Coherent scattering of pulsatile flow

Coherent scattering of pulsatile flow

Nemati, Mahsa

DOI

10.4233/uuid:518c6610-8614-4863-80a0-a888f40c3165

Publication date

2016

Document Version

Final published version

Citation (APA)

Nemati, M. (2016). Coherent scattering of pulsatile flow.

https://doi.org/10.4233/uuid:518c6610-8614-4863-80a0-a888f40c3165

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This work is downloaded from Delft University of Technology.

accompanying tlie Ph.D. thesis:

Coherent scattering of pulsatile flow

To be defended on Tlmrsday, June 16th 2016 at 15:00 in Delft by Mahsa Nemati

1. Blood flow measurements can be performed in the presence of motion arti-facts.

2. Laser speckle is a sensible tool for monitoring dynamic changes in flow, how-ever it is unable to distinguish its direction.

3. The spatial distribution of a speckle pattern can be studied using a frac-tal dimension, where the dimension changes can be directly related to the dynamic behavior of the sample.

4. Different analysis methods when applied to speckle patterns reveal comple-mentary uliaracteristics of the studied sample.

5. The properties of a complex system are better understood i f we start with a simple benchmark.

6. Systematic characterization experiments are time consuming, but provides much better insight.

7. A new research result can seem hke magic t i l l one masters i t , after which it becomes mundane.

8. The course of one's life is out of one's control when society regulates people based on outdated beliefs.

9. Bureaucratic regulation can in many cases go against common sense and logic.

10. Change is an inherent feature of living organisms.

These propositions are regarded as opposable and defendable, and as such have been approved by the promotor prof. dr. H. P. Urbach.

behorende bij het proefschrift:

Coherente verstrooiing van pulserende stromen

te verdeUgen op Donderdag 16 Juni 2016 om 15:00 te Delft door Mahsa Nemati

1. Bloedstromingsmetingen kunnen worden uitgevoerd de aanwezigheid van ar-tefacten ten gevolge van bewegingen.

2. Laser speckle is een zinnig gereedschap voor het waarnemen van dynamische stromingsveranderingen, echter het is niet in staat richting te onderscheiden. 3. De ruimtelijke verdeling van een specklepatroon kan worden bestudeerd door gebruik te maken van de fractale dimensie, waar verandering direct gerela-teerd is aan het dynamisch gedrag van het monster.

4. Diverse anatyse methoden toegepast op specklepatronen, onthullen comple-mentaire eigenschappen van het bestudeerde monster.

5. De eigenschappen van een complex system zijn beter inzichtelijk te maken door gebruik te maken van een eenvoudig referentie systeem.

6. Systematisch experimenteel werk is tijdrovend maar geeft een veel beter in-zicht.

7. Een nieuwe onderzoeksresultaat kan ongelofelijk lijken, maar als het ver-klaard is wordt het alledaags.

8. De loop van het leven is niet meer in eigen hand indien de gemeenschap voorschriften oplegt gebaseerd op verouderde opvattingen.

9. Bureaucratische regelgeving druist in veel gevallen in tegen gezond verstand en logica.

10. Verandering is een inherente eigenschap van levende organismen.

Deze stelUngen worden opponeerbaar en verdedigbaar geacht en zijn als zodanig goedgekeurd door de promotor prof. dr. H. P. Urbach.

P U L S A T I L E F L O W

Proefschrift

ter verkrijging van de graad van doctor

aan de Technische Universiteit Delft,

op gezag van de Rector Magnificus prof ir. K.C.A.M. Luyben,

voorzitter van het College voor Promoties,

in het openbaar te verdedigen op donderdag 16 june 2016 om 15:00 uur

door

Mahsa N E M A T I

Master of Science in Biomedical Engineering,

Delft University of Technology, Delft, The Netherlands,

promotor: Prof.dr. H.P. Urbach

copromotor: Dr.N. Bhattacliarya

Composition of the doctoral committee:

Rector Magnificus,

Prof.dr. H.P. Urbach

Dr.N. Bhattacharya

voorzitter

Technische Universiteit Delft, promotor

Technische Universiteit Delft, copromotor

Independent members:

Prof. dr. ir. L.J. van Vliet

Prof.dr.ir. J.W.M. Bergmans

Prof.dr. R.M. Aarts

Prof.dr.ir. W.Steenbergen

Prof.dr.ir. P. Kruit

Technische Universiteit Delft

Technische Universiteit Eindhoven

Technische Universiteit Eindhoven

Universiteit Twente

Technische Universiteit Delft, reserve member

This work was supported by the IOP Photonic Devices programme of NL-Agency

of the Dutch Ministry of Economic Affairs (Project number IPD 083359) and by

Stichting voor Technise Wetenschappen (STW).

Copyright © 2016 by M. Nemati

All rights reserved. No part of this publication may be reproduced, stored in a

retrieval system or transmitted in any form or by means: electronic, mechanical,

photocopying, recording or otherwise, without prior written permission of the

author.

An electronic version of this dissertation is available at

h t t p : / / r e p o s i t o r y . t u d e l f t . n l / d i s s e r t a t i o n s .

MIX V " 1 J « ^ Paper from ,

reBponsible aouröss

Contents iii

1 Introduction 1

1.1 Laser speckle f o r physiological signal measurements 2

1.2 Research p r o j e c t settings 4

1.3 Thesis .structure 4

2 Theory and analytical methods for flow measurement 7

2.1 L i g h t tissue i n t e r a c t i o n 8 2.1.1 N u m e r i c a l m o d e l i n g 11 2.2 Physics b e h i n d speckle 14 2.3 T i m e v a r y i n g speckle 20 2.3.1 T h e o r y o f f r a c t a l s 24 2.4 D a t a analysis 26 2.4.1 Laser speckle c o n t r a s t analysis 26

2.4.2 C o r r e l a t i o n based analysis 27 2.4.3 F r a c t a l based analysis 27

2.5 S u n n n a r y 29

3 Experimental setup for fluid parameter analysis 31

3.1 E x p e r i m e n t a l setup 32 3.1.1 F l o w g e n e r a t i o n 32 3.1.2 F l o w p r o p e r t i e s 33 3.2 F l u i d p r o p e r t i e s 34 3.2.1 G l y c e r o l S o l u t i o n 34 3.2.2 M i l k 35 3.3 E x p e r i m e n t a l p h a n t o m s f o r flow s t u d y 35 3.3.1 R e c t a n g u l a r based p h a n t o m 35 3.3.2 S t r a i g h t c y l i n d r i c a l based p h a n t o m 36 3.3.3 C a r o t i d a r t e r y based p h a n t o m 36 3.4 F l o w analysis and c o n t r a s t dependent flow \'ariables 37

3.4.1 Steady flow analysis 38 3.4.2 P u l s a t i l e flow analysis 42

4.1.1 O p t i c a l e x p e r i m e n t a l setups 46

4.1.2 F l u i d 47 4.1.3 P h a n t o m s 47 4.2 F u l l f i e l d o p t i c a l studies 47

4.2.1 P a r t i c l e i m a g i n g v e l o c i m e t r y 47 4.2.2 Laser speckle c o n t r a s t analysis 49

4.3 Results and Discussion 50 4.3.1 P I V measurements 50 4.3.2 Laser Speckle C o n t r a s t A n a l y s i s 50

4.3.3 S p e c t r a l analysis o f pulse f r o m P I V a n d L A S C A 51

4.4 S u m m a r y 54

5 Fractal analysis in speckle images 57

5.1 I n t r o d u c t i o n 57 5.2 P u l s a t i l e flow measurements 58 5.2.1 I n f l u e n c e o f s t a t i c scatterers 59 5.2.2 C o m p l e x p u l s a t i l e flow 60 5.2.3 In-vivo measurements 62 5.3 S u n n n a r y 64

6 Multi layer flow analysis using speckled speckle 67

6.1 I n t r o d u c t i o n 67 6.2 E x p e r i m e n t a l Setup 69 6.3 Results a n d Discussion 70

6.4 S u m m a r y 74

7 Flow analysis in presence of motion induced artifacts 75

7.1 E x p e r i m e n t a l measurements 75 7.1.1 E x p e r i m e n t a l setup 75 7.1.2 Speckle c o n t r a s t analysis f o r in-vitro e x p e r i m e n t s 77

