Explorations in Targeting Low Intensity Focused Ultrasound for Neuromodulation

237 Pages·2014·4.81 MB·English

by  Amit Prasanna Mulgaonkar

UCLA
UCLA Electronic Theses and Dissertations
Title
Explorations in Targeting Low Intensity Focused Ultrasound for Neuromodulation
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https://escholarship.org/uc/item/5kb2w0kw
Author
Mulgaonkar, Amit Prasanna
Publication Date
2014

Peer reviewed|Thesis/dissertation
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University of California
UNIVERSITY OF CALIFORNIA
Los Angeles

Explorations in Targeting Low Intensity Focused Ultrasound
for Neuromodulation

A dissertation submitted in partial satisfaction of the
requirements for the degree Doctor of Philosophy
in Biomedical Engineering

by

Amit Prasanna Mulgaonkar

2014
© Copyright by
Amit Prasanna Mulgaonkar
2014
ABSTRACT OF THE DISSERTATION
Explorations in Targeting Low Intensity Focused Ultrasound
for Neuromodulation

by

Amit Prasanna Mulgaonkar
Doctor of Philosophy in Biomedical Engineering
University of California, Los Angeles, 2014
Professor Warren Grundfest, Co-Chair
Professor William P. Melega, Co-Chair

It has recently been demonstrated by several researchers that ultrasound
at intensities well below the commonly accepted threshold for effect on humans
is potentially capable of reversibly modulating neuronal circuits and function.
However, several critical barriers exist to translating these theories and
techniques to the clinic as a non-invasive transcranial therapeutic or neural
research tool.
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The primary goal of thesis is to enable detailed exploration of the
relationship between the nature of the ultrasonic stimulus and a
neuromodulatory outcome by exploring the hypothesis that low intensity
ultrasound can be discretely targeted to neural structures to induce
neuromodulation. This work is undertaken with the ultimate goal of advancing
safe, controllable ultrasonic neuromodulation as a treatment for human
neurologic diseases through an exploration of targeting – the engineering
challenge of applying known quantities of ultrasound to known locations.
An experimental assay of the effect of hypothalamic sonication in the
Göttingen minipig was developed to explore targeted neuromodulation in the
brain of a larger animal model. A transducer, coupling system, and surgical
procedure were developed that allowed for spatially accurate stereotactic
transcranial sonication of deep-brain structures with known acoustic intensities.
A pilot study assaying the effect of ultrasonic stimulation targeted to the
hypothalamus in the minipig yielded preliminary evidence that a set of ultrasonic
pulsing parameters exist that can induce a statistically significant rise in heart
rate (>5%) coincident with ultrasonic stimulation.
Targeting was also explored through the development of an invasive
neurostimulation paradigm. Novel <1.8 mm diameter low frequency ultrasonic
microtransducers were developed, micro fabricated, and characterized for this
effort. The targeting potential for this paradigm was demonstrated in a feasibility
study in the rat. Targeting was further explored through the development of an
algorithm for effectively sampling the ultrasonic parameter space by nesting the
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prime drivers of bioeffects into a matched-pair sampling framework of acoustic
parameters.
With these results, this work provides an engineering foundation for
future systematic studies of ultrasonic neuromodulatory effects. Through the
exploration of targeting and parameter selection enabled by this work, rigorous
assays for ultrasonic neuromodulation can now be conducted.

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The dissertation of Amit Prasanna Mulgaonkar is approved.
Martin O. Culjat
Wentai Liu
Nader Pouratian
William P. Melega, Committee Co-Chair
Warren Grundfest, Committee Co-Chair

University of California, Los Angeles
2014

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This dissertation is dedicated to my Mom, Dad, loving sister Ashwini, and
grandparents. Without your unquestioning encouragement and support, across
countries and continents, none of this would have been possible. You have
inspired me by example, and set the standard to which I try to live and work.
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TABLE OF CONTENTS
ABSTRACT OF THE DISSERTATION .............................................................. II
TABLE OF CONTENTS ................................................................................. VII
LIST OF FIGURE… .................................................................................... XIII
LIST OF TABLES……………………………………………………………………………….XIX
LIST OF ACRONYMS ................................................................................... XXI
ACKNOWLEDGEMENTS ........................................................................... XXIII
VITA ..…………………………………………………………………………………………..XXVI
CHAPTER 1 : INTRODUCTION ................................................................. 1
1.1 ACUTE NEED FOR NEW NEUROMODULATION STRATEGIES ...................................... 3
1.2 ADVANCING ULTRASONIC NEUROMODULATION ................................................. 6
CHAPTER 2 : INTRODUCTION TO ULTRASONIC NEUROMODULATION ..... 9
2.1 FUNDAMENTALS OF ULTRASOUND ........................................................ 10
2.1.1 Wave-Nature of Ultrasound ................................................... 11
2.1.2 Intensity ............................................................................ 16
2.1.3 Reflection ........................................................................... 17
2.1.4 Attenuation ......................................................................... 19
2.2 HARNESSING ACOUSTIC BIOEFFECTS FOR THERAPY ................................... 20
2.2.1 Ultrasonic Bioeffects ............................................................ 20
2.2.2 Measures of Acoustic Exposure .............................................. 21
2.2.3 Acoustic Exposure and Bioeffect Regulatory Standards ............. 22
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2.2.4 Applications of Acoustic Bioeffects: Therapeutic Ultrasound ....... 24
2.3 FOCUSED ULTRASOUND SURGERY OF THE BRAIN ...................................... 26
2.4 ULTRASONIC NEUROMODULATION ........................................................ 28
2.4.1 Ultrasonic Neuromodulation in the Periphery ........................... 29
2.4.2 Ultrasound-Induced Ex Vivo CNS Neuromodulation .................. 30
2.4.3 Low and Lower Intensity Ultrasound-Induced In Vivo CNS
Neuromodulation ..................................................................................... 31
CHAPTER 3 : CRITICAL BARRIERS TO EFFECTIVE TRANSCRANIAL
ULTRASONIC NEUROMODULATION ............................................................. 36
3.1 IDENTIFICATION OF CRITICAL ULTRASONIC PARAMETERS ............................. 37
3.1.1 Frequency .......................................................................... 38
3.1.2 Intensity, Pressure, Sonication Scheme, and Duration .............. 39
3.2 NEUROMODULATORY SPECIFICITY ........................................................ 41
3.2.1 Targeting of Discrete Structures and Circuits ........................... 41
3.2.2 Interspecies Variability ......................................................... 43
3.3 EXPERIMENTAL BARRIERS ................................................................. 43
3.3.1 Role of anesthesia ............................................................... 43
3.3.2 Transcranial stimulation ....................................................... 44
3.3.3 Lack of standardized reporting scheme ................................... 46
CHAPTER 4 : TRANSDUCER CHARACTERIZATION .................................. 47
4.1 ACOUSTIC MEASUREMENT ................................................................. 47
4.1.1 Need for Spatial Characterization ........................................... 49
4.1.2 Acoustic Measurement Protocol ............................................. 50
Exploration of High Duty Cycle Pulse Measurements .............................. 54
4.2 POWER SYSTEMS ........................................................................... 57
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