Shedding some light on medical diagnosisDavid DelpyEngineeringand Physical Sciences Research Counci l, UK

WednesdaY,4 May- 9:45 a.m.

Optical diagnosis isone oftheoldesttechniques in medicine, andeven today isstill theway inwhichadoctor (consciously orunconsciously) obtains hisfirstinformationabouta patient(Le. whatisthepatient's colour,whatistheskin texture like? - all oftheseare optica l measures) . Over the lasthalfcentury, scientists andengineers have developed ever more sophisticated instruments in order toquantifythisrather subjective optical measurement made bytheclinician,andit is now possible, justbyusinglightto monitor anenormous (andgrowing)range ofparameters. Amajoradvantage of lightinthese applications isthat it issafe, andcan often beapplied at thebedside ina non-invasive manner,using simple and lightweight optical fibres. Thetalkwill illustratethewide range ofoptical monitoringtechniques thatare now becoming ava ilable, showinghow thisblossoming of new techniques hasoften resulted from thecoming togetherofnew developments inareas asdifferent asgenetics, missileguidance andoptical telecommunications.

Shedding some light on medical diagnosis

D.T. Delpy

Engineering & Physical Sciences Research Council, UK

0. 001nm 0.1nm 1nm 100nm 1000nm 10000nm

|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||X-rays Ultraviolet Visible Infrared

The Electromagnetic spectrum

True Colour Image Visible/Near InfraRed (NIR) ratio

Looking at the body surface: Imaging of a mole with a hyperspectral camera

Looking inside the body : the endoscope and the endoscopy “pill”

Images obtained when passing through the bowel (Given

Imaging System)

The electrically driven

endoscopy pill

Looking inside the body from the outside: the transparency of tissue

fetus hydrocephalus‘ If a candle was held behind his head, or the sun happened to be behind

it, the cranium appeared semi-transparent and this was more or less evident until he attained his fourteenth year’

Richard Bright, Guy’s Hospital, on a patient with hydrocephalus, 1831.

Georges de La Tour 1593-1652 Christ with St. Joseph in the Carpenter's Shop c. 1640

Early Optical imaging?

The absorption of light by major tissue chromophores

The Absorption Spectrum of blood

Wavelength [nm]

Abs

orpt

ion

[cm

-1M

-1]

100

1000

10000

100000

1000000

200 300 400 500 600 700 800 900 1000 1100

Hb02Hb

VISIBLE NEAR INFRAREDULTRAVIOLET

Hb

HbO2

NIR MeasurementRegion

The effect of wavelength on the distance light will penetrate into the skin

Multispectral imaging: 700 - 900 nm range

700nm 800nm 900nm

Blood vessel visualisation with the “Veinviewer”

Luminetx Inc, USA

Monitoring the movement of red blood cells in the surface vessels: the principles of laser

Doppler blood flow detection

Laser Doppler blood flow measurement versus burn depth: flow signal overlaid on normal image

Laser Doppler blood flow image of the lower legs in a subject with claudication (i.e. blockage

of a supplying artery)

Very small light bulb

Light Dependent Resistor

absorption

time

What else can the reflected light tell us: the finger plethysmograph

Pulse Rate

Blood oxygenation monitoring – the Pulse Oximeterabsorption

time

2 LED’s:

red + blue

Photodiode

Red light

Blue Light

Measuring the amount of light absorbed by each colour, will tell

us the colour of the arterial blood and therefore, the amount of oxygen it contains. – usually expressed as a “% Saturation”

Modern Pulse Oximeters

Looking deeper into tissue: Near Infrared Spectroscopy (NIRS) - Note: Any tissue can be studied. e.g. muscle, brain, the breast

LaserDiodes

LightDetector

Computer

HbO2

Hb

Time

Note: we need to know how far the light has travelled – see later!!

Light levels in Near Infrared Spectroscopy

Original NIRS

system: Baby Tilt Study

(1984)

Third generation Near Infrared Spectrometer

Long term Cerebral NIR Oscillations

Time (minutes)20 40 60 80 100 120 140 160

Δ co

nc (μ

mol

ar.c

m)

0

50

100

150

200

250

HbO2

Hbvol Hb

T im e (secon ds )0 1 0 2 0 3 0 4 0 5 0 6 0

H

bO2

( m

olar

.cm

)

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-2 0

-1 0

0

1 0

2 0

3 0

4 0

5 0

6 0

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Arb

. Uni

ts

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N a sa l A irflo w

H b O 2

P u lse W a ve fo rm

Cerebral NIR Respiratory and Cardiac Oscillations

What does NIRS show? What are its advantages?

Near Infrared muscle exercise studies

Localising NIRS measurements through careful positioning of the light source

and detector

Ordinary MR image of the brainfMRI images of the brain showing activation changes during 40 minutes of motor learning (red areas show where Hb has changed as a

result of the motor learning task)

An aside: Watching the brain think with functional Magnetic Resonance Imaging (fMRI)

Functional NIRS – watching the visual cortex at work (the checker board pattern flashes then stops)

Time (minutes)0 1 2 3 4 5 6 7 8 9 10

Δ con

cent

ratio

n (μ

mol

ar.c

m)

-25

-20

-15

-10

-5

0

5

10HbO2Hb

Functional NIRS of the infant visual cortex – the raw signals

T im e (s e c o n d s )

-1 0 0 1 0 2 0 3 0 4 0 5 0

co

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tratio

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mol

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H b O 2H b v o lH b

Functional NIRS of the infant visual cortex – the averaged signal

Mapping the activity on the whole surface of the brain:

The principles of NIRS Topographic Brain Imaging

UCL System

Hitachi Medical System

The patient interface

Cortical pain responses to a heel prick in infants (blood volume signal)

Slater et al (2006)

Optical Topography signals in the infant

Cortical pain responses to a heel prick in infants (2):Right heel

Optical Topography signals in the infant

Blood volume signal

QuickTime™ and aYUV420 codec decompressor

are needed to see this picture.