7.1.3 Speckle c o n t r a s t analysis f o r in-vivo e x p e r i m e n t s 79 7.2 C h a r a c t e r i z a t i o n o f in-vitro e x p e r i m e n t s o n m o t i o n i n d u c e d a r t i f a c t s 80

7.2.1 Speckle contrast analysis c o m p a r e d w i t h c o r r e l a t i o n f o r

ex-p e r i m e n t w i t h m o t i o n i n d u c e d a r t i f a c t s 82 7.3 P i x e l based analysis f o r f e a s i b i l i t y o f use i n c o m p a c t devices . . . . 85

7.4 S u m m a r y 86

8 Discussion and conclusions 89

8.1 Suggestions f o r f u t u r e w o r k 91

Acknowledgments 107

M o d e r n society lias an increasing d e m a n d f o r technologies f o r b e t t e r diagnosis a n d t r e a t m e n t . T h i s is d r i v e n b y t h e g r o w t h o f h e a l t h awareness and a s h i f t i n p o p u -l a t i o n demographics t o t h e aged. T h e concept of continuous h e a -l t h m o n i t o r i n g is one of t h e key f a c t o r s t o w a r d s h e a l t h i e r l i f e style, i m p r o v i n g the healthcare services a n d t o p r o v i d e a b e t t e r m o n i t o r i n g of chronic diseases. A new m a r k e t research has p r e d i c t e d a d r a m a t i c increase i n t h e n u m b e r of p o r t a b l e h e a l t h m o n i t o r i n g devices w h i c h can be used f o r m e d i c a l diagnostics or f o r h e a l t h and wellness m o n i t o r i n g . Cardiovascular disease is one of t h e most prevalent diseases nowadays a n d t h i s is w h y developing techniques t o m o n i t o r v i t a l signs are o f great interest. However, t h e r e is s t i l l a p o t e n t i a l need i n t h e m a r k e t t o address t h e expensive healthcare e q u i p m e n t and w o r l d w i d e i n e q u a l i t y i n access t o i t , t h r o u g h a cost e f f i c i e n t tech-nology. I n t h i s regard, o p t i c s based solutions are seen t o be a g r o w i n g field w h i c h can i n f l u e n c e t h e h e a l t h care i n d u s t r y .

One of t h e w e l l k n o w n and c l i n i c a l l y established devices is t h e pulse o x i m e t e r . I t is a non-invasive o p t i c a l based m e t h o d w h i c h measures t h e v o l u m e t r i c changes due t o a r t e r i a l expansion a n d c o n t r a c t i o n . B y m o n i t o r i n g t h e a m p l i t u d e v a r i a t i o n , t h e i n s t r u m e n t can measure t h e p u l s a t i o n rate. T h e m a i n w o r k i n g p r i n c i p l e is due t o l i g h t a b s o r p t i o n . W h e n a vessel expands due t o t h e heart beat, t h e v o l u m e o f t h e b l o o d flow increases, e v e n t u a l l y leading t o a lower measured signal due t o m o r e a b s o r p t i o n of l i g h t . B y p l a y i n g w i t h d i f f e r e n t l i g h t a b s o r p t i o n properties, t w o w a v e l e n g t h settings are capable o f measuring t h e o x y h e m o g l o b i n level i n t h e b l o o d . However, these devices are o n l j ' sensitive t o p e r i o d i c signals a n d t h e r e f o r e can n o t p r o v i d e an i n d i c a t i o n of tissue b l o o d flow. A d d i t i o n a l l y , these devices suffer f r o m a lack of r e q u i r e d precision a n d r e p e a t a b i l i t y of signals w h e n i t comes t o scenarios w i t h m o t i o n a r t i f a c t s . T o have c l i n i c a l l y reliable measurements, these devices r e q u i r e a steady e n v i r o n m e n t and contact w i t h t h e p a t i e n t ' s b o d y . T o address t h e challenges of designing non-contact m e t h o d s and signal a t t e n u a t i o n due t o m o t i o n a r t i f a c t s , we have d e m o n s t r a t e d another o p t i c a l technique. Laser speckle i m a g i n g is a low cost m e t h o d w h i c h can b r i n g a new d i m e n s i o n t o compliance a n d t r e a t m e n t , b y m o n i t o r i n g t h e h e m o d y n a m i c properties remotely. T h i s m e t h o d uses coherent properties o f l i g h t t o i l l u m i n a t e t h e sample and as t h e b l o o d propagates t h e s p a t i a l d i s t r i b u t i o n of l i g h t i n tissue changes, w h i c h can be t h e n m o n i t o r e d . T h i s m e t h o d was i n i t i a l l y developed t o measure b l o o d flow i n t h e r e t i n a . However, i n t h i s thesis we r e p o r t several measurements, t o address n o t onl}^ results f r o m p h a n t o m s b u t also f r o m d i f f e r e n t regions o f t h e b o d y such as finger n a i l or neck.

F u r t h e r e x p e r i m e n t s using t h i s t e c h n o l o g y are presented, w h i c h p r o v i d e a broader range of a p p l i c a t i o n s a n d d i f f e r e n t c o n f i g u r a t i o n s . These studies are a step f o r w a r d t o w a r d s t h e p o t e n t i a l o f using laser speckle techniques f o r assessing some o f t h e c o m m o n c l i n i c a l s i t u a t i o n s .

T h i s thesis r e p o r t s t h e p o s s i b i l i t y o f using laser speckle f o r m o n i t o r i n g p u l s a t i l e flow where i t investigates i t s f e a s i b i l i t y i n case of m o t i o n a r t i f a c t s . W e have s t u d i e d , designed a n d i m p l e m e n t e d d i f f e r e n t e x p e r i m e n t a l flow and o p t i c a l setups t o s t u d y laser speckle d y n a m i c s . Laser speckle d y n a m i c s is based o n m e a s u r i n g i n t e n s i t y fluctuation caused b y t e m p o r a l changes i n speckle p a t t e r n s . T h e p r i n c i p l e is r a t h e r s i m i l a r t o t h e technique of laser D o p p l e r , w h e r e there is a f r e q u e n c y s h i f t f r o m a m o v i n g scatterer w h i c h is used t o m o n i t o r t h e changes i n t h e sample. For laser speckle, t h e changes can be recorded d i r e c t l y using these interference p a t t e r n s . These are however d i f f e r e n t techniques where t h e same t h e o r e t i c a l p r i n c i p l e o f d y n a m i c l i g h t s c a t t e r i n g is a p p l i e d . T h i s has been o r i g i n a l l y s t u d i e d f o r single s c a t t e r i n g particles a n d was e x t e n d e d l a t e r o n t o h i g h l y s c a t t e r i n g m e d i u m . Laser speckle has shown p o t e n t i a l advantages over laser D o p p l e r due t o faster a c q u i s i t i o n .

In t h i s a p p r o a c h a v e r y h i g h s p a t i a l a n d t e m p o r a l r e s o l u t i o n b l o o d flow m a p can

be o b t a i n e d using single images, where t h e changes i n flow can be q u a n t i f i e d based o n s p a t i a l b l u r r i n g of t h e m .

T h e thesis begins w i t h a b r i e f i n t r o d u c t i o n t o t h e light-tissue i n t e r a c t i o n along w i t h d i f f e r e n t n u m e r i c a l m o d e l i n g techniques w h i c h are c o m m o n l y used t o r e t r i e v e tissue o p t i c a l properties. W e address t h e t h e o r y o f laser speckle a n d h o w t h e y are created. F u r t h e r m o r e , d i f f e r e n t analysis m e t h o d s f o r t h e speckle p a t t e r n d a t a are described. Since speckle is r a n d o m i n n a t u r e , we first need t o i n t r o d u c e t h e statis-t i c a l statis-t o o l s . I n statis-t h i s chapstatis-ter, we focus o n laser speckle constatis-trasstatis-t analysis, c o r r e l a statis-t i o n a n d f r a c t a l s w h i c h have been used i n t h e rest of thesis as t h e m a i n a n a l y t i c a l t o o l s .

