beyond conventional stereotaxic targeting: using
TRANSCRIPT
Beyond Conventional Stereotaxic Targeting:
Using Multiplanar Computed Tomography,
Optical Coherence Tomography and
Intracranial/Extravascular Ultrasound of the
Subarachnoid Space to Locate the Rhesus
Vestibular Nerve for Single Unit Recording
By
Shiyao Dong
A thesis submitted to Johns Hopkins University in conformity with the
requirements for the degree of Master of Science in Engineering
Baltimore, Maryland
August, 2016
© 2016 Shiyao Dong
All Rights Reserv
ii
Abstract
Single-neuron electrophysiologic recording of activity in the vestibular nerve and
vestibular nuclei of alert rhesus monkeys is a uniquely informative technique in the arsenal
of neurophysiologists who seek to elucidate adaptive neuronal signal processing that
mediate learning within vestibulo-ocular and vestibulo-spinal reflex pathways. The
traditional approach to targeting these structures with a recording microelectrode -
stereotactic guidance based on atlas coordinates - has changed little over the past half
century and is made difficult by the vestibular nerve’s mobility, mechanical compliance,
small caliber and relatively long distance from where a microelectrode enters the cranium
(typically at the base of a recording chamber surgically affixed to the parietal aspect of the
skull). The goal of the present study was to determine whether imaging techniques that
have recently gained prominence in clinical care might augment or replace the traditional
neurophysiologic method. Toward that end, we evaluated 3D multiplanar computed
tomography (3DCT), optical coherence tomography (OCT) and an intracranial/cisternal
adaptation of intravascular ultrasound (IVUS) as adjuncts to facilitate targeting the rhesus
vestibular nerve. Image guidance using CT scans acquired after recording chamber
implantation proved to be a simple and useful complement to traditional atlas-based
stereotaxis; however, atlas-based stereotaxis, 3DCT, OCT and IVUS offer complementary
advantages and disadvantages for targeting cranial nerves. Although OCT and IVUS
ultimately proved needlessly complex for our application, adaptation of those techniques
for intracranial/cisternal or intracranial imaging of cranial nerves, spinal nerves and other
structures adjacent to cerebrospinal fluid spaces may hold promise for intraoperative
guidance during minimal-access rhizotomy, biopsy and other neurosurgical procedures.
iii
Keywords: CT-guidance, vestibular nerve, stereotactic surgery, OCT, ultrasound
Thesis Review Committee:
Advisor:
Charles C. Della Santina, Ph.D. M.D.
Thesis Reviewer:
Chenkai Dai, Ph.D. M.D.
Kathleen Cullen, Ph.D.
iv
Acknowledgement
I really appreciate those people who help me a lot throughout my Master research,
especially members of Vestibular NeuroEngineering Laboratory. Without their help, this
thesis project wouldn’t be possible. I would like to thank Dr. Paul Bottomley, Dr. Jon Resar,
Dr. Caroline Garret, Dr. Yu Chen, Cardiac Cath lab at Johns Hopkins Hospital, Shashank
Sathyanarayana Hegde, Kelly Lane, and Nicole McIntosh for the help with equipment and
animals. I would like to thank Pengyu Ren for the help with animal surgery. I would like
to thank Dr. Chenkai Dai for the valuable advice and helpful guidance on my research
project. I would like thank Dr. Kathleen Cullen for reviewing my thesis.
Most of all, I’m really thankful to Dr. Charley Della Santina, my friendly, helpful
and responsible advisor, mentor and friend. He shared his experience and vision with me,
and provided me with essential skills and tools for research. His guidance helped me get
through lots of difficulties during my master research.
I would like to thank my family who taught me, loved me and supported me
throughout my life endeavors.
The project described was supported by NIH/NIDCD (R01-DC2390, R01DC9255)
and donors to the Johns Hopkins Vestibular NeuroEngineering Laboratory.
v
Table of contents
Abstract .............................................................................................................................. ii
Acknowledgement ............................................................................................................ iv
Table of contents ............................................................................................................... v
List of tables..................................................................................................................... vii
List of Figures ................................................................................................................. viii
Chapter 1 Introduction ................................................................................................. 1
1.1 Challenge in Single-Unit Recording in Rhesus Vestibular Nerve ................... 3
1.2 Current approaches to targeting a cranial nerve .............................................. 7
1.2.1 Conventional Stereotaxic Procedure .................................................... 8
1.2.2 Image-guided Stereotaxis ..................................................................... 9
1.3 Potential imaging techniques for nerve targeting .......................................... 12
1.3.1 Intravascular Ultrasound .................................................................... 13
1.3.2 Optical Coherence Tomography ........................................................ 15
1.4 Project Aims .................................................................................................. 20
Chapter 2 Post-operative CT Guidance for Single-unit Recording in Rhesus
Vestibular Nerve ............................................................................................................. 22
2.1 Experimental Subjects ................................................................................... 22
2.2 Materials and Methods .................................................................................. 22
2.2.1 Recording Chamber Implantation Surgical Procedures ..................... 23
2.2.2 CT Imaging and Analysis .................................................................. 26
2.3 Results............................................................................................................ 31
2.3.1 Measurement of Vestibular Nerve Location ...................................... 31
2.3.2 Experimental Validation and Errors Calibration ............................... 32
2.4 Discussion ...................................................................................................... 37
Chapter 3 Intracranial/Extravascular Application of OCT and IVUS for Imaging
the Subarachnoid Space ................................................................................................. 41
3.1 Experimental Subjects ................................................................................... 41
3.1.1 Phantom ............................................................................................. 41
3.1.2 Chinchilla Subject .............................................................................. 41
3.1.3 Rhesus Monkey Subjects ................................................................... 42
3.2 Surgical Procedures ....................................................................................... 42
3.2.1 Chinchilla Surgery ............................................................................. 42
vi
3.3 Intracranial/Extravascular Optical Coherence Tomography ......................... 43
3.3.1 Method ............................................................................................... 43
3.3.2 Results ................................................................................................ 46
3.4 Intracranial/Extravascular Ultrasound Imaging of the Subarachnoid Space . 52
3.4.1 Method ............................................................................................... 52
3.4.2 Results ................................................................................................ 52
3.5 Discussion ...................................................................................................... 55
Chapter 4 Conclusion ................................................................................................. 58
4.1 Post-Operative CT Guidance ......................................................................... 58
4.2 Intracranial Imaging of the Subarachnoid Space Using OCT and IVUS ...... 58
4.3 Future Directions ........................................................................................... 59
Reference List .................................................................................................................. 61
Curriculum Vitae ............................................................................................................ 68
vii
List of tables
Table 1-1 Comparison of OCT and IVUS ........................................................................ 17
Table 2-1. General information of experimental subjects ................................................ 22
Table 2-2. Location of porus acusticus in CT stereotaxic coordinate............................... 36
Table 2-3. Location of porus acusticus in CT chamber coordinate .................................. 36
Table 3-1.Comparison of OCT and IC/EVUS .................................................................. 55
viii
List of Figures
Figure 1-1. Rhesus Monkey Brain Atlas (Interaural -6.00 mm) ......................................... 5
Figure 1-2. Rhesus Monkey Brain Atlas (Interaural -5.55 mm) ......................................... 6
Figure 1-3.MRI-guided stereotaxic framework overview ................................................ 10
Figure 1-4. IVUS images of aortic dissection ................................................................... 14
Figure 1-5 Basic schematic of OCT working principle .................................................... 16
Figure 1-6. A camera image of the OCT probe on top of the human basal ganglia ......... 18
Figure 1-7. OCT images of a tympanic membrane (TM) ................................................. 19
Figure 2-1. Stereotaxic frame parameters ......................................................................... 25
Figure 2-2. CT 3D reconstruction in stereotaxic head coordinates .................................. 28
Figure 2-3. CT 3D reconstruction in recording chamber coordinate (left ear) ................. 29
Figure 2-4. XY Micromanipulator for single-unit recording ............................................ 30
Figure 2-5. Region of interest in CT 3D reconstruction ................................................... 33
Figure 2-6. Measurement of inner acoustic opening location in CT stereotaxic coordinate
(Animal ID: RhF234D) ..................................................................................................... 34
Figure 2-7. Measurement of inner acoustic opening location in CT chamber coordinate
(Animal ID: RhF234D) ..................................................................................................... 35
Figure 2-8.Location of porus acusticus in transverse plane of chamber coordinate ......... 38
Figure 3-1. Placement of OCT catheter inside penne embedded in gelatin ...................... 44
Figure 3-2.Simulation of placing OCT catheter through the floor of bulla in chinchilla
right ear under camera view .............................................................................................. 45
Figure 3-3. OCT image of a penne in the gelatin phantom .............................................. 47
Figure 3-4.OCT image of inner acoustic canal in chinchilla ............................................ 48
ix
Figure 3-5.Location of OCT catheter placement into the internal auditory canal and
cerebellopontine angle of a chinchilla placed just after euthanasia and then dissected after
OCT image acquisition. .................................................................................................... 49
Figure 3-6.Rhesus monkey inner acoustic opening on left side ....................................... 50
Figure 3-7.A slice of OCT side-view scan when catheter is placed in CSF space in the
post-mortem rhesus monkey on left side .......................................................................... 51
Figure 3-8.IC/EVUS side-view image of penne embedded in gelatin phantom ............... 53
Figure 3-9. Images of subarcuate parafloccular recess obtained using
intracranial/extravascular ultrasound in the cerebellopontine angle of a rhesus monkey
specimen. .......................................................................................................................... 54
Figure 3-10.Comparison of OCT and IC/EVUS in gelatin phantom ................................ 57
1
Chapter 1 Introduction
In normal individuals, the two vestibular labyrinths provide the central nervous
system (CNS) with sensation of head rotation and linear accelerations due to both gravity
and translational motion. These sensory inputs drive compensatory reflexes that maintain
posture and stabilize gaze so as to maximize visual acuity during head movement. Bilateral
loss of vestibular sensation due to ototoxic injury or other insults to both labyrinths is
disabling. Patients suffer from chronic disequilibrium, increased frequency of falls and
unstable vision during head movements typical of common daily activities like walking
and driving.[1-3] Most individuals with mild or moderate loss eventually compensate
through rehabilitative exercises that augment residual function, but those with profound
loss who fail to compensate have no good treatments options. There are approximately
64000 U.S adults who experience chronic, symptomatic profound loss of bilateral sensation
with no solution for relief.[4, 5] No clinical-approved treatment beyond rehabilitation
exists for these patients. Vestibular implants, which are neuroelectronic vestibular
prostheses designed to restore motion-modulated vestibular nerve activity, should provide
a solution to people with bilateral vestibular deficiency who experience chronic dizziness
even after rehabilitation, by restoring sensation of head motion and gravitational
orientation that normally drive vestibular reflexes.[6-10]
Normally, the eyes rotate opposite the direction of head rotation in order to stabilize
images on retinae. The angular vestibulo-ocular reflex (aVOR) drives the compensatory
eye rotation. Sensory input to the aVOR is provided by three mutually orthogonal
semicircular canals (SCC) in each inner ear’s vestibular labyrinth. In each SCC’s ampullary
2
nerve, the firing rates of vestibular afferents are modulated by the component of head
angular velocity about that SCC’s axis.[11-14] By measuring the resulting eye movement
in 3D, relative excitation of the ampullary nerves driving the reflex can be estimated.[15-
19] Suzuki, Cohen et al. demonstrated that delivering pulses of electrical stimulation to the
ampullary nerve via wire electrodes can elicit an aVOR about axes of rotation similar to
those elicited by the hydrodynamic excitation of the individual canals.[13, 20-26] The
vestibular prosthesis modulates electrical stimulation of surviving vestibular afferents
based on motion sensor input. A vestibular prosthesis directly stimulates vestibular afferent
fibers, which synapse on regions of the CNS that generate vestibular-mediated reflexes.
