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fully edited. Content may change prior to final publication. Citation information: DOI 10.1109/JSTQE.2015.2513667, IEEE Journal
of Selected Topics in Quantum Electronics
JSTQE-INV-NB2016-06138-2015 1
(Invited paper)
morphology with a resolution approaching that of conventional
AbstractOptical coherence tomography (OCT) is a promising histology, but without the need to excise or process specimens.
research tool for brain imaging and developmental biology. Currently, OCT has been widely used clinically in
Serving as a three-dimensional optical biopsy technique, OCT ophthalmology [4-10], cardiology [11-15], endoscopy [16-23],
provides volumetric reconstruction of brain tissues and dermatology [24-29] and oncology [24-29]. In recent years,
embryonic structures with micrometer resolution and video rate there has been a growing need for high-speed, high-resolution
imaging speed. Functional OCT enables label-free monitoring of
optical imaging modalities for neuroimaging and
hemodynamic and metabolic changes in the brain in vitro and in
vivo in animal models. Due to its non-invasiveness nature, OCT developmental biology. Recent development of high speed and
enables longitudinal imaging of developing specimens in vivo ultrahigh resolution OCT technologies [30-33] makes it
without potential damage from surgical operation, tissue fixation possible to reveal fast dynamics and cellular features of the
and processing, and staining with exogenous contrast agents. In brain and developing embryos. These benefits, combined with
this paper, various OCT applications in brain imaging and label-free and non-invasive imaging capabilities, OCT
developmental biology are reviewed, with a particular focus on becomes an attractive research tool for scientists working in
imaging heart development. In addition, we report findings on the these research fields.
effects of a circadian gene (Clock) and high-fat-diet on heart OCT has been demonstrated as a promising neuroimaging
development in Drosophila melanogaster. These findings
tool [34-36]. OCT enables non-invasive visualization of
contribute to our understanding of the fundamental mechanisms
connecting circadian genes and obesity to heart development and structures and functionality of the brain, which is valuable for
cardiac diseases. fundamental research and medical diagnosis. OCT reveals fine
structural details of brain tissues with the capability to resolve
Index Terms Biological systems, Biomedical optical imaging, individual neurons and myelinated fibers [34]. Moreover,
Brain, Cardiovascular system and Optical tomography. signals originated from brain activities, such as cerebral blood
flow/velocity, oxygen saturation and neural action potentials
can be characterized using functional OCT [36-38]. Both
I. INTRODUCTION structural and functional information provided by OCT has
Optical coherence tomography (OCT) [1-3] is one of most been utilized to study brain diseases, such as brain tumors [35]
rapidly developed optical imaging modalities of the last few and stroke [36].
decades. OCT imaging is analogous to ultrasound B-mode In developmental biology, OCT has been used to
imaging, measuring echo time delay of backscattered light. characterize morphological and functional development of
Instead of direct measurement of time delay of reflected organs, such as eyes [39], brain [40], limbs [41], reproductive
photons, OCT uses low coherence interferometry to map out organs [42] and the heart [11, 40, 43-45]. The embryonic heart
back-scattering properties from different depths of samples. especially, undergoes significant morphological and functional
OCT is able to provide in situ and in vivo images of tissue changes during development. Traditionally, structural changes
of the developing heart were evaluated based on histological
slides using standard light microscope. OCT is able to provide
This work is partially supported by Lehigh University Start-up Fund, NIH
grants R00EB010071, R15EB019704, R21EY026380, R03AR063271, micron-scale resolution images of cardiac morphology and
R01MH060009 and R01AG014713, and NSF grant 1455613. functionality in vivo without the need for heart dissection and
J. Men (jim614@lehigh.edu), Y. Huang (yoh213@lehigh.edu), J. Solanki processing. Moreover, OCT imaging is non-invasive, enabling
(jis915@lehigh.edu), X. Zeng, A. Alex (aneeshalexp@gmail.com), J. Jerwick longitudinal studies of the developing heart. To date, OCT has
(jrj215@lehigh.edu) and C. Zhou (chaozhou@lehigh.edu) are with the
Department of Electrical and Computer Engineering, Center for Photonics and been used extensively to study heart development in various
Nanoelectronics, and Bioengineering Program, Lehigh University, Bethlehem, animal models, including Xenopus [11], zebrafish [40],
PA, USA, 18015. chicken and quail [43], mouse [44] and Drosophila [45].
