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Optical imaging for the translational investigator
Nader Pouratian M.D. Ph.D.
Assistant Professor, UCLA Department of Neurosurgery
K30 Program, January 13, 2012
Acknowledgements
Laboratory of Neuro Imaging
Arthur W. Toga Ph.D.
Alyssa M. Ba M.D. Ph.D. Anne J. Blood Ph.D. K.C. Brennan Ph.D.
Andrew F. Cannestra M.D. Ph.D. Michael Guiou M.D.
Masahito Nemoto M.D. Ph.D. Sameer Sheth M.D. Ph.D.
Greg Wong Ph.D.
UCLA Brain Mapping
Susan Y. Bookheimer Ph.D. Nancy L. Sicotte M.D.
Mark Cohen Ph.D.
UCLA Neurosurgery
Neil Martin M.D. Donald Becker M.D.
Linda Liau M.D. Ph.D.
Three Goals:
1) Describe optical imaging methodology and signal etiology a) single-wavelength intrinsic signal imaging b) spectroscopic intrinsic signal imaging 2) Review examples of application in clinical neuroscience a) Investigation of neuro-vascular-metabolic coupling b) Characterization of other brain mapping signals 3) Validate the use of optical imaging as an mapping tool
Focus on:
Human applications, except where animal investigations paved the path for human translational studies
Electrocorticography Magnetic Source Imaging
LONI
• Reflectance/Absorbance mapping • Visible and near infrared light • Intrinsic or Extrinsic Contrast
Using OIS to characterize
neuro-vascular-metabolic coupling
Why OIS?
• Offers both high SPATIAL and TEMPORAL resolution relative to other neuroimaging
modalities
• Intrinsic contrast
• Multiwavelength imaging allows investigation of several physiological processes within the
same experiment
Intrinsic Signal Imaging
• Advantages
– No extrinsic dye – Delivery
– Toxicity
– Human application
– Only limited by imaging optics AND computer processing speed
• Single Wavelength
• Multiwavelength
• Spectroscopic
• small signals • trial averaging • stim/cntrl
ratio (t) = I (t) / I base
ratio (t) = ratio (t) – ratio (-0.25)
I base = { I (-1.0) + I (-0.75) + I (-0.5) + I (-0.25) } / 4
• The magnitude of optical intrinsic signals is calculated as the fractional change in reflected light intensity relative to the pre-stimulus baseline. • Pixel-by-pixel division and subtraction
Optical Imaging: Analysis
http://micro.magnet.fsu.edu/primer/java/reflection/specular/specularjavafigure1.jpg
Absorption Emission
Reflection Refraction
Scatter Diffraction
Where do Optical Imaging signals come from and how specific are they?
ELECTROMAGNETIC SPECTRUM
Sources of Intrinsic Optical Signals
• Absorption
– Δ Total Hgb
– Δ Hgb Oxygenation
– Δ Cytochrome Oxidation
• Light Scattering
– Δ Blood volume
– Δ Blood flow
– Vessel dilatation
– Neuronal swelling
– Glial swelling
LONI
Wavelength dependence of OIS
Optical Responses at Different Wavelengths
LONI
anterior
medial
lateral
posterior
FOREPAW HINDPAW
WHISKER BARREL
SPATIAL SPECIFICITY OF OPTICAL IMAGING MAPS: MAPPING OF MOUSE SOMATOSENSORY CORTEX
Visual Cortex Mapping – Differential Imaging
Subtract two stimulus conditions that activate “distinct neuronal populations” – subtract out “non-specific responses”
Shortcomings: (1) Artifacts may be stimulus specific
(2) Artifacts may not be synchronized with stimulation
(3) Identifying orthogonal activations is non-trivial
STABILITY OF OPTICAL IMAGING SIGNALS Mapping of Hindpaw cortex in Rodent
Day 0
Seconds after stimulus
Day 5
Day 10
Day 15
0.5 1.0 1.5 2.0 2.5 3.0
UCLA Laboratory of Neuro Imaging
0.4 %
OIS
0.2 mV
ECoG
Note change in OIS scale
X10-3
CORRELATION OF OIS WITH SEIZURE ACTIVITY
UCLA Laboratory of Neuro Imaging
Optical Imaging of Cortical Spreading Depression
Image changes in blood volume using the intravascular fluorescent dye Texas Red dextran (M. W. 70,000, Molecular Probes)
OPTICAL IMAGING FOR CHARACTERIZING DISEASE AND PHYSIOLOGY
Experience-Dependent Potentiation of Optical Responses
Intraop Brain Mapping Requirements
OIS fMRI Unit Activity
ECoG
Temporal Resolution
High
Spatial resolution
“Sufficient”
Spatial sampling
“Sufficient”
Biocompatibility& Signal Stability
Necessary
SNR High
Signal content Rich
Signal specificity
High
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Neurosurgery: Rare and unique opportunity to study the
awake functioning human brain
TRANSLATING OPTICAL IMAGING TO HUMAN APPLICATIONS
Median Nerve Stimulation
WHY TRANSLATE OPTICAL IMAGING FOR HUMAN APPLICATION?