Thus, the vestibular prosthesis can partly replace function of the lost labyrinth with an
electronic solution.
The Vestibular NeuroEngineering Laboratory (VNEL) at Johns Hopkins has done
significant work with the Johns Hopkins Multichannel Vestibular Prosthesis (MVP) from
its initial development,[6, 27, 28] including reduction in size and power consumption,[29]
reduction in channel cross-talk,[30] developing an understanding of the effect of stimulus
parameters,[31] and conducting chronic stimulation experiments.[32, 33] After initial
development in small mammals, VNEL translated MVP technology to rhesus monkeys,
demonstrating similarly favorable outcomes. VNEL recently initiated a first-in-human
clinical trial of a vestibular implant based on a modified cochlear implant.[34]
One of the key remaining challenges to vestibular prosthesis development is
vestibulo-ocular reflex (VOR) misalignment due to current spread to vestibular afferent
fibers beyond those in the targeted nerve branch.[30] When current spread incurs spurious
excitation of adjacent vestibular nerve branches, the prosthesis cannot selectively stimulate
3
each ampullary nerve. Higher current stimuli can increase the aVOR magnitude, but
meanwhile the eye rotation axis increasingly deviates from the ideal because of spurious
stimulation of other vestibular nerve branches.[30]
The 3D VOR axis is a good estimate of relative activity in the 3 ampullary nerves of
the implanted ear, but that 3-value vector is a greatly simplified estimate of neuron activity.
Single-unit recording, a more direct assay of measuring single-unit neuronal activity, is
needed to guide further optimization of designs that reduce VOR misalignment. By
combining single-unit recording in rhesus vestibular nerve during MVP stimulation with
3D VOR data, we can better understand current spread and refine a rigorous biophysical
model of neuronal activation by current spread.
1.1 Challenge in Single-Unit Recording in Rhesus Vestibular Nerve
Accurate targeting is required for single-unit recording in the rhesus vestibular nerve;
however, targeting the vestibular nerve for electrophysiology is a challenging task. Also
known as the eighth cranial nerve, the vestibulocochlear nerve splits into two large
divisions: the cochlear nerve and the vestibular nerve. The peripheral parts of the eighth
nerve travel a short distance medially from their respective neurosensory epithelia to
ganglia (i.e., clusters of nerve cell bodies near the vestibular labyrinth [Scarpa’s ganglion]
and within the central spiraling modiolus of the cochlea [the spiral ganglion]). From there,
the central part of the nerve travels through the internal auditory meatus (also called the
internal auditory canal, or IAC) alongside the facial nerve. Departing the IAC at the porus
acusticus (also called the internal acoustic meatus), the eighth nerve traverses a
cerebrospinal fluid filled space in the cerebellopontine angle before entering the brainstem
4
at the junction of the pons and medulla lateral to the facial nerve. The diameter of
vestibulocochlear nerve is about 0.9 mm in rhesus and 1 mm in human. [35-38] The length
of the vestibulocochlear nerve, from the glial-Schwann junction, where cochlear nerve and
vestibular nerve join together within the IAC, to the brainstem, is 10-13 mm in human.
5
Figure 1-1. Rhesus Monkey Brain Atlas (Interaural -6.00 mm)
Before entering brainstem, the rhesus vestibulocochlear nerve is about 45 mm inferior to bregma in
stereotactic coordinates. Adapted from: Paxinos, G., X.-F. Huang, and A.W. Toga, The rhesus monkey
brain in stereotaxic coordinates. 2000.
6
Figure 1-2. Rhesus Monkey Brain Atlas (Interaural -5.55 mm)
After entering brainstem, the rhesus vestibular nerve is about 44 mm inferior to bregma in stereotactic
coordinates. Adapted from: Paxinos, G., X.-F. Huang, and A.W. Toga, The rhesus monkey brain in
stereotaxic coordinates. 2000.
7
and 7-10 mm in females. Figure 1-1 shows a section of rhesus monkey brain from a
stereotaxic atlas by Paxinos, Huang and Toga,[39] illustrating the position of the
vestibulocochlear nerve before entering the brainstem. Figure 1-2 shows another section,
illustrating the position of vestibulocochlear nerve after entering brainstem. Rhesus
monkeys have similar size of vestibulocochlear nerve, the average diameter of which is
about 0.9 mm.[38] Only the portion of vestibulocochlear nerve that exits the IAC before
entering brainstem is available for placing recording electrode in, which is shorter than 10
mm. The superior-inferior distance from vestibulocochlear nerve to bregma (confluence of
sutures of frontal and parietal bones) according to the Paxinos et al. stereotaxic atlas is
about 44-45 mm.[39] Thus, the small size of the vestibular nerve, long distance to the nerve
from parietal cranium surface (where a recording electrode must enter the cranium in our
preparation), and inter-subject difference among rhesus monkeys combine to make
targeting the vestibular nerve difficult.
1.2 Current approaches to targeting a cranial nerve
Conventional stereotaxic guidance based on atlas coordinates has long been
successfully employed by investigators experienced in that technique to locate small targets
in brain and to perform action such as injection, stimulation and implantation, etc. The
development of computed tomography (CT) and more recently magnetic resonance
imaging (MRI) has greatly facilitated the conventional stereotactic procedure.
8
1.2.1 Conventional Stereotaxic Procedure
Conventional stereotaxic surgery includes three main components: (1) a stereotaxic
planning system including atlas and coordinate calculator, (2) a stereotaxic apparatus and
(3) a method for stereotaxic localization. Each available rhesus monkey brain atlas is based
one single animal,[39-41] which precludes correction for inter-subject variability, apart
from simply scaling all dimensions according to the relative length of the distance between
the left and right bony ear canal entrances (as determined by ear bar settings on a
stereotactic frame). In a typical stereotactic atlas, the three dimensions are: lateral-medial,
anterior-posterior and superior-inferior. Rhesus monkey brain atlases often use the bony
external auditory meatus, the inferior orbital ridges, and the bregma as landmarks. The
simple orthogonal stereotaxic apparatus uses a set of three Cartesian coordinates (x, y and
z) in an orthogonal frame of reference. Reid’s horizontal (Z) plane passes through the
interaural axis and the lowest point of the cephalic edge of each infraorbital ridge. Reid’s
coronal (X) plane is perpendicular to the Z plane and contains the interaural axis. Reid’s
midsagittal (Y) plane is perpendicular to the other two planes and lies along the head’s
plane of symmetry. Positive X, Y and Z are anterior, left and superior. Guide-bars in x, y
and z directions, fitted with high precision Vernier scales allow a neurophysiologist or
neurosurgeon to position the point of probe or electrode inside the brain, at the calculated
coordinates for the target structure, through a small craniotomy.
Single-unit recording of electrophysiological activity from individual afferent
neurons within the rhesus vestibular nerve has long been traditionally guided by atlas-based
stereotaxic planning.[42-44] To determine how deep the electrode should be inserted to get
the vestibular nerve, experienced researchers in field of vestibular study listen to the
9
characteristic sounds of neural activity when fed into an audio monitor.[45-47] They
approach the vestibular nerve through the floccular complex, which is identified by its eye
movement-related neural activity. As the recording microelectrode is advanced inferiorly
via a trajectory starting at posterosuperolateral parietal bone and passing through the
flocculus, entry into the vestibular nerve is typically preceded by a silence, indicating that
the electrode has left the cerebellum and is passing through cerebrospinal fluid in the
subarachnoid space of the cerebellopontine angle. After pushing all the way through and
then exiting the nerve, the microelectrode may travel a short distance (typically less than a
few mm) before hitting mater over the petrous part of the temporal bone, and event that
can blunt or otherwise damage the electrode tip and which is sometimes signified by abrupt
onset of 60 Hz noise in the output of the microelectrode preamplifier.
1.2.2 Image-guided Stereotaxis
In 1978, Russel Brown, an American physician, invented a device known as the N-
localizer.[48-55] The N-localizer enables guidance of stereotaxic surgery or radiosurgery
using tomographic images that are obtained via computed tomography (CT),[56-59]
magnetic resonance imaging (MRI),[60-62] or positron emission tomography (PET).[63,
64] Surgical precision is significantly improved because CT, MRI and PET permit accurate
visualization of intracranial anatomic detail. These imaging techniques can display
intracranial anatomy in 3-D images, allowing surgeons to register a patient’s cranial image
space to stereotaxic physical space with the help of external markers before surgery.
Surgeons now commonly use intracranial images preoperatively for stereotaxic planning
or during surgical interventions as guidance, and several commercial systems for image-
guided navigation during sinus and intracranial surgery are available.
10
Functional magnetic resonance imaging (fMRI) allows localization of brain regions
specialized for different perceptual and higher cognitive functions; however, the spatial
resolution with which fMRI can identify different levels of physiologic activity is orders
of magnitude more coarse than is possible with single-unit (i.e., individual neuron) electro-
physiological recording of neural activity using tungsten needle microelectrodes or glass
micropipettes. Ohayon et al. designed a novel framework for MRI-stereotaxic registration
and chamber placement for precise electrode guidance to recording site defined in MRI
space.[65] Figure 1-3 shows overview of the frame. The framework allows positioning a
recording chamber, according to pre-surgery planning, and is not limited to
Figure 1-3.MRI-guided stereotaxic framework overview
A region of interest is selected for targeting and a virtual chamber is placed. MRI scan is performed after
markers are attached. The software calculates the parameters to align the manipulators. Adapted
from[65].