X. Zeng (xianxu77@163.com) and Z. Zhang (zhangzhanmd27@126.com) In this paper, we provide a comprehensive review of OCT
are with the Third Affiliated Hospital of Zhengzhou University, Zhengzhou,
Henan, P.R. China, 450000. applications for brain imaging and developmental biology. In
R. E. Tanzi (tanzi@helix.mgh.harvard.edu) and A. Li addition, we include recent results from our groups ongoing
(ALI3@mgh.harvard.edu) are with the Genetics and Aging Research Unit, projects. We had previously shown that a circadian clock gene,
Department of Neurology, Massachusetts General Hospital and Harvard Cry, plays an essential role in heart morphogenesis and
Medical School, Boston, MA, USA, 02129.
* indicates equal contribution. function [45]. Here, we report the effect of another circadian
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JSTQE-INV-NB2016-06138-2015 2
Various neuroimaging modalities reveal brain structures and fundamental and clinical research to understand brain functions
functions at different anatomical levels. Computed tomography and disorders.
(CT), magnetic resonance imaging (MRI), positron emission
tomography (PET) and single-photon emission computed OCT resolves details of brain morphology: Utilizing
tomography (SPECT) are widely used clinical imaging broadband light sources and high-magnification objectives, the
modalities to evaluate brain structures and functions. high resolution extension of OCT, optical coherence
Functional MRI (fMRI) measures hemodynamic changes microscopy (OCM) [75, 76], can achieve 1-2 m resolution in
associated with local neuronal activity and is widely used to tissue in all three dimensions. OCM is able to resolve individual
study functional correlations of different brain regions [49-51]. neurons based on intrinsic optical contrast in rodent brains [34,
However, limited spatial and temporal resolutions of these 77, 78] and in human brain slices [79, 80]. Neurons are shown
imaging modalities prohibit their utility to evaluate fast neural as hyposcattering regions in OCM images (Fig. 1A, C). OCM
activities at cellular levels. Microelectrode arrays, revealed the same individual neurons observed in confocal
electroencephalography and magnetoencephalography directly microscopy (Fig. 1C, D) [78], two-photon microscopy [34, 77]
measure electronic signals originated from neural activities and histological slides [79, 80]. Neuron count obtained with
[52-57]. However, these methods have low spatial resolution OCM from 3D organotypic brain cultures also showed linear
and are susceptible to electrical noises and motion artifacts [58, correlation with confocal microscopy (Fig. 1E) [78].
59]. OCM can also resolve individual myelinated fibers ex vivo
Optical imaging, such as confocal microscopy and and in vivo [34, 81]. OCM revealed individual myelinated
two-photon microscopy, has been widely used in neuroscience fibers, shown as hyperscattering lines, matched well with
to study neural activities at the cellular level [60-62]. Confocal Gallayas myelin staining [34]. Combined with optical clearing
and two-photon microscopies utilize fluorescence contrast [82], OCM was used for depth-resolved quantification of
(mostly from exogenous dyes) to measure neuron morphology myelin contents several millimeters below the cortical surface
and distribution [63], ion concentration [64] and synaptic [34]. Furthermore, impaired myelination, shown as weaker
release [65], cerebral blood flow and angiograms [66, 67]. OCT reflected signals from nerve fibers, were observed in peripheral
offers a complementary method for neuroimaging. Based nervous system of Krox20 mutant mice [81].
solely on intrinsic optical contrast originating in the brain, OCT PS-OCT measures depth-resolved polarization information
can distinguish various brain structures, such as corpus of tissues, such as phase retardation and optic axis orientations,
callosum and hippocampus [68, 69], and reveal individual in order to resolve tissue microstructures with an improved
neurons and myelinated fibers [34]. Polarization-sensitive contrast [83-85]. PS-OCT can differentiate white matter from
OCT (PS-OCT) was utilized to localize nerve fiber bundles, the adjacent gray matter in ex vivo rat cerebral cortex [86].
characterize fiber bundle orientations, and obtain optical PS-OCT was sensitive to light polarization changes in nerve
tractography of the brain [70, 71]. Based on detection of fiber bundles and was used to effectively characterize fiber
Doppler shift and light scattering changes, OCT can be used to bundle orientations in fixed rat brains [70]. In addition,
measure cerebral blood flow and obtain angiograms in vivo [36, PS-OCT was also used to obtain optical tractography of ex vivo
72, 73]. Spectroscopic OCT has been recently developed to in rat brains [71]. Details of brain architecture and nerve fiber
measure cerebral blood oxygenation in live animals [74]. tracts were clearly resolved with PS-OCT based on tissue
Combining blood flow and oxygen saturation measurements birefringence contrast.
enables direct measurement of cerebral metabolism rate of
oxygen (CMRO2) [37]. Furthermore, OCT has been used to Functional OCT imaging of brain activity: Brain activity,
measure small light scattering and phase changes associated cerebral metabolism and cerebrovascular response are closely
with neuron action potentials [38]. Combining structural and related [87]. Functional OCT has been used to directly measure
functional information with high temporal and spatial vascular, hemodynamic and metabolic changes in animal brains
resolutions, OCT promises to be a powerful imaging tool for in response to neuronal activities [37, 38].