T h e laser speckle i m a g i n g has a s i m p l e e x p e r i m e n t a l setup yet a p o w e r f u l tech-nique. T h e setup m a i n l y consists of a laser t o i l l u m i n a t e t h e sample a n d generate t h e reflected speelde w h i c h are recorded t h r o u g h t h e i m a g i n g system. However, t h e s t u d y o f flow d y n a m i c s is r a t h e r a c o m p l e x p r o b l e m . T h e c o m p l e x behavior o f the flow can be due t o c o m p l e x i t y i n t h e geometry, or the fluid dependent p r o p -erties i t s e l f W e showed t h a t laser speckle i m a g i n g is able t o measure t h e changes i n flow w h i c h m a y arise due t o various p h y s i o l o g i c a l / e x p e r i m e n t a l c o n d i t i o n s . I n order t o be able t o compare a n d u n d e r s t a n d t h e influence of d i f f e r e n t p a r a m e t e r s i n d i v i d u a l l y , a series o f e x p e r i m e n t s using d i f f e r e n t e x p e r i m e n t a l setups have been c o n d u c t e d . These e x p e r i m e n t s have been done t o m o n i t o r t h e changes i n a sys-t e m a sys-t i c way, so i n i sys-t i a l l y sys-t h e measuremensys-ts were done f o r ssys-teady flow a n d sys-t h e n p u l s a t i l e flow. For each e x p e r i m e n t , t h e laser speckle p a t t e r n s have been f u r t h e r processed t o retrieve t h e r e q u i r e d i n f o r m a t i o n . W e also p r o v i d e a d e s c r i p t i o n over d i f f e r e n t e x p e r i m e n t a l components a n d p h a n t o m s w i t h d i f f e r e n t geometries.

T o e x t r a c t m a x i m u m i n f o r m a t i o n f r o m t h e flow d y n a m i c s , we i n t r o d u c e d an a l t e r n a t i v e b u t c o m p l i m e n t a r y m e t h o d t o s t u d y flow properties i n chapter 4. Par-t i c l e image v e l o c i m Par-t e r y ( P I V ) is a gold s Par-t a n d a r d Par-technique w h e n i Par-t comes Par-t o s Par-t u d y flow d y n a m i c s . T h e novelt}' a n d great advantage o f t h i s technique are its h i g h r e s o l u t i o n flow v e l o c i t y vector o f t h e w h o l e plane i n t h e flow. B y a d a p t i n g t h e o p t i c s o f t h e i l l u m i n a t i n g system a n d a p p l y i n g image-processing a l g o r i t h m s , we

r e p o r t e d t h e result f o r b o t h P I V and laser speckle m e t h o d . I n t h i s chapter, we r e p o r t our measurements a n d d a t a anal3'sis f o r t w o d i f f e r e n t geometries o f c j d i n -d r i c a l a n -d c a r o t i -d a r t e r y base-d p h a n t o m s . T h e p r e l i m i n a r y results -d e m o n s t r a t e -d t h e efficacy of c o m b i n i n g these t w o t e c h n i q u e f o r simultaneous f u l l - f i e l d i m a g i n g of flow d y n a m i c s .

T o broaden t h e scope o f thesis, we used t h e concept of f r a c t a l s t o s t u d y t h e changes i n speckle d a t a . F r a c t a l is a q u a n t i t a t i v e t o o l f o r u n d e r s t a n d i n g t h e chaos a n d c o m p l e x shapes i n n a t u r e . F r a c t a l analysis has been o f t e n used t o characterize randomness i n a series of data. T h e r e is a correlated randomness i n t h e d y n a m i c s changes o f speckle d a t a t h a t can be i n t e r p r e t e d b y ft'actals. W e show t h a t f r a c t a l d i m e n s i o n is able t o reveal p u l s a t i o n features i n a h i g h l y scattered m e d i u m . W e have r e p o r t e d a c o m p a r i s o n analysis between laser speckle c o n t r a s t a n d f r a c t a l d i m e n s i o n measured using d i f f e r e n t i a l b o x c o u n t i n g m e t h o d . These measurements have been done f o r a u n i f o r m flow channel i n a c y l i n d r i c a l p h a n t o m a n d also f o r a more c o m p l e x flow t h r o u g h a patient-specific c a r o t i d a r t e r y p h a n t o m .

W e have f u r t h e r r e p o r t e d a d i f f e r e n t speckle behavior t h r o u g h a layered s t r u c -t u r e c o n -t a i n i n g s -t a -t i c sca-t-terers. For -t h i s reason, we have f u r -t h e r i n v e s -t i g a -t e d -t h e concept o f f r a c t a l d i m e n s i o n t o s t u d y t h e so called 'speckled speckle' p a t t e r n s . R ' a c t a l analysis has been used t o characterize i r r e g u l a r t i m e d a t a series i n n o n -linear systems. T h e r e f o r e , we extended our analysis t o s t u d y t h e non--linear effect detected i n flow p u l s a t i o n caused b y t h e secondary r e f l e c t i o n o f speckle. W e sug-gest t h a t f r a c t a l d i m e n s i o n can give a b e t t e r d e s c r i p t i o n of r e a l i t y . A possible a p p l i c a t i o n of t h i s is t o use laser speckle t o investigate a w i d e v a r i e t y of p a t h o l o g -ical skeletal c o n d i t i o n s f o r instance, b y m e a s u r i n g t h e changes of flow d y n a m i c s inside a bone.

I n t h e last p a r t of t h e thesis, we s t u d y t h e effect of induced m o t i o n a r t i f a c t s using laser speckle images. These results have shown f o r t h e first t i m e t h e use of laser speckle against m o t i o n a r t i f a c t s . W e i n i t i a t e d t h e measurements t o s t u d y t h e i n f l u e n c e o f m o t i o n i n d u c e d a r t i f a c t s u s i n g laser speckle contrast analj'sis. T o f u r t h e r e x p l o i t these results, t h e measurements have been extended t o a larger range o f m o t i o n a n d we also r e p o r t e d a c o m p a r i s o n between laser speckle c o n t r a s t a n d c o r r e l a t i o n based analysis. B y t h e end of t h i s chapter, t o show t h e p o s s i b i l i t y of h a v i n g a m o r e compact device development based o n laser speckle, t h e f e a s i b i l i t j ^ o f using o n l y f e w pixels has been d e m o n s t r a t e d .

I n s u m m a r y , t h i s thesis has addressed e x p e r i m e n t a l l y , several o f t h e challenges w h i c h are faced i n case of developing a p o r t a b l e h e a l t h m o n i t o r i n g device. A l t h o u g h w o r k f o r t h i s thesis has been c a r r i e d o u t s p e c i f i c a l l y f o r h e a l t h care m o n i -t o r i n g , -t h e s -t u d i e d m e -t h o d s are n o -t l i m i -t e d -t o b i o m e d i c a l a p p l i c a -t i o n s and can be f u r t h e r a p p l i e d t o flow d y n a m i c s i n d i f f e r e n t cases,

I n de m o d e r n e samenleving bestaat een toenemende v r a a g naar technologien v o o r een betere diagnose en behandeling. D i t w o r d t ingegeven door de groei v a n het g e z o n d h e i d s b e w u s t z i j n en de toenemende v e r g r i j z i n g . H e t concept o m gezondheid v o o r t d u r e n d t e m o n i t o r e n is n v a n de b e l a n g r i j k s t e f a c t o r e n v o o r een gezondere l e v e n s s t i j l , v e r b e t e r i n g v a n de gezondheidszorg en een betere c o n t r o l e v a n c h r o n i -sche z i e k t e n . E e n n i e u w m a r k t o n d e r z o e k heeft een forse t o e n a m e v o o r s p e l d v a n het a a n t a l mobiele gezondheidtesters die k u n n e n w o r d e n toegepast v o o r medische diagnose o f m o n i t o r i n g van gezondheid en w e l z i j n . H a r t en v a a t z i e k t e n z i j n we-r e l d w i j d volksziekte n u m m e we-r n en d a a we-r o m is het v a n g we-r o o t belang o m technieken t e o n t w i k k e l e n die de v i t a l e f u n c t i e s k u n n e n c o n t r o l e r e n . E r is ook b e h o e f t e aan meer betaalbare technologie o m zo de w e r e l d w i j d e o n g e l i j k h e i d i n de beschikbaarheid v a n d u r e gezondheidsapparatuur aan t e p a k k e n . I n d i t opzicht v o r m e n oplossingen gebaseerd op f o t o m e t r i e een toenemende v e l d v o o r o n t w i k k e l i n g e n i n t e n behoeve v a n de gezondheidszorg.