11
vertical penetrations. It also permits implantation of chambers while the animal is simply
head fixed in the primate chair, detached from the stereotaxic frame.
CT-guided stereotaxic targeting has been used in humans for implantation of deep
brain stimulation electrodes and for craniofacial surgery.[66, 67] Eggers et al. proposed
intraoperative CT-guidance for craniofacial surgery with a fully automated registration,
which allows surgeons to navigate the operation without delay of patient-to-image
registration.[67] Neurosurgeons and neurotologists have increasingly embraced
preoperative virtual planning and intraoperative navigation to reduce the risk of
complications and to increase the efficiency and confidence with which they can work near
critical anatomic structures.[68] Similarly, neuroscience researchers should benefit from
CT-aided stereotaxis to refine their approaches to recording neurophysiologic activity of
small, hard-to-reach intracranial structures like the vestibular nerve.
Although experienced surgeons can complete procedures without image guidance,
the ability to precisely target and/or identify anatomic points of interest is cost-effective in
scenarios that require the surgeon to target a hard-to-find structure while avoiding large
blood vessels and other vital or fragile structures.[69] Similarly, although experienced
neurophysiologists can find their electrophysiologic targets through a combination of
frame-based stereotaxis, systematic sampling of a 3D grid volume encompassing the
expected location of the nerve of interest, directed search relying on the location of neurons
with recognizable firing patterns, patience and luck, image-guidance should provide a
useful adjunct to traditional stereotactic techniques.
12
Realizing this, Watanabe et al. developed a new system which introduces the idea
of CT-guided stereotaxis into conventional open neurosurgery[70]. Using metal markers,
they coregistered a preoperative CT imaging data set (for high resolution bone anatomy)
with patient’s head. They reported that this system makes it possible for a surgeon to
identify the operating site by obtaining real-time positional information in surgery
translated back onto CT images. However, for targeting the rhesus vestibular nerve, that
approach might suffer from errors arising during recording chamber implantation surgery.
CT scans obtained before chamber implantation may not be sufficient to accurately target
the nerve in each recording experiment after surgery. A more efficient solution involves
first surgically attaching a rigid recording chamber to the skull (using traditional
stereotactic targeting), then performing a high-resolution CT and 3D reconstructions along
mutually orthogonal planes that either contain or are perpendicular to the recording
chamber’s axis. We evaluated that approach in the present study.
1.3 Potential imaging techniques for nerve targeting
In addition to CT and MRI guidance, biomedical imaging techniques such as
intravascular ultrasound (IVUS) and optical coherence tomography (OCT) can image soft
tissue with better resolution, which could possibly help visualize vestibular nerve
intraoperatively or even directly observe the microelectrode as it is advanced into the nerve.
Stereotaxic procedures that require insertion of needle-type instrument into the brain serve
crucial roles in neurosurgery. The procedures are employed as aids to diagnosis in
management of various medical conditions including biopsy of tumors, assessment of
vessel wall plaques, and placement of electrodes that are used for signal recording and deep
brain stimulation (DBS).[71-73] Catheter-based IVUS and OCT have both established
13
roles in interventional cardiology as visualization aids during stent implantation. The small
size of IVUS and OCT catheters and the high resolution of these imaging modalities gives
these two intravascular imaging technologies potential to be applied in the subarachnoid
space to provide guidance for targeting cranial and spinal nerves.
1.3.1 Intravascular Ultrasound
The concept of intravascular ultrasound was first introduced by Born et al. in
1972.[74] IVUS is a catheter based system that allows physicians to acquire images of
diseased vessels from inside the artery. In the late 1980s, commercially available IVUS
catheter-based probes were used in both animals and humans.[75] Intravascular ultrasound
imaging, working in the range of 20-45 MHz, is the most commonly used intravascular
imaging modality (after dye-contrasted cine or flat panel CT fluoroscopic angiography) for
diagnosing coronary artery diseases or coronary heart diseases.[76] Imaging through blood
with large penetration (>5 mm) makes IVUS able to facilitate vessel modeling and plaque
morphology.[77, 78] The use of IVUS is currently being incorporated into several
modalities that will offer more real-time information in both the aorta and the treatment of
peripheral vascular disease.[76, 79-83] Figure 1-4 illustrates IVUS images along the
imaging catheter inside the subclavian artery.[81]
IVUS can provide a cross-sectional image of the vessel or other tissue within the
range, with resolution of 100-200 um and the imaging depth around 10 mm [81, 84]. These
features endow IVUS with potential to be applied outside the vasculature, deployed via a
recording microelectrode’s guide tube trocar through brain tissue and into cerebrospinal
fluid spaces, where it can be used for image guidance as an aid for nerve targeting in single-
14
unit recording or intracranial neurosurgery. An analogous approach might be used in the
cranium, in which IVUS might be renamed intracranial/extravascular ultrasound
(IC/EVUS).
Figure 1-4. IVUS images of aortic dissection
In aortic dissection, entry tear is the initial intimal tear that causes the blood to flow between the layers of
the wall of the aorta. These images, adapted from [81], show that IVUS can images a vessel wall with
sufficient resolution to identify an entry tear.
15
1.3.2 Optical Coherence Tomography
Optical coherence tomography (OCT) is a recently developed biomedical imaging
that has accelerated the research in the fields of medicine and biology. The capability of
OCT to perform high resolution, cross-sectional tomographic imaging of microstructure in
biological tissues has led this technology to be applied to surgical guidance and medical
diagnostics. Compared with IVUS, OCT provides higher resolution of around 10-20
um.[84-86] Like IVUS, needles and probes have been developed to integrate OCT into
intravascular catheters.
In essence, OCT probes detect and report the occurrence of reflection backward
along a beam path extending like a laser beam from and back to the OCT sensor.
Interferometry allows detection of these reflections and determination of how far each
reflection-generating boundary is from the sensor (Figure 1-5). The light source has a
bandwidth in the near-infrared spectrum with central wavelengths ranging from 1,250 to
1,350 nm. Tissue penetration, and therefore the depth over which OCT images tissue, is
limited to 1-3 mm.[87] Rapid, repetitive and systematic reorientation of the OCT sensor
allows a system to scan either a slice of tissue perpendicular to the catheter (side-viewing
OCT) or a conic section of tissue concentric with the catheter (forward-viewing OCT).
Side-view imaging OCT probes generate a 2D image of a disk of tissue
perpendicular to the axis of the OCT probe’s introducing catheter. A side-viewing system
consists of an optical fiber, a focusing lens and a prism or mirror for lateral deflection of
light. The entire apparatus spins within a surrounding catheter, allowing the OCT sensor’s
single line of sight to be scanned like a submarine periscope or an air traffic control radar
16
Figure 1-5 Basic schematic of OCT working principle
system. A constant-velocity “pull-back” of the rotating sensor along the axis of the catheter
allows one to sample many disc slices and then reconstruct them to image a 3D cylindrical
volume.[88, 89] In addition to intravascular imaging of vessel walls, side-view imaging
probes are used to image gland ducts and other hollow organs.[87]
Compared with side imaging probes, forward imaging probes are more challenging
to construct, because 3D image construction cannot easily be done by back-forth “pull-
back” translation. To acquire the 3D image of object, for example, the scanning is realized
by a piezoelectric transducer, galvanometer scanners or a microelectromechanical system.
[90-92] The scanning device in a forward imaging endoscope is usually placed at the distal
end of the system. That makes it very difficult to maintain the diameter small and have a
large working distance (WD) and broad field of view (FOV). If these technical challenges
can be overcome, Forward-viewing OCT seems especially well-suited to providing useful
image guidance during intracranial stereotaxic procedures, because the guide tube through
17
which the OCT imaging system is introduced is nominally pointing at the target one wants
to see.
Forward-scanning OCT (also called endoscopic OCT, or EOCT) has been applied
to detect diseases of the tympanic membrane and the middle ear, such as otitis media or
cholesteatoma.[94-96] Burkhardt et al. designed a 3D forward imaging EOCT at a large
WD with a large FOV and acquired images of tympanic membrane (Figure 1-7).[97]
Although a forward-scanning needle probe can be used to provide real-time feedback along
the line of sight as a microelectrode guide tube is inserted, the forward-viewing OCT
systems described so far do not provide as much field of view as side-view imaging systems.
Chen et al. at University of Maryland, College Park designed a forward-imaging needle-
type OCT probe for stereotaxic procedures intended to overcome this problem by using a
gradient-index (GRIN) rod lens, which has a gradual variation of refractive index and
provides variable length focus without the weight, size and fragility of a traditional lens,
(Figure 1-6).[93].
Table 1-1 summarizes performance parameters for IVUS and endoscopic OCT,
which are promising techniques for real-time guidance for intracranial surgery.[87]
Modality Axial Resolution Lateral Resolution Penetration depth Smallest
Catheter size
OCT 12-18 um 20-90 um 1.5-3 mm ~ 1 mm
IVUS 150-200 um 150-300 um 4-8 mm ~ 1 mm
Table 1-1 Comparison of OCT and IVUS
18
Figure 1-6. A camera image of the OCT probe on top of the human basal ganglia
The top yellow bar shows the full track of OCT reconstruction along the probe insertion direction. Labels:
extreme capsule (ex), claustrum (Cl), external capsule (ec), putamen (PUT), lateral medullary lamina (lml),
globus pallidus externa (GPe) and globus pallidus interna (GPi).Adapted from [93].
19
Figure 1-7. OCT images of a tympanic membrane (TM)
(A) The red arrow points at the umbo, the deepest point of the TM. (B) Manubrium of malleus (MM). (C)
Top view OCT image of the TM. (D) Top view camera picture, the umbo (*) and the MM (**).(E) 3-D OCT
image of the TM. Scale bars:1 mm. Adapted from [97].
20
1.4 Project Aims
Although experienced neuroscience researchers can successfully target the rhesus
vestibular nerve for single-unit recording using traditional atlas-based stereotaxis, finding
the nerve can be a challenging and laborious task that requires weeks of months of hunting
with a microelectrode, systematically making passes through a grid of tracks surrounding
the trajectory estimated using skull landmarks and a stereotactic atlas from a different
animal. Differences between atlas and experimental subjects, small size of the nerve and
long distance to the nerve from craniotomy combine to make it take long time targeting the
nerve before recording electrophysiological activity. Thus, there is a need for a guidance
method to help locate the nerve more efficiently.
The aim of this project was to evaluate a method of image guidance based on post-
operative CT scans (obtained after surgical placement of a recording chamber on the
parietal calvarium) in searching for vestibular afferents that:
1. individualizes targeting for the specific subject under study, rather than relying
on an atlas created from a different specimen;
2. provides direct guidance to help calibrate the placement of recording
microelectrode; and is
3. accessible to researchers with less experienced in stereotaxic procedures.