Time resolved measurements to separate the effects of absorption from scatter

t

tt

t

The (temporal) Impulse Response Function of tissue to a pulse of laser light can be used to distinguish between the effects of scatter and absorption.

It also allows us to know the optical pathlength from the mean time of flight

Finally it allows us a better estimate on where the light has travelled and hence permit tomographic (i.e. full 3D) imaging

~ ns

~ ps

Pulsed Laser

Time of flight

No.

of p

h ot o

n s

Time Resolved Measurement Principles

Clock

Time of Flight Measurement of Optical Pathlength across the Baby Head – 5cm source/detector spacing

Input pulseDetected TPSF

Sourcefibres

Detectorfibres

The principles of time resolved measurements for optical tomography

NB. All measurements are made at two different wavelengths

The MONSTIR imaging systemBACK SIDE FRONT

Multi-channel Opto-electronic Near-infrared System for Time-resolved Image Reconstruction

Tomographic image reconstruction requires knowing where the detected light has travelled

Forward model: Intensity and time of flight photon distributions are calculated using TOAST (Time resolved Optical Absorption &

Scattering Tomography

QuickTime™ and a decompressor

are needed to see this picture.

NIRS tomography applied to the breast: Imaging the extra blood volume and different blood

oxygenation in tumours

The optical mammography scanning

table (note no breast compression)

Optical tomography images

Magnavist enhancedMRI image

1 week beforesurgery

1 week aftersurgery

fibroadenoma

3 months aftersurgery

6 months aftersurgery

9 months after surgery, straight after FNA of cyst.

cyst double cyst

Interstitial laser photocoagulation treatment of fibroadenoma26-year-old subject

superficial injury due to FNA

inflammation due to laser surgery

12 months aftersurgery

residualfibroadenoma

NIRS Optical tomography of the infant brain - the “Creche Helmet”

A baby undergoing an optical tomography study

Optical image: 32-week female infant

Anatomical slices of pre- term brain

Positron Emission Tomography (PET) image: of adult brain

Optical Tomography images of the normal infant brain

Positron Emission Tomography (PET) images of neonate brain

Upper – normalLower – post asphyxia

Static imaging of haemorrhage

Optical Tomography images of the abnormal infant brain

Motor Cortex Activation in Infants

Passive movement ofLeft Arm

Passive movement ofRight Arm

Tomographic mapping of functional activation of the motor cortex in the neonate(Sequential sagittal slices displayed from a full 3D image)

Final Example – a technique not yet in clinical use:Photoacoustic imaging – physical principles

Optical absorption

Impulsive heating (<1oC)

Rapid thermoelastic expansion

Broadband (~100MHz) acoustic emission

“Time-of-flight” based image

reconstruction

Nanosecond NIR laser pulses

tumour blood vessels

Incident NIR high peak power pulse causes rapid expansion of the absorber. The acoustic wave can be picked up using ultrasound transducers

Photo-acoustic imagingPhoto-acoustic imaging is able to examine features with NIR contrast but with resolution similar to ultrasound:

Perfused tumour

Photoacoustic imaging of the rat brain

(Image obtained through intact skull and skin)

In vivo photoacoustic image of rat brainX. Wang et al., Nature Biotechnology 21(7), pp. 803–806, 2003

The futures bright:

The futures:

OPTICAL SENSING & IMAGING

Thanks

Contributors:

Clive AldridgeSimon ArridgeTopun AustinTiziano BinzoniTony BishopTara BlandGilberto BrancoDavid BrownGuy BrownTim CheatleChris CooperMark CopeKate CosteloeTony CostelloGergely CsibraBrian DavidsonMauren de SouzaRoberto de BlasiGeofrey De VisscherEnrico De VitaHamid DehghaniMichael DouekArlene DuncanDavid EdwardsHamid El-DesokyLouise EnfieldMatthias EssenpriesNick EverdellMarco FerrariMike FirbankLaure Gendron

…and many many others!

Funders:

Action Medical ResearchBBSRCEPSRCEuropean UnionHamamatsu Photonics KKHitachi Medical LtdMRCRoyal SocietySwiss National Science FoundationWellcome TrustWolfson Foundation

Adam GibsonFelix GoraCornelia HagmanDavid HallPat HamiltonSally HarkinsJem HebdenJulian HentyElizabeth HillmanMutsu HiraokaVeronica HollisPeter HopeIan HutchinsonMark JohnsonDavid JennionsPeck KohJan LauferTing LeeTerence LeungTim LovellDave KirkbyMatthias KohlIvo KweeSteve MatcherJudith MeekAladangady NarendraEiji OkadaHuw Owen-ReeceChristos PanagiotouDonald PeeblesCaroline Reid

Os ReynoldsClare RichardsonGed RidgewayFlorian SchmidtMartin SchweigerAlex SeifalianRebecca SimpsonMartin SmithRoger SpringettIlias TachtsidisMartin TisdallIan TullisTharshan VaithianathanPiet van der ZeeKoen van RossemRussell WatsonKevin WellsSusan WrayJohn WyattRoza YusofGiovanni Zaccanti

Hopefully not!!

Use of prior information

First optical tomography of neonatal brain

Benaron (1995-2000)~12 infantsScan time ~6 hours

Benaron (1995)

First optical topography of stroke

Non-scattering regions

Diffusion equation:low scattering region

Void model