De Pulse-oximeter is een bekend en k l i n i s c h bewezen i n s t r u m e n t . H e t is een op f o t o m e t r i e gebaseerde non-invasieve m e t h o d e , waarmee v o l u m e veranderingen i n de aders door u i t z e t t i n g en c o n t r a c t i e w o r d e n gemeten. D o o r d a t het signaal i n s t e r k t e v a r i e e r t m e t de v u l l i n g van de slagaders, kan het i n s t r u m e n t berekenen w a t de freciuentie v a n de h a r t s l a g is. De w e r k i n g is gebaseerd op het p r i n c i p e v a n l i c h t a b s o r p t i e . B i j u i t z e t t i n g v a n een b l o e d v a t door een h a r t s l a g w o r d t er meer bloed i n het bloedvat gestuwd; daardoor neemt de l i c h t a b s o r p t i e toe en w o r d t er een lager signaal gemeten. D o o r het toepassen van verschillende absorptie-eigenschappen k a n m e t twee golflengtes de hoeveelheid o x y h e m o g l o b i n e i n het bloed w o r d e n gemeten. Deze a p p a r a t u u r is echter alleen gevoelig v o o r periodieke signalen en levert daardoor geen i n d i c a t i e v a n weefseldoorbloeding. B o v e n d i e n heeft d i t t y p e a p p a r a t u u r last v a n v e r m i n d e r d e precisie en reproduceerbaarheid v a n signalen als gevolg a r t e f a c t e n die d o o r beweging w o r d e n v e r o o r z a a k t . V o o r k l i n i s c h b e t r o u w b a r e m e t i n g e n is d a n o o k een stabiele o m g e v i n g en contact m e t de p a t i n t vereist. T e n einde de u i t d a g i n g e n aan t e gaan een contactloze m e t h o d e te o n t w e r p e n en s i g n a a l v e r z w a k k i n g door beweging t e v e r m i j d e n , hebben we een a l t e r n a t i e v e optische techniek gedemonstreerd.

Laser speckle i m a g i n g is een goedkope m e t h o d e , die een nieuwe dimensie k a n brengen i n toepassing en b e h a n d e l i n g b i j op a f s t a n d m o n i t o r e n v a n de h e m o d y -namische eigenschappen. B i j deze m e t h o d e w o r d t coherent l i c h t toegepast o m het lichaamsdeel t e b e l i c h t e n ; t i j d e n s het s t r o m e n v a n het bloed v e r a n d e r t de l i c h t

-ter, i n d i t p r o e f s c h r i f t r a p p o r t e r e n w i j verscheidene m e t i n g e n w a a r b i j n i e t alleen r e s u l t a t e n v a n f a n t o m e n , m a a r o o k v a n lichaamsdelen zoals v i n g e r , nagel o f hals w o r d e n g e b r u i k t . E r w o r d e n meerdere e x p e r i m e n t e n gepresenteerd w a a r b i j v a n deze techniek g e b r u i k is g e m a a k t , waarmee een breder scala v a n toepassingen e n van verschillende c o n f i g u r a t i e s w o r d t geboden. Deze studies z i j n een s t a p v o o r -w a a r t s v o o r de i n z e t b a a r h e i d v a n laser speckle technieken i n sommige g e b r u i k e l i j k e klinische situaties. I n d i t p r o e f s c h r i f t w o r d t de m o g e l i j k h e i d beschreven o m 'laser speckle' t o e te passen o m pulserende s t r o m e n t e m o n i t o r e n . H e t onderzoek gaat over de toepasbaarheid b i j bewegingsartefacten. E r z i j n verschillende e x p e r i m e n -tele s t r o m e n en optische o p s t e l l i n g e n bestudeerd, o n t w o r p e n en g e m p l e m e n t e e r d o m dynamische eigenschappen v a n 'laser speckle' te bestuderen. De d y n a m i s c h e eigenschappen v a n 'laser speckle' w o r d e n bepaald door het m e t e n v a n i n t e n s i -t e i -t s v e r a n d e r i n g e n -t e m e -t e n , die w o r d e n v e r o o r z a a k -t door -t e m p o r e l e fluc-tua-ties i n speelde p a t r o n e n . H e t p r i n c i p e is v e r g e l i j k b a a r m e t de laser D o p p l e r techniek, w a a r b i j er een f r e q u e n t i e v e r s c h u i v i n g p l a a t s v i n d t door een bewegende v e r s t r o o i e r die w o r d t g e b r u i k t o m de veranderingen i n het specimen te m e t e n . V o o r 'laser speelde' k u n n e n deze v e r a n d e r i n g e n d i r e c t w o r d e n vastgelegd door g e b r u i k t e m a -ken v a n deze i n t e f e r e n t i e p a t r o n e n . D i t z i j n echter verschillende technie-ken w a a r i n dezelfde theoretische principes v a n dynamische l i c h t v e r s t r o o i i n g w o r d e n toegepast. D i t is o o r s p r o n k e l i j k onderzocht v o o r enkelvoudige deeltjes; l a t e r w e r d d i t u i t g e -b r e i d t o t een sterk v e r s t r o o i e n d m e d i u m . 'Laser speckle' heeft p o t e n t i l e v o o r d e l e n l a t e n zien t e n opzichte v a n de Laser D o p p l e r m e t h o d e , m e t name door de snellere data-acquisitie. B i j deze benadering kan een een bloedstroomlcaart m e t zeer hoge r u i m t e l i j k e en t e m p o r e l e resolutie w o r d e n verkregen m e t behulp v a n a f z o n d e r l i j k e beelden, w a a r b i j de veranderingen i n de .stroming k u n n e n w o r d e n g e k w a n t i f i c e e r d op basis v a n r u i m t e l i j k e vervaging. H e t p r o e f s c h r i f t begint m e t een k o r t e i n t r o -d u c t i e v a n i n t e r a c t i e tussen l i c h t en weefsel t e z a m e n m e t verschillen-de numerieke modelleringstechnieken, die g e w o o n l i j k w o r d e n g e b r u i k t voor het bepalen v a n de optische eigenschappen van weefsel. Vervolgens b e s c h r i j v e n we de t h e o r i e van 'laser speckle' en hoe d i t fenomeen ontstaa. D a a r n a w o r d e n de verschillende ana-l y s e m e t h o d e n v o o r de speckana-le p a t r o o n d a t a beschreven. Aangezien speckana-le v a n o r i g i n e w i l l e k e u r i g is, m o e t e n we eerst de statistische methodes b e s c h r i j v e n . I n d i t h o o f d s t u k r i c h t e n we ons o p 'laser speckle' contrast-analyse, correlatie en f r a c t a l s die z i j n g e b r u i k t i n de rest v a n het p r o e f s c h r i f t als b e l a n g r i j k s t e analytische me-thodes. De o p s t e l l i n g die g e b r u i k t is v o o r 'laser speckle' i m a g i n g is erg eenvoudig, o m d a t deze v o o r n a m e l i j k bestaat u i t een laser v o o r het b e l i c h t e n v a n het specimen en het genereren v a n het gereflecteerde speckle p a t r o o n d a t w o r d t opgenomen m e t een camera. De s t u d i e v a n s t r o m i n g s d y n a m i c a is complex. H e t complexe gedrag v a n de s t r o m i n g k a n w o r d e n v e r o o r z a a k t door de c o m p l e x i t e i t van de geometrie of door de vloeistofspecifieke eigenschappenzelf. W e hebben aangetoond d a t m e t 'laser speckle' i m a g i n g de veranderingen i n de s t r o m i n g k u n n e n w o r d e n gemeten die k u n n e n o n t s t a a n door verschillende fysiologische / experimentele o m s t a n d i g -heden. O m de i n v l o e d v a n de verschillende p a r a m e t e r s t e k u n n e n v e r g e l i j k e n en te k u n n e n b e g r i j p e n , is een serie e x p e r i m e n t e n u i t g e v o e r d m e t een a a n t a l