Although our focus was on image guidance in the form of CT 3D reconstructions,
which relies on technology now widely available in most academic medical centers, we
also explored catheter-based imaging techniques including intravascular ultrasound (IVUS)
21
and optical coherence tomography (OCT) to facilitate targeting the vestibular nerve more
precisely following the CT guidance.
22
Chapter 2 Post-operative CT Guidance for Single-unit
Recording in Rhesus Vestibular Nerve
We performed multiplanar CT scans on rhesus monkeys after recording chamber
implantation. Locations of the internal acoustic opening for both sides, where the vestibular
nerve bundle leaves the internal auditory canal to traverse the cerebellopontine angle on its
way from the inner ear to the brainstem, were measured with respect to recording chamber
coordinates for recording navigation and in stereotaxic coordinate for comparison. Details
of the experiment procedure are described in respective sections.
2.1 Experimental Subjects
Five rhesus monkeys were used for experiments, which were performed in
accordance with a protocol approved by the Johns Hopkins Animal Care and Use
Committee. Details about the five rhesus monkeys are shown in Table 2-1.
No. Animal ID Weight (kg) Sex Implanted Ears IVUS test OCT test
1 RhF234D 5.2 F Both No No
2 RhF247E 5.3 F Both No No
3 RhM46xH 4.5 M Both No No
4 RhF4617J 6.0 F Both Yes(post-
mortem)
Yes(post-
mortem)
5 RhM54AM 6.0 M Both No No
Table 2-1. General information of experimental subjects
2.2 Materials and Methods
All experiments were performed in accordance with protocols approved by the
Johns Hopkins Animal Care and Use Committee, which is accredited by the Association
23
for the Assessment and Accreditation of Laboratory Animal Care (AAALAC) International
and consistent with European Community Directive 86/609/EEC.
2.2.1 Recording Chamber Implantation Surgical Procedures
Five rhesus monkeys weighting 4-7kg were used for evaluating CT guidance to
facilitating single unit recording from vestibular nerve afferent neurons. Surgical
procedures were carried out under strict sterile conditions. Animals were sedated with
ketamine (0.2 mg/kg), treated with prophylactic IV cefazolin, endotracheally intubated and
maintained under deep anesthesia via inhalation of 1.5-5 % isoflurane in oxygen. Surgical
preparation was done in stages so as to limit the operative time and shorten the recovery
period for any single anesthetic exposure. In the first surgery, a head-restraining cap was
permanently affixed on the calvarium using dental acrylic affixed to multiple titanium bone
screws.
Before chamber implantation, we positioned a skull from a monkey of body size
similar to the animal on which we planned to operate in the stereotaxic frame, securing it
in place using ear bars, an incisor bar and a nose clamp. We then positioned a chamber
holder so that its axis passed from ipsilateral parietal cortex through the cerebellum to the
porus acusticus (i.e., the medial opening of the internal auditory canal) while avoiding
major blood vessels (Figure 2-1). Stereotaxic manipulator parameters were recorded for
later use during chamber implantation surgery.
We then positioned the animal to be studied on the stereotactic frame. Using the
previously determined settings, we positioned a 1.9 cm diameter titanium recording
chamber over the parietal calvarium and marked its location on the scalp and, after skin
24
incision and elevation, on the skull. A ~1 cm diameter craniotomy was drilled within the
region of calvarium encircled by the mark, and the chamber was cemented in place using
dental cement (3M ESPE ProTemp®II or OrthoJet®). A hairless, split-thickness skin graft
was harvested, meshed and applied to the exposed dura, then held in place using antibiotic-
impregnated GelFoam® and sterile packing.[98] The packing was removed and replaced
every other day starting 7 days post-op and continuing until the dura was completely
covered by skin. This technique can yield a clean, dry, easy-to-maintain recording chamber
floor that is almost entirely free of granulation tissue, significantly reducing the risk of
infection, blood loss, CSF leakage and animal distress that might otherwise occur with
daily debridement. The skin grafts act as a biologic dressing, sealing itself closed after
guide tube removal.
A second recording chamber was placed using the same techniques, typically on
the same day and in a position approximately at the mirror image across the midsagittal
plane from the first chamber.
25
Figure 2-1. Stereotaxic frame parameters
Stereotaxic setting parameters: (a) XY-slide for right and left, Medial-Lateral slide for right and left. (b)
Vertical azimuth for right, horizontal azimuth for right. (c) Vertical azimuth for left, horizontal azimuth for
left and upper slide.
26
2.2.2 CT Imaging and Analysis
Monkeys maintained under propofol IV infusion anesthesia and endotracheally
intubated were imaged in a high-resolution CT scanner (Toshiba Aquilion One). A guide
tube containing a tungsten recording microelectrode was inserted along the axis of each
recording chamber, advanced through skin graft, dura, parietal/occipital cortex, tentorium,
and cerebellum toward the presumed location of the porus acusticus, then left in place
temporarily while a CT scan was performed using a bone algorithm, step scan mode, a 120
kV source collimated to 0.5-mm slice thickness at full-width half maximum, and a (120
mm)2 region of interest imaged on a 512 x 512 voxel/slice matrix, creating voxels of 0.4 x
0.4 x 0.3 mm.
To define the location of the porus acusticus, we used two different coordinate
systems (Figure 2-2 and Figure 2-3). We used stereotactic coordinates using Reid’s planes.
Reid’s horizontal (Z) plane passes through the interaural axis and the lowest point of the
cephalic edge of each infraorbital ridge. Reid’s coronal (X) plane is perpendicular to the Z
plane and contains the interaural axis. Reid’s midsagittal (Y) plane is perpendicular to the
other two planes and lies along the head’s plane of symmetry. Positive X, Y and Z are
anterior, left and superior. To define locations with respect to each of the two cylindrical
recording chambers, we defined a chamber coordinate system resulting in which the Zc
axis for a given chamber is the axis of that chamber, the Yc axis is perpendicular to Zc of
the same chamber and intersects the Zc axis of the other chamber, and Xc is perpendicular
27
to both Zc and Yc. Positive Xc, Yc and Zc are approximately anterior, left and superior
with respect to the skull and the stereotactic coordinate system.
In single-unit recording experiments, we placed an X-Y micromanipulator (Figure
2-4) on the chamber with its X, Y-axis in alignment with the chamber coordinate. Based
on the location of target measured in CT chamber coordinate, we changed
micromanipulator settings and passed tungsten electrodes through a guide tube to target
the ipsilateral porus acusticus.
28
Figure 2-2. CT 3D reconstruction in stereotaxic head coordinates
29
Figure 2-3. CT 3D reconstruction in recording chamber coordinate (left ear)
30
Figure 2-4. XY Micromanipulator for single-unit recording
31
2.3 Results
2.3.1 Measurement of Vestibular Nerve Location
As described previously, the vestibular nerve the petrous temporal bone’s
posteromedial face via the porus acusticus (inner acoustic opening). Therefore, we used
CT reconstructions to measure the location of porus acusticus as the landmark for targeting
the nerve.
In the rhesus monkey skull anatomy, another constant feature is a subarcuate
parafloccular recess, which is close to the porus acusticus on the petrous part of the
temporal bone and similar in size (Figure 2-5). The recess, within which a portion of the
cerebellar paraflocculus sits encircled by the three semicircular canals of the ipsilateral
labyrinth, is posterior and superior to the porus acusticus. For different individuals, the
distance between subarcuate parafloccular recess and porus acusticus may be different, but
the relative position is almost the same. This relation served as our criterion to distinguish
these two similar structures and find the location of porus acusticus. Once the porus
acusticus is identified in CT transverse view, we choose one point as our target location for
measurement, which would be about 0.5 mm medial of the porus acusticus and far enough
from nearby bone surfaces to reduce the risk that the recording electrode may hit the bone
in later experiment. Figure 2-6 and Figure 2-7 show the example of measurement in CT
scan. Same measurement method has been applied to all five experimental subjects. Table
2-2 and table 2-3 shows the measurement results. The internal auditory canals are roughly
coaxial with the external bony auditory canals (where the stereotaxic ear bars go) and the
porus acusticus in rhesus is about 1-1.1 cm off midline. Since internal acoustic opening is
32
a hole instead of a single point, one cannot uniquely define or measure its precise location
in CT scan. We measured the location estimated as the center of the nerve exiting the porus
acusticus twice per ear and took the average as the final result. The distances from porus
acusticus to the chamber axis in X-Y plane on both sides for five monkeys were all smaller
than the chamber radius, indicating that the traditional method of stereotactic targeting we
used for chamber placement was adequate to at least ensure that the nerve would be
accessible via each chamber, if only one knows where to look.
2.3.2 Experimental Validation and Errors Calibration
As described previously, based on measurements of vestibular nerve location in
chamber coordinates, we inserted recording electrode through guide tube navigated by the
XY micromanipulator to target ipsilateral vestibular nerve. If we didn’t successfully target
the nerve at the first time, we would pull out and insert the electrode several times or change
XY micromanipulator setting by 0.1 mm per time, then reinsert electrode through guide
tube. We found the vestibular nerve and successfully recorded afferent units in a single
afternoon of electrophysiologic recording during the first experiment after chamber
implantation for monkey 54A and for monkey 4617. Previously, without using CT
guidance, it usually took us 3-4 months to find the vestibular nerve through a systematic
electrophysiologic survey of activity in a volume about the location expected from
traditional stereotactic targeting.
33
Figure 2-5. Region of interest in CT 3D reconstruction
In CT 3D reconstruction :(a) skull base with guide tube in left side chamber. (b) view of left lateral skull with
guide tube from medial side. (c) view through craniotomy from left chamber floor.
34
Figure 2-6. Measurement of inner acoustic opening location in CT stereotaxic coordinate (Animal ID: RhF234D)
35
Figure 2-7. Measurement of inner acoustic opening location in CT chamber coordinate (Animal ID: RhF234D)
36
Table 2-2. Location of porus acusticus in CT stereotaxic coordinate
Location of internal acoustic opening on left and right side in five monkeys measured from 3D reconstruction
in stereotaxic coordinate (cm). Lat+ = lateral, Med- = medial, Ant+ = anterior, Pos- = Posterior, Sup+ =
superior, Inf- = inferior
Table 2-3. Location of porus acusticus in CT chamber coordinate
Location of internal acoustic opening on left and right side in five monkeys measured from 3D reconstruction
in chamber coordinate (cm). X+/X- = X-axis, Y+/Y- = Y-axis, Z+/Z- = Z-axis.
