuromodulation of Deep Cerebral Structures 111

Hippocampal Neuromodulation With Ultrasound 112

Cortical Neuromodulation in Large Animals and Humans 114

Mechanisms of Ultrasonic Neuromodulation 115

Clinical Applications of FUS Neuromodulation 115

Future Clinical Applications of FUS Neuromodulation 117

Conclusions 118

References 118

Introduction

High-intensity focused ultrasound (HIFU) was originally developed in the 1950s as a neurosurgical tool to create discrete, thermal lesions within the brain.^1,2 However, its widespread adoption was limited by energy dissipation at the skull, which resulted in heating of the scalp and cortical surface. Over the past 15 years, advances in transcranial delivery of ultrasound have rejuvenated an interest in its use among neurosurgeons and neuroscientists.^3–9 Currently, ablative HIFU is being investigated as a treatment for movement disorders, brain tumors, and a wide array of neurological diseases.^10–15

Acoustic energy has long been known to influence the activity of electrically excitable tissues including cardiac and skeletal muscles,¹⁶ peripheral nerves,^17–25 and the central nervous system. In the central nervous system, high-intensity ultrasound has been used to reversibly inhibit neuronal activity by heating below the temperature threshold for tissue ablation, while low-intensity focused ultrasound (LIFU) has been used to transiently activate and depress neuronal function through nonthermal mechanisms. Although ultrasound-based neuromodulation has been studied for more than half a century, modern studies are emerging which demonstrate the ability to harness acoustic energy for neuromodulation with the exciting potential for noninvasive brain mapping and scientific discovery.

Physics of Ultrasound

Ultrasound can be defined as sound or acoustic pressure waves beyond the range for human hearing (>20 kHz). Ultrasound propagation requires a medium that is ideally a liquid or solid. As an ultrasonic pressure wave travels through a given medium, particles within it may displace and oscillate. The particle’s movement within the medium is a reflection of the magnitude of the pressure wave and the elasticity of the medium.^26–28

Like other waveform energies that follow simple harmonic motion, ultrasound can be characterized by its frequency, wavelength, velocity, amplitude, power, and intensity (Table 5.1 and Fig. 5.1). Similar to electrical resistance, ultrasound waves propagating through media encounter resistance, termed acoustic impedance. Acoustic impedance is largely dependent on the density of the medium. As ultrasound travels from one medium to another, acoustic impedance mismatch results in reflection or absorption of energy at the interface. This is especially important for therapeutic and experimental brain applications of ultrasound since there is a high mismatch between the skull and soft tissues (e.g., scalp and brain).²⁸

Table 5.1

Common Terminology Used in Ultrasound Neuromodulation

Term	Definition	Units
Frequency	Waves/second	1/s or Hertz (Hz)
Wavelength	Distance between wave peaks	mm
Velocity	Speed of propagation	cm/s
Amplitude	Magnitude of displacement within a medium	Megapascal (MPa)
Power	Rate of energy flow	Watts (W)
Intensity	Power/area	Watts/cm^2
Pulse repetition frequency	Number of pulses in 1 s	kHz
Duty cycle	Percentage of time ultrasound is on during a pulsing protocol	None

Figure 5.1 Continuous versus pulsed ultrasound. Ultrasound can be operated either continuously or in a pulsed fashion, and is defined by various parameters including amplitude, wavelength, frequency, and the pulse repetition frequency (PRF).

The Food and Drug Administration has a long history in regulating the safety of ultrasound used for medical imaging. Current safety measures include thermal index (TI) and mechanical index (MI), which reflect the likelihood of ultrasound causing thermal or biomechanical effects, respectively, in the tissue. The TI is defined as the ratio of the power used to that required to raise the temperature of the tissue by 1°C. The MI, typically used when a patient receives ultrasound contrast agents, provides an estimate of the risk of nonthermal bio effects. MI is defined as the peak negative pressure applied over the square root of the center frequency.²⁹

Other safety metrics include various measures of the amount of energy delivered to the tissue, and can be calculated based on the power and frequency of the applied ultrasound. Medical imaging ultrasound typically operates at frequencies between 2 and 20 mega-Hertz (MHz), while ultrasound used in therapeutic and experimental neurological applications is lower in frequency, ranging between 0.2 and 2 MHz.^26–28 Since ultrasound can be delivered in a continuous or pulsed fashion, defining measures of ultrasound intensity becomes complex. The average intensity of an ultrasound protocol is simply defined as the total power delivered divided by the beam area (W/cm²). Intensity does not provide a measure of the rate of energy accumulation in the tissue, so other intensity-related metrics must be considered. Spatial and temporal peak intensities refer to the instantaneous maximum intensity delivered at any one location or time, respectively (Fig. 5.2). Additionally, spatial average intensity (averaged over the beam area) and the temporal average intensity (averaged over a single pulse repetition period) are sometimes calculated. The pulse average intensity is equivalent to the temporal average intensity over the duty cycle. From these five basic intensity measures, several more standards can be calculated, as shown in Table 5.2.^26–28 Safety metrics are often reported using the spatial peak temporal average intensity, which is an excellent predictor of thermal effects. Current diagnostic ultrasound devices are limited to an MI of 1.9 and spatial peak, temporal average intensity of 720 mW/cm².^29,30

Figure 5.2 Ultrasound intensity measurements. Ultrasound safety metrics are often defined in terms of a variety of intensity values. Several intensity measures can be calculated, especially when pulsed ultrasound is applied.

Table 5.2

Ultrasound Intensity Metrics

Intensity metric	Abbreviation	Definition
Average intensity	I	Total power/beam area
Spatial peak	ISP	Highest intensity within beam
Temporal peak	ITP	Highest instantaneous intensity
Spatial average	ISA	Average intensity over beam area
Temporal average	ITA	Average intensity over pulse repetition period
Pulse average	IPA	Average intensity over one pulse
Spatial peak temporal average	ISPTA	$I_{SATA}\left(\frac{I_{SP}}{I_{SA}}\right)$
Spatial peak pulse average	ISPPA	$\frac{I_{SATA}\left(\frac{I_{SP}}{I_{SA}}\right)}{dutycycle}$
Spatial average pulse average	ISAPA	$\frac{I_{SATA}}{dutycycle}$
Spatial average temporal average	ISATA	$\frac{I_{TA}}{beamarea}$

Ultrasound has been classified as either high or low intensity. HIFU is typically used to induce coagulative necrosis and may use power levels that exceed 1000 W/cm². Even at low temperatures before tissue ablation, high-intensity ultrasound can induce tissue cavitation. Cavitation occurs when high-intensity ultrasound beams passing through a liquid generate areas of extremely low pressure, which causes low-pressure boiling and produces small gas bubbles in the tissue.^26–28 These bubbles then oscillate in the ultrasonic field. At suitably low intensities, these microbubbles may enter stable cavitation, expanding and contracting in a sustainable, periodic fashion (Fig. 5.3). However, when these microbubbles are subjected to higher intensities, they may collapse violently in a process called inertial cavitation. Inertial cavitation can damage tissue by producing extremely high local temperatures, powerful jet streams and/or high concentrations of free radicals.^26–28 The propensity for microbubble formation and cavitation raises concerns for HIFU ablation and has resulted with the implementation of cavitation monitoring. Theoretically, stable cavitation could be monitored and ha...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Biographies
• List of Contributors
• Preface
• Acknowledgments
• Introduction—Opportunities and Challenges
• Section I: Creativity Theory and Performing Artists
• Section II: New Modes of Therapy
• Section III: Innovative Thinking
• Index