ver-schillende opstellingen. Deze e x p e r i m e n t e n z i j n gedaan o m op een sj'stematisclie m a n i e r de veranderingen t e m o n i t o r e n . I n eerste i n s t a n t i e v o o r een c o n t i n u e s t r o -m i n g en vervolgens v o o r een pulserende. V o o r elk e x p e r i -m e n t z i j n de laser speckle p a t r o n e n verder v e r w e r k t o m de gevraagde i n f o r m a t i e t e v e r k r i j g e n . W e bieden ook een b e s c h r i j v i n g v o o r verschillende experimentele c o m p o n e n t e n en f a n t o m e n m e t verschillende g e o m e t r i e n . I n h o o f d s t u k 4 i n t r o d u c e r e n we een a l t e r n a t i e v e en c o m p l e m e n t a i r e m e t h o d e o m de eigenschappen v a n de s t r o m i n g t e bestuderen, teneinde zoveel m o g e l i j k i n f o r m a t i e u i t de dynamische eigenschappen t e v e r k r i j g e n . ' P a r t i e l e image v e l o c i m e t r y ' ( P I V ) is een gouden s t a n d a a r d techniek als het gaat o m b e s t u d e r i n g v a n de dynamische eigenschappen v a n s t r o m i n g e n . De v e r n i e u -w i n g en het g r o t e voordeel v a n deze t e c h n i e k is de hoge-resolutie stroomsnelheids-vector v a n het gehele v l a k i n de s t r o o m . D o o r aanpassing v a n de o p t i e k v a n het belichtingssj'steem en het toepassen van beeldverwerkingsalgoritmes, b e s c h r i j v e n we het r e s u l t a a t v a n zowel P I V als de 'laser speckle m e t h o d e ' . I n d i t h o o f d s t u k b e s c h r i j v e n we onze m e t i n g e n en gegevensanalyse v o o r twee verschillende geome-t r i e n v a n cilindrische en op de halsslagader gebaseerde f a n geome-t o m e n . De v o o r l o p i g e r e s u l t a t e n demonstreren de m o g e l i j k h e i d o m deze twee technieken t e c o m b i n e r e n voor g e l i j k t i j d i g e f u l l - f i e l d i m a g i n g v a n dynamische stromingseigenschappen. O m de r e i k w i j d t e v a n het p r o e f s c h r i f t te verbreden, h e b b e n we g e b r u i k g e m a a k t vair het b e g r i p f r a c t a l s o m de veranderingen i n speckle d a t a te bestuderen. R-actals w o r d e n g e b r u i k t v o o r het b e g r i j p e n v a n chaos en complexe v o r m e n i n de n a t u u r . Fractale analyse w o r d t vaak g e b r u i k t o m de w i l l e k e u r i n een reeks van d a t a te karakteriseren. E r is sprake v a n een gecorreleerde w i l l e k e u r i n de dynamische veranderingen v a n speckle gegevens die k u n n e n w o r d e n genterpreteerd door f r a c -tals. W e t o n e n aan d a t m e t b e h u l p v a n fractale dimensie p u l s a t i e m e t i n g e n i n een zeer v e r s t r o o i e n d m e d i u m k u n n e n w o r d e n u i t g e v o e r d . We r a p p o r t e r e n een ver-gelijkende analyse tussen laser speckle contrast en gemeten f r a c t a l e dimensie m e t b e h u l p v a n de ' d i f f e r e n t i a l b o x c o u n t i n g ' m e t h o d e . Deze m e t i n g e n z i j n gedaan voor een u n i f o r m stroomlcanaal i n een c i l i n d r i s c h f a n t o o m en ook v o o r een meer complexe s t r o m i n g door een p a t i n t s p e c i f i e k halsslagader f a n t o o m . V o o r t s hebben we een ander specklegedrag beschreven, v e r o o r z a a k t door een gelaagde s t r u c t u u r m e t statische verstrooiers. M e d e h i e r o m hebben we het b e g r i p f r a c t a l e dimensie verder onderzocht o m de zogenaamde gespikkelde speckle p a t r o n e n te bestuderen. Fi-actale analyse is g e b r u i k t o m onregelmatige tijdgegevensreeksen te Itarakterise-ren i n n i e t - l i n e a i r e systemen. D a a r o m hebben we onze analj^se u i t g e b r e i d o m het n i e t - l i n e a i r e effect te bestuderen d a t k a n w o r d e n waargenomen i n s t r o o m p u l s a t i e s , o n t s t a a n door secundaire reflectie v a n speckle. W i j stellen vast d a t f r a c t a l e d i m e n -sie een meer nauwkeurige weergave oplevert v a n de w e r k e l i j k h e i d . Een m o g e l i j k e toepassing h i e r v a n is o m 'laser speckle' t e g e b r u i k e n v o o r het onderzoeken v a n een g r o t e v a r i a t i e v a n pathologische skeletcondities, b i j v o o r b e e l d door het m e t e n v a n de v e r a n d e r i n g e n i n s t r o m i n g s d y n a m i c a b i n n e n een b o t . I n het laatste deel v a n het p r o e f s c h r i f t , bestuderen we het effect v a n genduceerde bewegingsartefacten, m e t b e h u l p v a n 'laser speckle' beelden. Deze r e s u l t a t e n t o o n d e n v o o r het eerst het g e b r u i k v a n 'laser speckle' i n aanwezigheid van bewegingsartefacten. W e z i j n de m e t i n g e n gestart o m de i n v l o e d v a n bewegingsartefacten t e bestuderen door het g e b r u i k van 'laser speckle' contrast-analyse. O m deze r e s u l t a t e n verder te

onderzoeken, z i j n de m e t i n g e n u i t g e b r e i d naar een g r o t e r bewegingsbereilc en r a p -p o r t e e r d e n we o o k een v e r g e l i j k i n g tussen analyse v a n laser s-peckle c o n t r a s t en o-p correlatie gebaseerde analyse. A a n het einde v a n d i t h o o f d s t u k l a t e n we zien d a t het haalbaar is een compacter a p p a r a a t op basis van 'laser speckle' o n t w i k k e l e n , als g e b r u i k w o r d t gemaakt v a n een b e p e r k t a a n t a l pixels. Samengevat z i j n i n d i t p r o e f s c h r i f t diverse u i t d a g i n g e n waarmee m e n g e c o n f r o n t e e r d w o r d t b i j het o n t -w i k k e l e n v a n mobiele gezondheidtesters, experimenteel behandeld. A l h o e -w e l het p r o e f s c h r i f t specifiek v o o r m o n i t o r i n g i n de gezondheidszorg is u i t g e v o e r d , beper-ken de bestudeerde methodes zich n i e t t o t biomedische toepassingen; ze k u n n e n ook w o r d e n toegepast b i j s t r o o m d y n a m i c a i n andere disciplines.

I n t r o d u c t i o n

If you can't explain it simply, you don't understand it well enough.