37
2.4 Discussion
Guidance using 3D reconstructions of a CT scan obtained after initial placement of
a recording chamber using traditional stereotactic targeting is an efficient and effective
method that helps target the rhesus vestibular nerve for single-unit recording. We
accomplish this by registering the location of the porus acusticus relative to a chamber’s
axis identified in CT scans and determining parameters for a micromanipulator XY stage
mounted on the chamber that navigates and holds a guide tube and recording electrode.
Although a low sample number precludes a statistically rigorous comparison between the
traditional stereotaxic method alone and traditional stereotaxis augmented by post-
operative CT guidance, the latter was more efficient in our experience, With the help of the
post-operative CT guidance, vestibular afferent neurons were precisely located in the first
experiment after chamber implantation in the two rhesus monkeys for which we used this
technique,.
CT guidance using 3D reconstructions obtained after surgical attachment of a
recording chamber to the calvarium provides a safety net in case of inaccuracies of
stereotactic targeting (e.g., due to differences between the study subject and atlas), and it
gives the surgeon flexibility. For example, if a large meningeal vessel is in the path that
had been planned for a guide tube, the surgeon can reorient the chamber on the fly during
surgery without fear of later failing to find the nerve.
In the rhesus brain stereotaxic atlas we use,[39] the position the portion of
vestibular nerve that comes out of porus acusticus is about: posterior 0.06 cm, inferior 0.10
38
cm and lateral 0.85 cm. Compared with the atlas, in our results, the position is more anterior
and superior, which shows quite obvious inter-subject difference.
Although we still used a traditional stereotactic approach to initially place the
recording chambers, our method does not require that a chamber be very accurately
oriented, as long as the target lies along a path accessible by a guide tube passed parallel
to the chamber’s axis via a craniotomy. As Figure 2-8 shows, in all five monkeys, the
distances from porus acusticus to the chamber axis are all smaller than the chamber radius,
which means the nerve can be reached within the range of chamber. Navigation of electrode
is all based on the CT scan measurements.
Figure 2-8.Location of porus acusticus in transverse plane of chamber coordinate
Part (a) shows the location of porus acusticus in chamber coordinate on left side for five rhesus monkeys,
part (b) shows the right side. Red dots represent targets. The black dot represents chamber axis, and the
black ring shows the location of the ~3.5 cm diameter chamber.
39
The CT method also provides accurate and precise information regarding the
distance from parietal dura to the vestibular nerve, which is another parameter needed to
identify the location of the nerve efficiently. This saves time and reduces the risk of damage
to the animal’s brainstem and to the recording microelectrodes, because it permits one to
quickly and reliably pass the guide tube until it stops just before the nerve while not injuring
the nerve or adjacent vessels. Inserting electrodes with image guidance can therefore
reduce complications compared to standard stereotaxic surgery and therefore reduce the
risk to an animal subject. Moreover, by helping to maximize data yields per animal, CT
guidance can reduce the number of animals needed to obtain data for a given experiment.
Despite the advantages of CT guidance, several modes of targeting failure remain.
First, the guide tube may bend or tilt subtly when penetrating scar tissue near the
craniotomy skull surface, which causes the end of guide tube to move away from planned
position. The tendency for this to occur can be reduced by ensuring the guide tube is rigid,
held to the XY stage in a way that ensures it remains perpendicular to the stage, and filed
so that its tip is concentrically beveled. (Typical slant-beveled spinal needles tend to bend
as they are advanced through tissue.) Second, the outer diameter of tungsten
microelectrodes (120 um) is typically much smaller than the inner diameter of guide tube
(1mm), so a microelectrode advanced beyond the tip of a guide tube may bend when
penetrating hard scar tissue or being squeezed by the core of tissue that may enter the guide
tube lumen as the guide tube is inserted. Third, one can accurately target the
vestibulocochlear nerve with a guide tube and yet not selectively impale individual axons
in a way that yields high signal-to-noise recordings. Because the cell bodies of vestibular
nerve afferents are in the fundus of the internal auditory canal, they are shielded by bone
40
and inaccessible to microelectrodes inserted via a parietal craniotomy. Tungsten
microelectrodes with tips of ~1-3 um may be too large to isolate vestibular primary afferent
axons with diameter less than ~10 um. Fourth, one may accurately target the 7th/8th cranial
nerve bundle but miss the vestibular divisions by being ~200 um too anterior, instead
hitting only facial nerve motor neurons and cochlear afferents. Finally, changes in head
orientation can cause the brainstem to shift position within the skull. The effect of such
movement should be minimized by targeting the nerve where it leaves the bone at the porus
acusticus. However, clinical magnetic resonance imaging scans acquired with patients
lying supine commonly show the 7th/8th nerve complex resting against the posterior lip of
the porus (C Della Santina, personal communication), suggesting that a point coaxial with
the internal auditory canal may not necessarily lying within the center of the nerve.
41
Chapter 3 Intracranial/Extravascular Application of OCT and
IVUS for Imaging the Subarachnoid Space
We explored two real-time imaging techniques that are currently applied to
cardiology intervention surgery: intravascular optical coherence and intravascular
ultrasound. We sought to determine whether these highly refined intravascular
technologies, which are already approved by the United States Food & Drug
Administration for intravascular use in interventional cardiology and interventional
neuroradiology, might be adapted for intracranial/extravascular imaging of structures
in the subarachnoid space.
3.1 Experimental Subjects
3.1.1 Phantom
We made a phantom for image testing by embedding spaghetti and penne pasta in
a bowl full of red gelatin to simulate the CSF space. The inner diameter of penne pasta is
about 5mm and the thickness of penne wall is about 1.5 mm.
3.1.2 Chinchilla Subject
An immediately post-mortem adult wild-type 450g female chinchilla (Chinchilla
lanigera) was used for experiments, which were performed just after euthanasia following
a separate, terminal single unit recording experiment performed under deep general
anesthesia in accordance with a protocol approved by the Johns Hopkins Animal Care and
Use Committee.
42
3.1.3 Rhesus Monkey Subjects
A post-mortem rhesus monkey (RhF4617J) was used for IVUS and OCT
experiments, which was performed in accordance with a protocol (Protocol#: PR12M318)
approved by the Johns Hopkin Animal Care and Use Committee.
3.2 Surgical Procedures
3.2.1 Chinchilla Surgery
A chinchilla was used to study OCT immediately after euthanasia following a
terminal single-unit recording experiment performed as part of a different study. The
chinchilla had been anesthetized with 3-5% isoflurane anesthesia and sterilely prepped.
Skin was locally anesthetized (0.5% bupivacaine with 1:100K epinephrine). Enrofloxacin
antibiotic prophylaxis was given. A patch of skin was excised between the mastoid bullae,
and holes were drilled in the roof of each bulla using otologic drill. GelFilm® and/or
GelFoam® were used to shield the middle ear and ossicles from the mastoid bulla. Dental
cement (3M ESPE ProTemp®II or OrthoJet®) was used to conformally fill the
superomedial recess of each bulla, with the cement joining across the midline adjacent to
the skull to form a rigid cast around the central portion of the skull. A phenolic post was
embedded in the cement and oriented 10o pitched back a plane tangent to the central portion
of the visible skull (so that when animals was restrained with the post in the 45o pitch-nose-
down slot of a Plexiglass restraint, the chinchilla’s mean horizontal semicircular canal axis
was Earth vertical).
43
Immediately following the single unit experiment, the animal was euthanized under
deep inhalational anesthesia. A hole was then opened on the floor of bulla 1mm anterior
and medial to the anterior semicircular canal ampulla using an otologic drill, to create a
port into the internal auditory canal for inserting an OCT imaging catheter.
3.3 Intracranial/Extravascular Optical Coherence Tomography
3.3.1 Method
For the intracranial OCT imaging experiment, we used a St. Jude Medical® C7XR
unit with a C7 Dragonfly IV imaging catheter with OCT flush, 100 frames/sec, pullback
rate 2cm/s. the outer diameter of catheter is 0.9mm. The imaging resolution is about 20um
in greatest dimension. The system is available to perform pullback side-viewing image
scan with length of 55mm.
First, we performed an OCT imaging test in the penne-gelatin phantom to simulate
the situation of cerebrospinal fluid (CSF) space around porus acusticus. Figure 3-1 shows
the OCT images obtained by inserting a 30 mm-length of the catheter roughly along the
axis of penne inside the gelatin. We triggered the pullback scanning and the transducer
moved backward while scanning.
For the chinchilla experiment, we performed an OCT imaging scan to examine the
inner acoustic canal in an animal immediately after euthanasia by passing the catheter
through a hole opened on the floor of bulla via which the 7th/8th nerve complex had been
accessed for single unit recording as part of a separate research protocol (Figure 3-2).
(Whereas we approach the rhesus vestibular nerve for single unit recording via the parietal
cranium, we typically approach the chinchilla internal auditory canal via the bulla, so the
44
never is directly visible in the latter case.) The chinchilla head was then dissected to
determine where the OCT probe had been.
Next, we placed the catheter near the left porus acusticus in a rhesus monkey skull
and performed the image scanning to visualize its bone structure in OCT.
Finally, we passed an OCT catheter inside CSF through the guide tube navigated
by the CT measurement of target in a post-mortem monkey head (RhF4617J).
Figure 3-1. Placement of OCT catheter inside penne embedded in gelatin
45
Figure 3-2.Simulation of placing OCT catheter through the floor of bulla in chinchilla right ear
under camera view
46
3.3.2 Results
Stacks of OCT side-view images were acquired with imaging diameter of 5mm,
which nicely constructed a 3D image of the penne pasta (Figure 3-3). The tiny circle in the
center of image is the catheter around the OCT probe. The larger, oval orange curve with
fading shade outside it is the imaging of interface between gelatin and wall of penne. The
infrared light hardly penetrates the penne’s inner wall and mostly reflects back or is
absorbed by the pasta, so the outer wall/gelatin boundary is not detected by OCT.
An OCT 3D reconstruction was acquired via pullback scanning after the catheter
was passed through the floor of the bulla and into the internal auditory canal and
cerebellopontine angle of a chinchilla immediately post-mortem (Figure 3-4). We can
clearly identify two black holes near each other on the surface of some dense matter which
is likely to be the bone. The landmark in 3D reconstructed image is identical to the real
bone structure, which was exposed after dissecting the chinchilla’s head (Figure 3-5).
OCT 3D reconstruction (Figure 3-6 b) was also done after pullback scanning near
porus acusticus in a rhesus monkey skull (Figure 3-6 a), which clearly shows the porus
acusticus and subarcuate parafloccular recess compared with CT 3D reconstruction (Figure
3-6 c).