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Fig. 3. OCT angiographs of cerebral areas of mice before (A) and after (B) one week permanent distal middle cerebral artery occlusion (dMCAO). (C, D) Zoomed
images indicated significant pial collateral growth (white arrows), dural vessel dilation (dotted arrows). Irregular capillary bed in (D) suggested vascular remodeling
and possible angiogenesis. Images reproduced from reference [36] with permission.
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TABLE I
NUMBER OF FLIES IN EACH EXPERIMENTAL GROUP AT VARIOUS DEVELOPMENTAL STAGES
Fly groups / Developmental stages L2 L3 PD1 PD2 PD3 PD4 PD5 AD1
24B-GAL4/+ 10 10 19 18 19 11 9 16
UAS-dClock-RNAi; 24B-GAL4 15 13 11 14 13 12 10 12
24B-GAL4-HFD 26 20 17 18 15 18 12 14
L2, 2nd instar larva; L3, 3rd instar larva; PD1-5, pupa day 1 through 5; AD1, adult day 1
models, our group has found that alterations in expression of a However, the functional role of Clock gene in cardiac
highly conserved Drosophila ortholog of human SOX5 gene, development has not been confirmed. As a follow up study of
Sox102F, led to enlarged and irregular heart tube, decreased the association between the circadian gene Cry and heart
HR and reduced cardiac wall velocity, which may contribute to development, we have recently examined the effect of another
the pathogenesis of multiple cardiac diseases or traits [163]. circadian gene Clock on HR and CAP in Drosophila. The
ortholog of human Clock gene in Drosophila is dClock. In this
The Circadian rhythm gene dCry regulates heart study, the dClock was silenced by RNAi using the UAS-GAL4
development: Circadian rhythms are fundamental biological system. The UAS-dClock flies were mated with the 24B-GAL4
phenomena that recur regularly over approximately a 24-hour driver flies (UAS-dClock-RNAi; 24B-GAL4, abbreviated as
cycle and affect living beings ranging from tiny microbes to dClock-RNAi). Flies that expressed a heterozygous 24B-GAL4
higher order animals including humans [176]. Circadian driver alone were used as control (24B-GAL4/+). HR and CAP
rhythms are also related to cardiovascular functions and of all the flies were measured every 24 hours from the 2nd
pathologies [177]. Cardiovascular disorders, such as instar larva (L2), to 3rd instar larva (L3), pupa day 1-5 (PD1-5),
myocardial ischemia, acute myocardial infarction, sudden and adult day 1 (AD1), respectively. Number of flies measured
cardiac death and cardiac arrhythmias, were also demonstrated at each developmental stage is listed in Table 1.
with clear circadian rhythm related temporal patterns [178]. Fig. 7A shows representative M-mode images of control and
Circadian rhythms are controlled by circadian clocks [179]. dClock-RNAi flies at 2nd instar larva, early pupa and adult day 1.
The architecture of mammal clock is highly conserved with Slower heartbeat at larva and early pupa stages, and faster
Drosophila [180]. The Drosophila cryptochrome (dCry) heartbeat on AD1 were observed in dClock-RNAi flies (Fig.
encodes a major component of the circadian clock negative 7B). In the control flies, the HR decreased from 355 16
feedback loop [179, 181]. Recently, our group found that RNA beating per minute (bpm) on L2 to 4 5 bpm on PD3, and then
silencing of the dCry in the Drosophila heart and mesoderm increased to 317 86 bpm on AD1. In dClock-RNAi flies, HR
resulted in slower HR, decreased CAP, smaller heart chamber changed from 234 48 bpm at L2 to 1 3 bpm on PD3, and
size, pupal lethality and segment polarity related phenotypes, then increased to 418 51 bpm at AD1. Significant slower HR
which indicate that dCry plays an essential role in heart (p < 0.05) were observed in dCock-RNAi flies compared to
morphogenesis and function [45]. controls at L2, L3 and early pupa stages, while the HR was
significantly higher in dCock-RNAi flies on AD1 (p < 0.05).