A l b e r t E i n s t e i n

C o n t i n u o u s m o n i t o r i n g of p h y s i o l o g i c a l signals has been a t o p i c o f increasing i m p o r t a n c e i n m o d e r n society, A n increasing d e m a n d f o r personal healthcare services, due t o f a c t o r s such as aging p o p u l a t i o n , changes i n l i f e s t y l e or t h e i n d i -v i d u a l p u r s u i t o f h e a l t h and wellness [1] creates a need f o r reliable, continuous a n d non-invasive devices f o r t h e measurement of physiological signals. I n order t o ad-dress t h i s increasing d e m a n d f o r a m b u l a t o r y m o n i t o r i n g and services s u r r o u n d i n g i t , technology has been leaning t o w a r d s a new era of h e a l t h m o n i t o r i n g devices. T h e usage o f such devices can p o t e n t i a l l y reduce t h e costs associated w i t h regu-lar h e a l t h assessment measurements p e r f o r m e d b y h e a l t h professionals a n d reduce t h e stress associated w i t h h o s p i t a l v i s i t s , a l l o w i n g t h e p a t i e n t t o r e m a i n connected t o t h e i r home e n v i r o n m e n t . T h e c o n t i n u o u s m o n i t o r i n g of physiological signals is m o t i v a t e d b y several factors, such as demographic changes (aging p o p u l a t i o n ) , changes i n l i f e s t j d e w h i c h reflect u p o n p o p u l a t i o n h e a l t h and an increased con-science and desire t o w a r d s a h e a l t h i e r lifestyle. Regular m o n i t o r i n g devices can help people t r a c k t h e i r d a i l y a c t i v i t i e s and i m p r o v e t h e i r lifestyles. W i t h i n t h i s t a r g e t g r o u p t h e m a i n d e m a n d is f o r m o n i t o r i n g v i t a l signs such as b l o o d flow, pressure, o x y g e n a t i o n a n d heart rate. A l t h o u g h such devices are c u r r e n t l y used i n regular c l i n i c a l p r a c t i c e based o n diff'erent techniques like a n g i o g r a p h j ' [2], u l -t r a s o u n d [3], m a g n e -t i c resonance i m a g i n g [4] or laser D o p p l e r i m a g i n g [5], i -t is challenging t o a p p l y these techniques i n a n o n - c o n t r o l l e d e n v i r o n m e n t , where t h e i n d i v i d u a l f o l l o w i t s normal life.

One key challenge is t h e a b i l i t y t o create devices w h i c h can be used w i t h o u t d i r e c t c l i n i c a l supervision w h i l e being c o m f o r t a b l e , unnoticeable a n d w i t h no side

effects f o r t h e user. D u e t o i t ' s non-invasive n a t u r e , o p t i c a l m e t h o d s have been regarded as a p r o m i s i n g approach t o w a r d s t h i s end. These techniques have been a p p l i e d i n m e d i c a l settings f o r diagnostics a n d m o n i t o r i n g a p p l i c a t i o n s [ 0 , 7 ] . A v e r y c o m m o n example of such a device is t h e pulse o x i m e t e r . I t s w o r k i n g p r i n c i p l e is based o n t h e p h o t o p l e t h y s m o g r a m ( P P G ) w h i c h q u a n t i f i e s v o l u m e t r i c changes i n b l o o d f l o w [8]. T h e device i l l u m i n a t e s t h e s k i n a n d measures t h e changes i n l i g h t a b s o r p t i o n at each cardiac cycle. These devices can be a p p l i e d t o d i f f e r e n t sites o f t h e b o d y using either r e f l e c t i o n or t r a n s m i s s i o n designs. However, despite t h e f r e q u e n t use o f these devices, t h e y require v e r y s t e a d y m e a s u r i n g c o n d i t i o n s as t h e t e c h n i q u e suffers f r o m m o t i o n a r t i f a c t s . T h e m a i n measurement errors are due t o sensor m o v e m e n t w i t h respect t o skin. A l s o r e p e t i t i v e m o t i o n induces sloshing of venous b l o o d w h i c h can create a d i f f e r e n t p u l s a t i o n c o m p a r e d t o a r t e r i a l b l o o d . I n a d d i t i o n , v a s o m o t i o n or t h e vessel d i a m e t e r v a r i a t i o n s due t o m o v e m e n t lead t o errors [9,10].

I n t h e f r a m e w o r k o f research t h e m a i n focus is o n developing a non-invasive m e t h o d w h i c h m o n i t o r s t h e behavior of cardiovascular system. T h e v i t a l parame-ters w h i c h need t o be q u a n t i f i e d i n diagnosis are revealed by m e a s u r i n g p u l s a t i o n characteristics o f f l o w . I n t h i s thesis, we t a r g e t o n t h e research challenges i n devel-o p i n g a ndevel-on-invasive, m devel-o t i devel-o n r devel-o b u s t , p devel-o r t a b l e device f devel-o r b l devel-o devel-o d fldevel-ow sensing. Fdevel-or t h i s purpose we explore t h e use of a laser speckle based s o l u t i o n .

1.1 Laser speckle for physiological signal

measure-ments

S i m i l a r t o laser D o p p l e r i m a g i n g techniques, laser speckle can m o n i t o r m i c r o vascular b l o o d flow or tissue p e r f u s i o n [11], However, laser speckle has t h e a d -vantage o f a simple a n d inexpensive setup w h i c h has shown p r o m i s i n g results i n b i o m e d i c a l a p p l i c a t i o n s [12]. T h e i n i t i a l use of laser speckle was i n i m a g i n g t h e b l o o d flow i n r e t i n a [13]. I t s b i o m e d i c a l a p p l i c a t i o n has been f u r t h e r expanded f o r skin [14], b r a i n [15] a n d t h e i n t e r i o r of t e e t h k n o w n as p u l p [16]. Laser speckle can be f u r t h e r used as an a m b u l a t o r y m o n i t o r i n g device, as t h e c u r r e n t o p t i c a l m e t h -ods ( P P G based) are h i g h l y susceptible t o m o t i o n a r t i f a c t s . For such a p p l i c a t i o n , t h e m o s t c o m m o n sources o f m o t i o n a r t i f a c t s are caused b y b o t h t h e r e l a t i v e b o d y and sensor p o s i t i o n v a r i a t i o n s a n d t h e absolute b o d y m o t i o n .

Laser speckle is created as coherent l i g h t scatters f r o m d i f f u s e or r o u g h surfaces. D u e t o o p t i c a l p a t h differences of t h e scattered l i g h t , c o n s t r u c t i v e or d e s t r u c t i v e interference takes place. T h i s signal is collected using an i n t e n s i t y detector w i t h a finite a p e r t u r e a n d recorded as a g r a n u l a r p a t t e r n o f d a r k a n d b r i g h t spots. A n y m o v e m e n t i n t h e m e d i a , such as e v o l u t i o n o f cell or movement of red b l o o d cells, causes t h e speckle p a t t e r n s t o change. T h i s h i g h s e n s i t i v i t y of speckle t o m i n o r changes can be a p o w e r f u l t o o l f o r s t u d y i n g t h e d y n a m i c s of fluctuation i n t h e b l o o d flow. T h e i m p o r t a n c e o f b l o o d flow m o n i t o r i n g can be observed i n s t u d y i n g t h e heart valve d y n a m i c s , or i n diagnosing v a r i a t i o n s i n b l o o d vessel

stiffness w h i c l i t y p i c a l l ) ' is a sign of cardiac disease: changes i n t h e stiffness o f arteries a n d veins, creates a d i f f e r e n t range o f speed o f d i l a t a t i o n waves a n d t h a t e v e n t u a l l y results i n a n i r r e g u l a r range of flow speed. T h e laser speckle technique has b o t h a t e m p o r a l a n d a s p a t i a l characteristic, as t e m p o r a l a n d s p a t i a l i n t e n s i t y v a r i a t i o n of t h e speckle p a t t e r n c o n t a i n i n f o r m a t i o n over t h e d y n a m i c p r o p e r t i e s . T h i s m e t h o d provides a t w o d i m e n s i o n a l m a p of localized b l o o d flow d y n a m i c s . T o explore t h e advantages of t h i s technique, we have used laser speckle as t h e m a i n t o o l t o measure p u l s a t i l e flow.