Unfortunately, in the OCT image acquired from scanning in the post-mortem rhesus
monkey assisted by post-operative CT guidance (Figure 3-7), we can hardly identify any
structures. In one of the image scans, a dark blurry area close to the shields of catheters
could be CSF since no reflection occurred there. The areas that have bright boundary and
fade in radial gradient could be either soft tissue or bone. We could not confidently relate
47
them to any anatomic landmarks that would help find the porus acusticus or the vestibular
nerve.
Figure 3-3. OCT image of a penne in the gelatin phantom
Top left section shows the 3D reconstruction of part of the penne’s inner wall within the pullback scanning
range. Top right section shows the slice of side-view image, location of which is indicated by the white circle
in the left section. Lower section shows a cross-sectional image along catheter axis, orientation of which is
indicated by the yellow in the top left section.
48
Figure 3-4.OCT image of inner acoustic canal in chinchilla
Two black holes can be identified as porus on the surface of dense matter, facing toward a small space free
of reflection.
49
Figure 3-5.Location of OCT catheter placement into the internal auditory canal and cerebellopontine
angle of a chinchilla placed just after euthanasia and then dissected after OCT image acquisition.
Red circle is the area of internal auditory canal, where vestibular afferent nerves of different semicircular
canals join together. The view is from the contralateral side, after removal of the brain and brainstem.
50
Figure 3-6.Rhesus monkey inner acoustic opening on left side
Rhesus monkey inner acoustic canal: (a) endoscopic photograph of an OCT catheter placed near internal
acoustic opening on bony skull specimen, (b) Optical coherence tomography shows bone/CSF interfaces, (c)
CT 3D reconstruction.
51
Figure 3-7.A slice of OCT side-view scan when catheter is placed in CSF space in the post-mortem
rhesus monkey on left side
52
3.4 Intracranial/Extravascular Ultrasound Imaging of the
Subarachnoid Space
3.4.1 Method
For the intracranial/extravascular ultrasound (IC/EVUS) experiment, we used a
Volcano CORE® mobile unit, operating at 10 frames/sec with the Volcano Eagle-Eye®
Platinum IVUS imaging catheter. The outer diameter of catheter is 1.1mm. The system is
available to perform side-viewing scans and construct a cross-sectional image centered on
the transducer. The imaging resolution is about 200 um in greatest dimension. The
ultrasound unit can provide a real-time side-view image with imaging diameter of 10mm
but it doesn’t have the automatic pullback function we used with our OCT imaging unit.
First, we performed IC/EVUS imaging test in the pasta-gelatin phantom to simulate
the situation of cerebrospinal fluid (CSF) space around porus acusticus by inserting the
catheter roughly along the axis of penne inside the gelatin, which is similar to the approach
in the OCT experiment. We then used post-operative CT guidance on a rhesus monkey
head specimen with implanted chambers and passed the IC/EVUS catheter through brain
tissue through the guide tube navigated by the CT measurement of target. We manually
pulled back the catheter. Due to constraints on availability of OCT and IVUS equipment
for use with animal specimens, we could not perform IC/EVUS in a live animal.
3.4.2 Results
As Figure 3-8 shows, the ultrasound penetrates the penne and a cross-sectional
image of penne is readily detected. The small bright white circle is identified as the shield
53
of catheter and the larger bright circle-like shape is identified as the transverse view of
penne. In one of the ultrasound images scanned in CSF space on the right side in the rhesus
monkey head specimen (Figure 3-9 a), we found an angular structure formed by two short
bright edges.
Figure 3-8.IC/EVUS side-view image of penne embedded in gelatin phantom
The boundary between the outer wall of the penna and the gelatin can be clearly identified, which cannot be
seen in OCT due to light absorption.
54
Figure 3-9. Images of subarcuate parafloccular recess obtained using intracranial/extravascular
ultrasound in the cerebellopontine angle of a rhesus monkey specimen.
Subarcuate parafloccular recess in (a) IC/EVUS side-view scan (b) CT 3D reconstruction (c) CT cross-
sectional image (d) CT cross-sectional image with measurement of the angular structure
55
The angle is approximately 62o, and lengths of two edges are about 4mm and 5mm after
scaling to real space. We retrieved 3D CT reconstruction of the specimen (Figure 3-9 b),
and found that the subarcuate parafloccular recess had a sharp-angle opening. A cross-
sectional CT image (Figure 3-9 c) shows a similar structure as seen in the IC/EVUS image.
As measured in CT scan, the angle is approximately 60° and the lengths of bone edges are
about 4.9mm and 5.3mm (Figure 3-9 d). Measurements from the IC/EVUS image and the
CT image are basically the same, which suggests that IC/EVUS can identify bone/CSF
boundaries like the porus acusticus and subarcuate parafloccular recess, if they have
already been seen on a CT 3D reconstruction. However, even with advance knowledge of
the anatomy from the CT dataset, we could not identify any structure that appeared to be
the vestibular nerve on IC/EVUS.
3.5 Discussion
Comparing the OCT and IC/EVUS images of the penne-gelatin phantom (Figure
3-10), we can see that OCT has better spatial resolution than ultrasound, but IC/EVUS is
able to penetrate the penne and provides both a larger imaging depth and definition of the
outer pasta/gelatin boundary. Summary of comparison is shown in Table 3-1.
Techniques Catheter Model Imaging Depth Resolution Catheter
Diameter
Automatic
Pullback
Function
Images
through
optical
opaque
material
OCT C7 Dragonfly
(St. Jude
Medical)
5 mm in
diameter
~20 um 2.7F
(0.9mm)
Yes No
IC/EVUS Eagle-Eye
Platinum
10 mm in
diameter
~200 um 3.5F
(1.2 mm)
No Yes
Table 3-1.Comparison of OCT and IC/EVUS
56
In the immediately postmortem chinchilla specimen, OCT 3D reconstruction
apparently showed the porus acusticus and subarcuate parafloccular fossa, which although
unnecessary in that experimental preparation (we can already see the chinchilla 7th/8th nerve
directly), served as a useful proof of concept. Unfortunately, our attempts at performing
OCT imaging inside CSF space in the post-mortem rhesus monkey did not result in images
from which we could identify the vestibular nerve, porus acusticus, or other anatomic
landmarks. There are several possible causes for the failure. First, soft tissue and possibly
blood in CSF make the OCT light reflect back and generate blurring artifacts, which limits
the field of view and penetration depth. Regardless of any other source of failure, the major
limitation of OCT for our application was the shallow penetration depth. Second, the guide
tube might not have been pointed at the right target, so the porus acusticus or subarcuate
parafloccular recess might have been completely out of the imaging range. Third, inability
to image along the guide tube axis with our side-viewing OCT system precluded seeing
where the guide tube was headed. Finally, the lack of OCT catheters designed and intended
for our intended use required that we instead use a clinical model of OCT catheter intended
for coronary artery imaging that would not allow us to advance the OCT imaging unit to
the end of the unit’s protective catheter sheath. To overcome this, we had to cut the end of
the sheath, allowing bodily fluids to back fill into the catheter and perhaps cloud the image.
As for IC/EVUS, although its resolution is not as high as OCT, it has larger
penetration through soft tissue. The IC/EVUS images we obtained (Figure 3-9) clearly
show the bone boundaries of the subarcuate parafloccular recess, as confirmed by CT scan.
IC/EVUS provided clear contrast between bone and other tissue, which can help identify
bone landmarks that can help one target the vestibular nerve if the catheter is within 10 mm
57
of the porus acusticus. However, the IVUS probe is slightly larger than the 1.0 mm inner
diameter guide tube we normally use.
Figure 3-10.Comparison of OCT and IC/EVUS in gelatin phantom
Images of the penne in gelatin: (a) camera view of the penne in gelatin (b) OCT side-view image of the penne
(c) IC/EVUS side-view image of the penne
58
Chapter 4 Conclusion
4.1 Post-Operative CT Guidance
Compared with the conventional stereotaxic method, augmenting traditional
stereotaxis with post-operative CT guidance as presented in this thesis was more efficient
and more effective in helping researchers find the rhesus vestibular nerve. This method
doesn’t completely depend on an atlas or require the monkey to be physically attached to
the stereotaxic frame in recording stage, which allows for more flexibility in surgical
technique and allows a neurophysiologist to find the vestibular nerve despite inter-subject
anatomic differences. Moreover, this method provides intuitive image guidance on where
and how deep the guide tube and electrode should be inserted to reach the target. Having
accurate measurements from a CT scan greatly reduces the risk of overinsertion, so one
can avoid inadvertently cutting the nerve during guide tube insertion or damaging the
microelectrode by driving it into a bone wall. CT imaging units with adequate resolution
are widely available in academic medical centers, and 3D reconstruction software is readily
available to research labs.
4.2 Intracranial Imaging of the Subarachnoid Space Using OCT and
IVUS
OCT and ultrasound within CSF spaces like the cerebellopontine angle offer
complementary advantages for targeting cranial nerves. When passed through the guide
tube of a single-unit recording set-up, optical coherence tomography probes can provide
direct view of intracranial tissue and bone structures through a small craniotomy.
59
Unfortunately, in our experience, optical blurring and a shallow penetration depth limited
the ability to visualize the porus acusticus or the vestibular nerve in post-mortem and live
rhesus monkeys using OCT.
Our intracranial adaptation of IVUS offered a larger imaging depth and ability to
see through optically opaque or translucent material (probably including nerve, dura and
brain), but its resolution is not as high as optical coherence tomography. The large
penetration depth enables it to detect bone structures beyond soft tissues within the range.
Visualization of the bone landmarks in US images has the potential to serve as real-time
guidance for targeting cranial nerves in electrophysiologic experiments.
Adaptation of intravascular OCT and IVUS systems for intracranial/extravascular
imaging of cranial and spinal nerves may hold promise for intraoperative guidance in
minimal-access rhizotomy and other clinical procedures that require precise spatial
targeting of neural structures through narrow channels. Further development of OCT is
needed in imaging penetration. It would be great if OCT and IVUS are combined in one
modality for targeting, which will have large imaging penetration depth for detecting more
structures and high resolution for detecting soft tissues.
4.3 Future Directions
Although the post-operative CT guidance can already give us direct and precise
guidance to reach the porus acusticus, imprecision in our estimate of the exact direction
and size of vestibular nerve coming out of the porus acusticus still make targeting a
challenge. To visualize the vestibular nerve, coregistering 3D reconstructions of both CT
and MRI imaging could be considered. To perform MRI after chamber implantation, the
60
chambers and guide tube would need to be replaced by non-ferrous, nonmagnetic material.