Cheap, portable, relatively simple to implement CLINICAL BENEFITS -potentially more precise mapping of eloquent cortex RESEARCH OPPORTUNITIES -awake (or anesthetized) human with exposed brain -high resolution mapping (spatial, temporal) -can test high level function -can test fundamental hemodynamics -can compare with fMRI, ephys -can compare normal and pathological tissue
CONSTRAINTS AND CHALLENGES OF OPTICAL IMAGING IN HUMANS
(1) REQUIRES CORTICAL EXPOSURE -> NEEDS TO BE DONE DURING NEUROSURGERY (2) OPERATING ROOM CONSTRAINTS -limited space and time -little/no control of anesthesia -restricted field of view -some tissue likely abnormal -THE BRAIN MOVES (3) CONSTRAINTS OF OPTICAL IMAGING MAPS -surface map, not tomographic
STRATEGIES TO OVERCOME BRAIN MOVEMENT DURING INTRAOPERATIVE OPTICAL IMAGING
Movement correction by Warping Algorithms
OIS OF EPILEPTIFORM ACTIVITY IN HUMAN
Haglund MM et al Nature 1992
Haglund MM et al J Neurophysiol 2005
Optical spatial properties and topographic Specificity
UCLA Laboratory of Neuro Imaging
Sato et al Cereb Cortex 2005
Intraoperative imaging of individual digit representations
Language Mapping
Cannestra A et al NeuroImage 1996
SIMILARITY OF HUMAN AND RODENT INTRINSIC SIGNALS
TIME COURSE
REFRACTORY PERIOD
Optical Imaging Applications: Intermodality Comparisons
Confirmation and Explanation
LONI
Comparison of
iOIS and fMRI
Cannestra, Pouratian, Bookheimer,
Martin, Becker, and Toga
Cerebral Cortex (in press)
UCLA Laboratory of Neuro Imaging
LONI
Tongue Activations
1 cm
1 cm
1 cm
fMRI Sulcal
2.36 ± 1.40 cm2
iOIS Gyral
5.07 ± 1.52 cm2
p=.035 (paired two-tailed t-test)
Avg Activation Size
1 cm
1 cm
LONI Error Bars = Standard Deviation
Conclusions and Implications
• BOLD and positive 610 nm OIS are both spatially and temporally correlated
• Signal disparities may be related to differences in sensitivities and other signals, like light scattering, contributing to OIS
NEAR FUTURE TRANSLATION
OPTICAL SPECTROSCOPY
X
Y
Entire image at single wavelength
X
Wavelegnth
(separated by prism)
Single column entire wavelength spectrum
Spectroscopic Imaging: Applying a Modified Beer-Lambert Law
2-D OPTICAL SPECTROSCOPY
• Sacrifice spectral resolution to retain spatial resolution – image at distinct wavelengths during separate trials and then integrate in post-hoc analysis using same formulas
Bhatia et al Neurosurg Focus 2008
Intraoperative spectroscopy
Using optical reflectance below the surface: near infrared reflectance probe
Giller et al J Neurosurg 2009
MORE DISTANT FUTURE TRANSLATIONS?
Extrinsic fluorescence imaging,
Phosprescence quenching imaging,
and
Intrinsic fluorescence imaging
Raabe et al Neurosurgery 2003
2D IMAGING OF BLOOD FLOW: Infrared fluorescence of indocyanine green dye
INTRINSIC FLUORESCENCE IMAGING IN MOUSE – NADH FLUORESCENCE
Husson TR et al, J Neurosci 2007
INTRINSIC FLUORESCENCE IMAGING IN MOUSE -Flavoprotein fluorescence
Imaging of Oxygen Phosphorescence Quenching The kinetics of the oxygen concentration changes can be derived from these decay times using the Stern-Volmer equation:
τ0/τ = 1 + Kqτ0PO2 where τ and τ0 are the measured and zero-oxygen phosphorescence lifetimes, PO2 is the oxygen tension, and Kq is the second-order rate constant for quenching of phosphorescence.
BEYOND HEMOGLOBIN -LIGHT SCATTER
Stepnoski et al PNAS 1991
Rector DM et al. NeuroImage 2005
IMAGING AT NEURONAL SPEED: FAST LIGHT SCATTER SIGNALS
FAST LIGHT SCATTER SIGNALS IN HUMAN? NONINVASIVELY?
Gratton and Fabiani, Int J Psychophysiol 2001
Probably not… See Steinbrink J et al NeuroImage 2005.
2D IMAGING OF BLOOD FLOW: LASER SPECKLE FLOWMETRY
Zhang and Murphy PLOS Biol 2007
Dunn AK et al J Cereb Blood Flow Metab 2001
TOMOGRAPHIC IMAGING: OPTICAL COHERENCE TOMOGRAPHY
Boppart SA Psychophysiol 2003 Chen Y et al J Neurosci Methods 2008
Bohringer et al Acta Neurochir 2009
Intraoperative OCT
TOMOGRAPHIC METHODS: LAMINAR OPTICAL TOMOGRAPHY
Near Infrared Spectroscopy: A Variant of Optical Imaging
NONINVASIVE OPTICAL MEASUREMENT: NEAR INFRARED SPECTROSCOPY (NIRS)
Obrig and Villringer J Cereb Blood Flow Metab 2001
Boas and Dale Appl. Opt. 2005
Optical Imagings: Clinical Applications
UCLA Laboratory of Neuro Imaging
Use rare and unique neurosurgical opportunities to study the awake functioning human brain
Bill Speier.
In
preparation.
SUMMARY
• Even with limitations (invasiveness, slow hemodynamic signal) optical imaging in animals and humans is a valuable research tool. – Anatomical localization
– Functional characterization (activity)
– Metabolic measurement (oximetry, flowmetry, mitochondrial redox activity)
• Crucial limitations are being overcome – High speed imaging
– Tomographic imaging