T o s t u d y t h e flow d y n a m i c s , we s t a r t e d b y b u i l d i n g a laser speckle e x p e r i m e n -t a l se-tup -t o m o n i -t o r -the p u l s a -t i l e flow. G i v e n -t h e i m p o r -t a n c e of c h a r a c -t e r i z i n g t h e r e q u i r e d features of t h e device w h e n u l t i m a t e l y i t ' s applied i n practice, we c o n s t r u c t e d an e x p e r i m e n t a l setup o n a s i m p l i f i e d m o d e l of t h e real s i t u a t i o n . I n c o l l a b o r a t i o n w i t h L i f e T e c G r o u p , we have developed a n in-vitro m o d e l of a b l o o d channel w i t h d i f f e r e n t channel depths i n a m e d i u m w h i c h m i m i c s t h e s k i n scat-t e r i n g p r o p e r scat-t i e s . Obviously, care musscat-t be scat-t a k e n i n i n scat-t e r p r e scat-t i n g scat-t h e resulscat-t as scat-t h e h u m a n b o d y is a c o m p l e x system and differences i n in-vivo behavior s h o u l d be expected. T h i s c o m p l e x i t y originates f r o m v a r i a t i o n i n micro-vascular s t r u c t u r e of each i n d i v i d u a l a n d d i f f e r e n t vessel geometry. T h e difference i n b l o o d rheol-ogy is another f a c t o r as any aggregation of r e d b l o o d cells can change t h e o p t i c a l p r o p e r t i e s of t h e b l o o d flow and influences t h e laser speckle measurements [17]. Moreover, w i t h non-invasive m o n i t o r i n g we do n o t have d i r e c t access t o b l o o d flow since t h i s is accessed t h r o u g h a layered s k i n s t r u c t u r e . D u e t o such f a c t o r s , laser speckle can o n l y r e p o r t b l o o d flow changes rather t h a n absolute values. I n order t o come u p w i t h a solid p l a t f o r m , the in-vitro measurements can p r o v i d e a g o o d reference of t h e b l o o d flow p r i n c i p l e as a n i n i t i a l step.

I n a d d i t i o n t o t h e above studies, we s t u d i e d t h e c o m b i n a t i o n of laser speckle techniques w i t h d i r e c t i m a g i n g ones, such as p a r t i c l e image v e l o c i m e t r y ( P I V ) . U s i n g P I V , we can measure t h e c o m p l e m e n t a r y parameters of t h e flow d y n a m i c s as i t can accurately c o m p u t e t h e flow v e l o c i t j ' using t r a c i n g particles. B o t h laser speckle a n d P I V have t h e a b i l i t y t o c a p t u r e entire o p t i c a l field f o r t h e flow mea-surement a n d c o m b i n a t i o n of these t w o techniques can p r o v i d e a b e t t e r i n s i g h t i n t o flow d y n a m i c s . These e x p e r i m e n t s were r e p o r t e d f o r t h e s t u d y o f p u l s a t i l e flow using v e n t r i c u l a r assist device i n a patient-specific c a r o t i d a r t e r y p h a n t o m . T h i s was done t o also cross reference t h e technique i n t h e same p h a n t o m .

T h e analysis o f d y n a m i c speckle p a t t e r n s can be q u a n t i f i e d using laser speckle contrast, w h i c h is defined as t h e r a t i o of s t a n d a r d d e v i a t i o n over t h e average of i n t e n s i t y fluctuations. T h i s can be calculated f o r each r a n d o m d i s t r i b u t i o n s of b r i g h t a n d d a r k p a t t e r n s . I n order t o s t u d y d y n a m i c s o f t h e physical p r o b l e m , m o r e a d d i t i o n a l measures need t o be done where we c a p t u r e a t i m e sequence o f images a n d calculate t h e speckle contrast f o r each p a t t e r n . F u r t h e r m o r e , we i n t r o d u c e d a n a d d i t i o n a l a p p r o a c h t o measure t h e t i m e fluctuation d y n a m i c s of speckle images based o n f r a c t a l analysis. These measurements have been p e r f o r m e d i n c o m p a r i s o n w i t h laser speckle analysis a n d f o r d i f f e r e n t e x p e r i m e n t a l c o n f i g u r a t i o n s . T h e m u l t i s c a l e analysis of speckle d a t a using f r a c t a l based techniques provides a deeper

insiglrts i n t o t h e system. T o d e m o n s t r a t e t h a t , t h e fractal analysis has been a p p l i e d t o a d i f f e r e n t s c a t t e r i n g c o n f i g u r a t i o n w h e r e t h e scattered w a v e f r o n t o f t h e p u l s a t i l e f l o w has been p r o p a g a t e d t h r o u g h a layered s t r u c t u r e .

I n t h i s thesis, we emphasize o n t h e i m p o r t a n c e of h a v i n g a flow measurement setup i n t h e first place w h i c h allows t o s i m u l a t e t h e various real-life c o n d i t i o n s under w h i c h t h e system is i n t e n d e d t o be used. M o t i o n a r t i f a c t is a key challenge i n any p o r t a b l e a p p l i c a t i o n as i t d i s t o r t s t h e d a t a a n d reduces t h e signal q u a l i t y s i g n i f i c a n t l y , t h e r e f o r e i n f i u e n c i n g i t s a p p l i c a b i l i t y i n ( o p t i c a l based) h e a l t h m o n i -t o r i n g devices. T h e r e already have been m a n y a -t -t e m p -t s -t o deal w i -t h -t h i s p r o b l e m based o n b o t h h a r d w a r e a n d s o f t w a r e approaches. Such approaches i n t r o d u c e t h e use of a d d i t i o n a l sensors such as trackers a n d accelerometers [18,19], piezo and pressure [20], or c o m b i n a t i o n s o f t h e above [21] t o be a p p l i e d as a noise refer-ence signal. T h e second approach is m a i n l y using s o f t w a r e based techniques f o r r e d u c i n g t h e m o t i o n a r t i f a c t s , a i m at i m p r o v i n g t h e signal q u a l i t y , using d i f f e r e n t techniques such as t h e wavelet t r a n s f o r m [22], a d a p t i v e noise c a n c e l l a t i o n , least mean square [23,24] a n d o t h e r nonlinear m e t h o d s [25]. I n most cases, these m e t h -ods help t o decrease t h e n u m b e r of false alarms b u t n o t t o remove t h e i n f l u e n c e o f a r t i f a c t s t o t a l l y .

T o s t u d y t h e influence of m o t i o n a r t i f a c t s , we p e r f o r m e d b o t h p h a n t o m based and in-vivo e x p e r i m e n t s . T o l o o k i n t o t h e i n i t i a l p r o b l e m of m o t i o n a r t i f a c t s , we a r t i f l c i a l l y s i m u l a t e d t h e i n d u c e d m o t i o n a r t i f a c t s i n a c o n t r o l l e d lab e n v i r o n m e n t . T h i s allowed us t o deepen t h e u n d e r s t a n d i n g o f t h e p a r a m e t e r range under w h i c h laser speckle c o u l d be a p p l i e d . T h e in-vivo measurements p r o v i d e d us w i t h a v a l i d a t i o n of t h e approach.

1.2 Research project settings

T h e p r o j e c t s t a r t e d as a c o l l a b o r a t i o n between O p t i c s Research G r o u p o f D e l f t U n i v e r s i t y of Technology ( T U D e l f t ) a n d E i n d h o v e n U n i v e r s i t y o f Technologj', P h i l i p s Research a n d L i f e T e c G r o u p , E i n d h o v e n . T h i s p r o j e c t has been p e r f o r m e d i n close c o l l a b o r a t i o n w i t h P h i l i p s as an i n d u s t r y p a r t n e r . T h i s enables a clear focus o n t h e problems faced b y c u r r e n t devices i n t h e m a r k e t a n d t o n a r r o w t h e research t o m a r k e t gap. T h e c o n t r i b u t i o n s f r o m t h e academic side have been focused o n researching t h e usage o f laser speckle based techniques t o r e t r i e v e d a t a i n r e a l - w o r l d continuous m o n i t o r i n g s i t u a t i o n s .