Recent progress in intravascular MRI [99-101] also holds promise as another means by
which a high resolution imaging unit can be introduced via a guide tube into the
subarachnoid space, whether for targeting the vestibular nerve in rhesus monkeys or for
analogous neurosurgical procedures in humans.
61
Reference List
1. Blatt, P.J., et al., The reliability of the Vestibular Autorotation Test (VAT) in
patients with dizziness. J Neurol Phys Ther, 2008. 32(2): p. 70-9.
2. Minor, L.B., Gentamicin-induced bilateral vestibular hypofunction. JAMA, 1998.
279(7): p. 541-4.
3. Crawford, J., Living without a Balancing Mechanism. New England Journal of
Medicine, 1952. 246(12): p. 458-460.
4. Ward, B.K., et al., Prevalence and impact of bilateral vestibular hypofunction:
results from the 2008 US National Health Interview Survey. JAMA
Otolaryngology–Head & Neck Surgery, 2013. 139(8): p. 803-810.
5. Della Santina, C.C., et al., Current and future management of bilateral loss of
vestibular sensation - an update on the Johns Hopkins Multichannel Vestibular
Prosthesis Project. Cochlear Implants Int, 2010. 11 Suppl 2: p. 2-11.
6. Della Santina, C.C., A.A. Migliaccio, and A.H. Patel, A multichannel semicircular
canal neural prosthesis using electrical stimulation to restore 3-D vestibular
sensation. Ieee Transactions on Biomedical Engineering, 2007. 54(6): p. 1016-
1030.
7. Gong, W.S. and D.M. Merfeld, Prototype neural semicircular canal prosthesis
using patterned electrical stimulation. Annals of Biomedical Engineering, 2000.
28(5): p. 572-581.
8. Gong, W.S. and D.M. Merfeld, System design and performance of a unilateral
horizontal semicircular canal prosthesis. Ieee Transactions on Biomedical
Engineering, 2002. 49(2): p. 175-181.
9. Chiang, B., G.Y. Fridman, and C.C. Della Santina, Enhancements to the Johns
Hopkins Multi-Channel Vestibular Prosthesis Yield Reduced Size, Extended
Battery Life, Current Steering and Wireless Control. Association for Research in
Otolaryngology. 2009. Baltimore, MD.
10. Della Santina, C.C., A.A. Migliaccio, and A.H. Patel, Electrical stimulation to
restore vestibular function - development of a 3-D vestibular prosthesis. 27th
Annual IEEE Engineering in Medicine and Biology. 2005. Shanghai,China.
11. Della Santina, C.C., et al., Orientation of human semicircular canals measured by
three-dimensional multiplanar CT reconstruction. J Assoc Res Otolaryngol, 2005.
6(3): p. 191-206.
12. Carey, J.P. and C.C. Della Santina, Principles of applied vestibular physiology.
Cummings: Otolaryngology: Head & Neck Surgery. 4th ed. Philadelphia, PA:
Elsevier Mosby, 2005. 3: p. 3115-3159.
13. Ewald, J., Physiologische untersuchugen uber das Endorgans des Nervus Octavus:
Bergmann. 1892.
14. Wilson, V. and G. Jones, Mammalian vestibular physiology Plenum New York.
1979.
15. Robinson, F.P. and P.G. Murphy, The Validity of Measuring Eye Movements by
Direct Observation. Science, 1932. 76(1964): p. 171-2.
62
16. Robinson, D.A., A Method of Measuring Eye Movement Using a Scleral Search
Coil in a Magnetic Field. Ieee Transactions on Biomedical Engineering, 1963.
Bm10(4): p. 137-&.
17. Aw, S.T., et al., Three-dimensional vector analysis of the human vestibuloocular
reflex in response to high-acceleration head rotations .2. Responses in subjects
with unilateral vestibular loss and selective semicircular canal occlusion. Journal
of Neurophysiology, 1996. 76(6): p. 4021-4030.
18. Aw, S.T., et al., Three-dimensional vector analysis of the human vestibuloocular
reflex in response to high-acceleration head rotations .1. Responses in normal
subjects. Journal of Neurophysiology, 1996. 76(6): p. 4009-4020.
19. Migliaccio, A.A., et al., Inexpensive system for real-time 3-dimensional video-
oculography using a fluorescent marker array. J Neurosci Methods, 2005. 143(2):
p. 141-50.
20. Cohen, B., S. Shanzer, and J. Suzuki, Nystagmus Induced by Stimulation of Single
Nerves from Semicircular Canals. Federation Proceedings, 1963. 22(2): p. 338-&.
21. Cohen, B., J. Suzuki, and M.B. Bender, Eye Movements from Semicircular Canal
Nerve Stimulation in Cat. Annals of Otology Rhinology and Laryngology, 1964.
73(1): p. 153-&.
22. Cohen, B. and J. Suzuki, Eye Movements Produced by Vestibular Nerve
Stimulation. Electroencephalography and Clinical Neurophysiology, 1963. 15(1):
p. 152-&.
23. Cohen, B. and J.I. Suzuki, Eye Movements Induced by Ampullary Nerve Stimulation.
American Journal of Physiology, 1963. 204(2): p. 347-&.
24. Cohen, B. and J.I. Suzuki, Phases of Central Excitability Evoked by Ampullary
Nerve Stimulation. Federation Proceedings, 1964. 23(2p1): p. 414-&.
25. Suzuki, J., B. Cohen, and M.B. Bender, Compensatory Eye Movements Induced by
Vertical Semicircular Canal Stimulation. Experimental Neurology, 1964. 9(2): p.
137-&.
26. Suzuki, J.I., et al., Implantation of electrodes near individual vestibular nerve
branches in mammals. Ann Otol Rhinol Laryngol, 1969. 78(4): p. 815-26.
27. Della Santina, C., A. Migliaccio, and A. Patel, Electrical stimulation to restore
vestibular function development of a 3-d vestibular prosthesis. Conf Proc IEEE Eng
Med Biol Soc, 2005. 7: p. 7380-5.
28. Rahman, M.A., et al., Restoring the 3D vestibulo-ocular reflex via electrical
stimulation: the Johns Hopkins multichannel vestibular prosthesis project. Conf
Proc IEEE Eng Med Biol Soc, 2011. 2011: p. 3142-5.
29. Chiang, B., et al., Design and Performance of a Multichannel Vestibular Prosthesis
That Restores Semicircular Canal Sensation in Rhesus Monkey. Ieee Transactions
on Neural Systems and Rehabilitation Engineering, 2011. 19(5): p. 588-598.
30. Fridman, G.Y., et al., Vestibulo-ocular reflex responses to a multichannel
vestibular prosthesis incorporating a 3D coordinate transformation for correction
of misalignment. J Assoc Res Otolaryngol, 2010. 11(3): p. 367-81.
31. Davidovics, N.S., et al., Effects of biphasic current pulse frequency, amplitude,
duration, and interphase gap on eye movement responses to prosthetic electrical
stimulation of the vestibular nerve. IEEE Trans Neural Syst Rehabil Eng, 2011.
19(1): p. 84-94.
63
32. C. Dai, G.Y.F., N.S. Davidovics, B. Chiang, J.H. Ahn, and C.C. Della Santina,
Restoration of 3D vestibular sensation in rhesus monkeys using a multichannel
vestibular prosthesis. Hear Res, Aug 2011.
33. C. Dai, G.Y.F., B. Chiang, N.S. Davidovics, T.A. Melvin, K.E. Cullen, and C.C.
Della Santina, Cross-axis adaptation improves 3D vestibulo-ocular reflex
alignment during chronic stimulation via a head-mounted multichannel vestibular
prosthesis. Exp Brain Res, Mar 4 2011.
34. Carey, J., Multichannel Vestibular Implant Early Feasibility Study. In:
ClinicalTrials.gov[Internet].Bethesda(MD): National Library of Medicine (US).
2000-[cited 2016 Aug 9]. Available from:
https://clinicaltrials.gov/ct2/show/NCT02725463 NLM Identifier: NCT02725463.
35. Sildiroglu, O., et al., Evaluation of cochlear nerve size by magnetic resonance
imaging in elderly patients with sensorineural hearing loss. Radiol Med, 2010.
115(3): p. 483-7.
36. Jaryszak, E.M., et al., Cochlear Nerve Diameter in Normal Hearing Ears Using
High-Resolution Magnetic Resonance Imaging. Laryngoscope, 2009. 119(10): p.
2042-2045.
37. Nakamichi, R., et al., Establishing Normal Diameter Range of the Cochlear and
Facial Nerves with 3D-CISS at 3T. Magnetic Resonance in Medical Sciences, 2013.
12(4): p. 241-247.
38. Gacek, R.R. and G.L. Rasmussen, Fiber analysis of the statoacoustic nerve of
guinea pig, cat, and monkey. Anat Rec, 1961. 139: p. 455-63.
39. Paxinos, G., X.-F. Huang, and A.W. Toga, The rhesus monkey brain in stereotaxic
coordinates. 2000.
40. Saleem, K.S. and N.K. Logothetis, Atlas of the rhesus monkey brain in stereotaxic
coordinates: a combined mri and histology. 2006: Academic Press.
41. Saleem, K.S. and N.K. Logothetis, A combined MRI and histology atlas of the
rhesus monkey brain in stereotaxic coordinates. 2012: Academic Press.
42. Sadeghi, S.G., et al., Effects of canal plugging on the vestibuloocular reflex and
vestibular nerve discharge during passive and active head rotations. Journal of
neurophysiology, 2009. 102(5): p. 2693-2703.
43. Haque, A., D.E. Angelaki, and J.D. Dickman, Spatial tuning and dynamics of
vestibular semicircular canal afferents in rhesus monkeys. Exp Brain Res, 2004.
155(1): p. 81-90.
44. Angelaki, D.E. and J.D. Dickman, Spatiotemporal processing of linear
acceleration: primary afferent and central vestibular neuron responses. J
Neurophysiol, 2000. 84(4): p. 2113-32.
45. Sylvestre, P.A. and K.E. Cullen, Quantitative analysis of abducens neuron
discharge dynamics during saccadic and slow eye movements. Journal of
Neurophysiology, 1999. 82(5): p. 2612-2632.
46. Sadeghi, S.G., L.B. Minor, and K.E. Cullen, Response of vestibular-nerve afferents
to active and passive rotations under normal conditions and after unilateral
labyrinthectomy. Journal of neurophysiology, 2007. 97(2): p. 1503-1514.
47. Cullen, K.E. and L.B. Minor, Semicircular canal afferents similarly encode active
and passive head-on-body rotations: implications for the role of vestibular
efference. J Neurosci, 2002. 22(RC226): p. 1-7.
