Optical imaging for the translational investigatorb) Characterization of other brain mapping signals...

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