Silencing another circadian gene, dClock, resulted in CAP, in both groups (Fig. 7C), decreased significantly when
altered HR and CAP: The circadian locomotor output cycles the flies developed into pupa. From PD4, CAP started to
kaput (Clock) is another crucial gene in the circadian clock increase and returned to ~97% on AD1. No significant
feedback loop. It encodes CLOCK protein which plays a central differences were observed in CAP between dCock-RNAi and
role in regulating circadian rhythms [179]. Clock has been control flies. Collectively, RNAi silencing of dClock gene
found to be necessary for normal cardiac function [182]. resulted in significant difference in HR at various
developmental stages. These findings indicated that dClock
affects heart development. The regulatory effects of two
circadian genes, Cry and Clock, affirmed the important role of
the circadian genes on heart development and function.
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of Selected Topics in Quantum Electronics
JSTQE-INV-NB2016-06138-2015 14
Jing Men received her B.S degree at Northeast Normal member of Henan Medical Association, Henan Preventive
University in China in 2010, and then graduated from Peking Medicine Association. She is also the Chairman of Inspection
University in 2014 (M.S). Currently, she is a PhD student in the Branch and Microorganism and Immunity Branch of Henan
Bioengineering program of Lehigh University in the USA. Her Medical Association.
current research interests include OCT imaging in
developmental biology and optogenetic pacing in fruit flies. Rudolph E. Tanzi obtained his PhD from Harvard University
in 1990 and is currently the Joseph P. and Rose F. Kennedy
Yongyang Huang received his B.S. degree in physics from Professor of Neurology at Harvard Medical School. At
Peking University in 2013. He is currently a PhD student at Massachusetts General Hospital, Dr. Tanzi serves as
Lehigh University. His current research interests include Vice-Chair of Neurology and Director of the Genetics and
developing ultrahigh-speed OCT system and utilizing OCT Aging Research Unit. He is a fellow of the American Academy
system for various biomedical applications. for the Advancement of Science Fellow, and was won the
Potamkin Prize, the Metropolitan Life Award, and the
Jitendra Solanki received his B.Sc., M.Sc. and PhD degrees in Smithsonian American Ingeniuty Award for his research on
Physics from the Devi Ahilya University, India, in 2005, 2007 Alzheimers disease.
and 2014, respectively. He is experienced in the field of OCT
and biosensors, particularly O2 and glucose sensors. He is Airong Li obtained her PhD from University of Oxford School
currently a post-doctoral associate at Lehigh University. of Medicine in 1996 and completed a post-doctoral training at
Yale University School of Medicine. She is currently an
Xianxu Zeng graduated from China Medical University (MD, assistant professor of Neurology at Harvard Medical School
2006). She is currently the Associate Chief Physician and and Massachusetts General Hospital. Dr. Li is a member of
Deputy Director of Pathology at the Third Affiliated Hospital American Society of Human Genetics, Genetics Society of
of Zhengzhou University. She was a visiting scientist at Lehigh America, and Society for Neurosciences and Project
University in 2013-2014. Management Institute.
Aneesh Alex graduated from Cochin University of Science and Chao Zhou graduated from Peking University in China (B.S.,
Technology, Kerala, India (Integrated M.Sc. in Photonics, 2001), obtained his Ph.D. degree from the University of
2007), obtained his Ph.D. degree in Biomedical optics from the Pennsylvania (2007), and received post-doctoral training from
Cardiff University, Wales, UK (2011), and received Massachusetts Institute of Technology. He is currently a P. C.
post-doctoral training from Medical University Vienna, Austria Rossin assistant professor in electrical engineering and
and Lehigh University, PA, United States. He is currently a bioengineering at Lehigh University. He is a member of the
research fellow at GlaxoSmithKline Plc. He is a member of the Institute of Electrical and Electronics Engineers (IEEE),
International Society for Optical Engineering (SPIE), Optical International Society for Optical Engineering (SPIE), Optical
Society of America (OSA) and American Association of Society of America (OSA), American Heart Association
Pharmaceutical Scientists (AAPS). (AHA), and the International Society for Cerebral Blood Flow
and Metabolism (ISCBFM).
Jason Jerwick graduated from Lehigh University (B.S. 2015)
and is a current graduate student in Electrical Engineering at
Lehigh University.
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