64
48. Khan, F.R. and J.M. Henderson, Deep brain stimulation surgical techniques.
Handb Clin Neurol, 2013. 116: p. 27-37.
49. Brown, R.A. and J.A. Nelson, Invention of the N-Localizer for Stereotactic
Neurosurgery and Its Use in the Brown-Roberts-Wells Stereotactic Frame.
Neurosurgery, 2012. 70(6): p. 173-176.
50. Brown, R.A. and J.A. Nelson, The Origin and History of the N-Localizer for
Stereotactic Neurosurgery. Cureus, 2015. 7(9): p. e323.
51. Tse, V.C., M.Y.S. Kalani, and J.R. Adler, Techniques of Stereotactic Localization.
Principles and Practice of Stereotactic Radiosurgery, 2015: p. 25.
52. Saleh, H. and B. Kassas, Developing stereotactic frames for cranial treatment.
Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy, 2014: p. 153.
53. Arle, J., Development of a classic: The Todd-Wells apparatus, the BRW, and the
CRW stereotactic frames, in Textbook of Stereotactic and Functional Neurosurgery.
2009, Springer. p. 453-467.
54. Sharan, A.D. and D.W. Andrews, Stereotactic frames: technical considerations.
NEUROLOGICAL DISEASE AND THERAPY, 2003. 58: p. 11-20.
55. Apuzzo, M.L. and C.A. Fredericks, The Brown-Roberts-Wells system, in Modern
stereotactic neurosurgery. 1988, Springer. p. 63-77.
56. Heilbrun, M.P., et al., Preliminary experience with Brown-Roberts-Wells (BRW)
computerized tomography stereotaxic guidance system. J Neurosurg, 1983. 59(2):
p. 217-22.
57. Thomas, D.G., R.E. Anderson, and G.H. du Boulay, CT-guided stereotactic
neurosurgery: experience in 24 cases with a new stereotactic system. J Neurol
Neurosurg Psychiatry, 1984. 47(1): p. 9-16.
58. Goerss, S., et al., A Computed Tomographic Stereotactic Adaptation System.
Neurosurgery, 1982. 10(3): p. 375-379.
59. Brown, R.A., A computerized tomography-computer graphics approach to
stereotaxic localization. J Neurosurg, 1979. 50(6): p. 715-20.
60. Heilbrun, M.P., et al., Brown-Roberts-Wells stereotactic frame modifications to
accomplish magnetic resonance imaging guidance in three planes. Appl
Neurophysiol, 1987. 50(1-6): p. 143-52.
61. Leksell, L., D. Leksell, and J. Schwebel, Stereotaxis and nuclear magnetic
resonance. J Neurol Neurosurg Psychiatry, 1985. 48(1): p. 14-8.
62. Thomas, D.G., et al., Stereotaxic biopsy of the brain under MR imaging control.
AJNR Am J Neuroradiol, 1986. 7(1): p. 161-3.
63. Maciunas, R.J., et al., Positron emission tomography imaging-directed stereotactic
neurosurgery. Stereotact Funct Neurosurg, 1992. 58(1-4): p. 134-40.
64. Levivier, M., et al., Use of stereotactic PET images in dosimetry planning of
radiosurgery for brain tumors: Clinical experience and proposed classification.
Journal of Nuclear Medicine, 2004. 45(7): p. 1146-1154.
65. Ohayon, S. and D.Y. Tsao, MR-guided stereotactic navigation. Journal of
Neuroscience Methods, 2012. 204(2): p. 389-397.
66. Vega, R.A., K.L. Holloway, and P.S. Larson, Image-guided deep brain stimulation.
Neurosurg Clin N Am, 2014. 25(1): p. 159-72.
65
67. Eggers, G., B. Kress, and J. Muhling, Fully automated registration of
intraoperative computed tomography image data for image-guided craniofacial
surgery. J Oral Maxillofac Surg, 2008. 66(8): p. 1754-60.
68. Ferroli, P., et al., Advanced 3-Dimensional Planning in Neurosurgery.
Neurosurgery, 2013. 72: p. A54-A62.
69. Ferroli, P., et al., Advanced 3-dimensional planning in neurosurgery. Neurosurgery,
2013. 72 Suppl 1: p. 54-62.
70. Watanabe, E., et al., Three-dimensional digitizer (neuronavigator): new equipment
for computed tomography-guided stereotaxic surgery. Surgical neurology, 1987.
27(6): p. 543-547.
71. Colbassani, H.J., et al., CT-assisted stereotactic brain biopsy: value of
intraoperative frozen section diagnosis. J Neurol Neurosurg Psychiatry, 1988.
51(3): p. 332-41.
72. Venkataramana, N.K., et al., Open-labeled study of unilateral autologous bone-
marrow-derived mesenchymal stem cell transplantation in Parkinson's disease.
Transl Res, 2010. 155(2): p. 62-70.
73. Lang, A.E., et al., Randomized controlled trial of intraputamenal glial cell line-
derived neurotrophic factor infusion in Parkinson disease. Ann Neurol, 2006.
59(3): p. 459-66.
74. Bom, N., C. Lancee, and F. Van Egmond, An ultrasonic intracardiac scanner.
Ultrasonics, 1972. 10(2): p. 72-76.
75. Liu, J.B. and B.B. Goldberg, Catheter-based intraluminal sonography. J
Ultrasound Med, 2004. 23(2): p. 145-60.
76. Li, X., et al., Integrated IVUS-OCT imaging for atherosclerotic plaque
characterization. Selected Topics in Quantum Electronics, IEEE Journal of, 2014.
20(2): p. 196-203.
77. Nissen, S.E., et al., Intravascular Ultrasound Assessment of Lumen Size and Wall
Morphology in Normal Subjects and Patients with Coronary-Artery Disease.
Circulation, 1991. 84(3): p. 1087-1099.
78. Nicholls, S.J., et al., Intravascular ultrasound in cardiovascular medicine.
Circulation, 2006. 114(4): p. E55-E59.
79. Lee, J.T. and R.A. White. Basics of intravascular ultrasound: an essential tool for
the endovascular surgeon. in Seminars in vascular surgery. 2004. Elsevier.
80. Lee, J.T., T.D. Fang, and R.A. White. Applications of intravascular ultrasound in
the treatment of peripheral occlusive disease. in Seminars in vascular surgery.
2006. Elsevier.
81. Marrocco, C.J., et al., Intravascular Ultrasound. Seminars in Vascular Surgery,
2012. 25(3): p. 144-152.
82. Rogacka, R., A. Latib, and A. Colombo, IVUS-guided stent implantation to improve
outcome: a promise waiting to be fulfilled. Current cardiology reviews, 2009. 5(2):
p. 78-86.
83. Jiang, J., et al., The application of intravascular ultrasound imaging in the
diagnosis of aortic dissection. Zhonghua wai ke za zhi [Chinese journal of surgery],
2003. 41(7): p. 491-494.
66
84. Brezinski, M.E., et al., Assessing atherosclerotic plaque morphology: comparison
of optical coherence tomography and high frequency intravascular ultrasound.
Heart, 1997. 77(5): p. 397-403.
85. Brezinski, M.E., et al., Optical coherence tomography for optical biopsy.
Properties and demonstration of vascular pathology. Circulation, 1996. 93(6): p.
1206-13.
86. Fujimoto, J.G., et al., High resolution in vivo intra-arterial imaging with optical
coherence tomography. Heart, 1999. 82(2): p. 128-33.
87. Bezerra, H.G., et al., Intracoronary optical coherence tomography: a
comprehensive review clinical and research applications. JACC Cardiovasc Interv,
2009. 2(11): p. 1035-46.
88. Yaqoob, Z., et al., Methods and application areas of endoscopic optical coherence
tomography. J Biomed Opt, 2006. 11(6): p. 063001.
89. Kang, W., et al., Endoscopically guided spectral-domain OCT with double-balloon
catheters. Opt Express, 2010. 18(16): p. 17364-72.
90. Moon, S., et al., Semi-resonant operation of a fiber-cantilever piezotube scanner
for stable optical coherence tomography endoscope imaging. Opt Express, 2010.
18(20): p. 21183-97.
91. Sun, J. and H. Xie, MEMS-Based Endoscopic Optical Coherence Tomography.
International Journal of Optics, 2011. 2011.
92. Pan, Y., et al., Hand-held arthroscopic optical coherence tomography for in vivo
high-resolution imaging of articular cartilage. J Biomed Opt, 2003. 8(4): p. 648-
54.
93. Liang, C.P., et al., A forward-imaging needle-type OCT probe for image guided
stereotactic procedures. Opt Express, 2011. 19(27): p. 26283-94.
94. Nguyen, C.T., et al., Non-invasive optical interferometry for the assessment of
biofilm growth in the middle ear. Biomed Opt Express, 2010. 1(4): p. 1104-1116.
95. Djalilian, H.R., et al., Optical coherence tomography of cholesteatoma. Otol
Neurotol, 2010. 31(6): p. 932-5.
96. Djalilian, H.R., et al., Imaging the human tympanic membrane using optical
coherence tomography in vivo. Otol Neurotol, 2008. 29(8): p. 1091-4.
97. Burkhardt, A., et al., Endoscopic optical coherence tomography device for forward
imaging with broad field of view. J Biomed Opt, 2012. 17(7): p. 071302.
98. Ahn, J.H., C. Dai, and C.C. Della Santina, Skin grafting facilitates the maintenance
of head recording chambers for neurophysiological recording. Journal of
neuroscience methods, 2013. 215(2): p. 161-163.
99. Hegde, S.S., Y. Zhang, and P.A. Bottomley. Accelerated, motion-corrected high-
resolution intravascular MRI at 3T. in Proceedings of the International Society for
Magnetic Resonance in Medicine... Scientific Meeting and Exhibition.
International Society for Magnetic Resonance in Medicine. Scientific Meeting and
Exhibition. 2013. NIH Public Access.
100. Hegde, S.S., Y. Zhang, and P.A. Bottomley, Acceleration and motion‐correction
techniques for high‐resolution intravascular MRI. Magnetic resonance in medicine,
2015. 74(2): p. 452-461.
67
101. Bottomley, P., Y. Zhang, and S.S. Hegde, Methods and apparatus for accelerated,
motion-corrected high-resolution mri employing internal detectors or mri
endoscopy. 2013, Google Patents.
68
Curriculum Vitae
Shiyao Dong was born in Xi’an, Shaanxi, China on February 1st, 1992. After
graduating from the Gaoxin No.1 High School, he attended the Zhejiang University. In
2010, he graduated from the Zhejiang University with a B.S in Biomedical Engineering.
His research interests include: biomedical engineering and data mining.