1.3 Thesis structure

T h i s thesis is focused o n laser speckle analysis created f r o m a p u l s a t i l e flow, a n d i t is organized as follows:

C h a p t e r 2: W e s t a r t w i t h a n i n t r o d u c t i o n t o l i g h t tissue i n t e r a c t i o n . T h e phys-i c a l s t u d y a n d n u m e r phys-i c a l approaches f o r processphys-ing data. T h phys-i s phys-is f o l l o w e d w phys-i t h a

b r i e f survey over laser speckle techniques. F i n a l l y , d i f f e r e n t d a t a analj'sis m e t h o d s , useful i n t h e c o n t e x t o f subsequent chapters are i n t r o d u c e d .

C h a p t e r 3: T h i s chapter provides a general u n d e r s t a n d i n g over d i f f e r e n t pa-rameters w h i c h have a m a j o r influence i n m o n i t o r i n g p u l s a t i l e f l o w . T h e t i m e dependent analysis of speckle p a t t e r n s was used t o s t u d y t h e i n f l u e n c e of d i f f e r e n t parameters, such as p a r t i c l e c o n c e n t r a t i o n or v o l u m e of f l u i d and influence o f s t a t i c particles due t o bone a n d tissue f o r instance. T h e d i f f e r e n t e x p e r i m e n t a l setups a n d p h a n t o m s are described.

C h a p t e r 1: T h i s chapter i n t r o d u c e s t h e c o m b i n a t i o n o f laser speckle c o n t r a s t analj^sis ( L A S C A ) w i t h another k n o w n m e t h o d i n fluid d y n a m i c s , p a r t i c l e i m a g i n g v e l o c i m e t r y ( P I V ) . These f u l l - f i e l d o p t i c a l techniques have b o t h been used t o s t u d y flow a n d e x t r a c t c o m p l e m e n t a r y parameters. L A S C A can p r o v i d e a q u i c k s t u d y of signal fluctuations over t i m e so t h a t t r a n s i e n t phenomena can be recorded a n d observed. P I V can be used f o r a detailed s t u d y of t h e cause o f t h e phenomena. T h i s is perhaps also v e r y u s e f u l f o r s t u d y i n g geometries w i t h flow i n s t a b i l i t y . A p r e l i m i n a r y c o m p a r a t i v e measurement between P I V a n d L A S C A t o s t u d y p u l s a t i l e flow u s i n g v e n t r i c u l a r assist device i n a patient-specific c a r o t i d a r t e r y p h a n t o m is r e p o r t e d .

C h a p t e r 5: I n t h i s chapter, a d i f f e r e n t approach t o w a r d s d a t a processing o f acquired speckle d a t a is i n t r o d u c e d . T h e f r a c t a l n a t u r e of speckle is e x p l o r e d . Moreover, same set of e x p e r i m e n t a l d a t a w h i c h was discussed i n t h e previous chapter, was analyzed w i t h t h i s technique. T h i s was used t o compare t h e f r a c t a l anal}^sis w i t h t h e s t a n d a r d analj'sis used f o r laser speckle p a t t e r n s .

C h a p t e r G: T h i s chapter addresses t h e problems of a c q u i r i n g and a n a l y z i n g flow d a t a i n t h e presence of multi-laj^ered m e d i u m . W e r e p o r t a c o m p a r i s o n o n t h e acquired d a t a using laser speckle and f r a c t a l analysis.

C h a p t e r 7: F i n a l l y , a key r e q u i r e m e n t f o r p o r t a b l e , continuous m o n i t o r i n g de-vices is addressed i n t h i s chapter. T h e measurement o f flow i n presence o f m o t i o n a r t i f a c t s . W e address using t h e speckle d y n a m i c s f o r m e a s u r i n g a p u l s a t i l e flow i n a noisjr e n v i r o n m e n t .

W e conclude t h e thesis w i t h a chapter discussing t h e c o n t r i b u t i o n s o f t h e thesis and c o n c l u d i n g t h i s m a n u s c r i p t .

Theory and analytical

methods for flow

measurement

It is the theory which decides what can be observed.

A l b e r t E i n s t e i n

Coherent l i g h t scattered from d i f f u s e m e d i a can reveal t h e u n d e r l y i n g phe-n o m e phe-n o phe-n active i phe-n t h e media. D y phe-n a m i c l i g h t s c a t t e r i phe-n g is t h e s t u d y of t h e decay rate o f t h e a u t o c o r r e l a t i o n f u n c t i o n of t h e scattered l i g h t as a result of scatterer m o t i o n . Laser speckle i m a g i n g ( L S I ) together w i t h laser D o p p l e r flowmetry [26] or d i f f u s i n g wave spectroscopy ( D W S ) [27] are techniques t h a t have evolved f r o m t h e p r i n c i p l e of d y n a m i c l i g h t s c a t t e r i n g ( D L S ) . T h e laser speckle i m a g i n g has t h e advantage of e v a l u a t i n g t h e sample w i t h o u t scanning a n d images a w i d e field o f v i e w w i t h a simple a n d inexpensive a p p a r a t u s . T h e o b j e c t i v e o f t h i s thesis is t o appl}^ t h i s m e t h o d f o r t h e case o f s t u d y i n g flow. For t h i s a p p h c a t i o n , i t is essen-t i a l essen-t o u n d e r s essen-t a n d essen-t h e l i g h essen-t p r o p a g a essen-t i o n i n essen-t h e sample. T h e p r o p a g a essen-t i o n of l i g h essen-t t h r o u g h a d i f f u s e d sample and h o w t h e l i g h t w i l l be scattered is m a i n l y defined by m a t e r i a l p r o p e r t i e s . A s i n t h i s s t u d y we e x p l i c i t l y aims t o measure t h e b l o o d flow in-vivo, we p r o v i d e a n overview of l i g h t and tissue i n t e r a c t i o n . T h i s chapter is i n t e n d e d t o p r o v i d e a b r i e f i n t r o d u c t i o n t o u n d e r s t a n d t h e b a c k g r o u n d of t h e s t u d i e d phenomena a n d overview o f t h e m a i n t e r m s w h i c h w i l l be used i n t h e rest of t h i s thesis. I t i n t r o d u c e s , t h e tissue o p t i c a l p r o p e r t i e s along w i t h d i f f u s e l i g h t t r a n s p o r t regimes. These regimes are i m p o r t a n t w h e n q u a n t i t a t i v e measurements are o f interest. T h e r e are c e r t a i n a p p r o x i m a t i o n s t h a t are a p p l i e d at each regimes, i n order t o describe l i g h t d i s t r i b u t i o n accurately. B y a p p l y i n g these theorems w i t h some p r i o r knowledge, f o r instance t h e separation distance between t h e i l l u m i n a -t i o n source and de-tec-tor, we can re-trieve -tissue o p -t i c a l proper-ties f r o m d i f f e r e n -t p r o p a g a t i o n models. I n section 2.1.1 some o f t h e c o m m o n l y used models and ap-p r o x i m a t i o n w i l l be m e n t i o n e d . T h e n , we i n t r o d u c e w h a t sap-peckles are a n d h o w

t h e y are created. A s t h e p h e n o m e n o n w h i c h leads t o t h e g e n e r a t i o n of speckles is r a n d o m , s t a t i s t i c a l techniques are m a i n l y used i n s t u d y i n g a n d p a r a m e t e r i z i n g t h e m . T h e d a t a analysis w h i c h have been used t o s t u d y laser speckle images are m e n t i o n e d b y t h e end o f t h i s chapter.

2.1 Light tissue interaction

B i o l o g i c a l samples are generally o p t i c a l l y t u r b i d a n d h i g h l y a b s o r b i n g w h e n s t u d -ied in-vivo. T h e s t r u c t u r e can be r a t h e r inhomogeneous a n d have a r e f r a c t i v e i n d e x higher t h a n air (assuming m o s t o f t h e b o d y is w a t e r ) . W h e n l i g h t i l l u m i n a t e s a d i f f u s e m e d i a like tissue t h e electromagnetic r a d i a t i o n is absorbed, scattered and reflected. I t is u s e f u l t o n o t e t h a t i n t h e a b s o r p t i o n process, l o n g w a v e l e n g t h pho-tons deposit lower energy c o m p a r e d t o short w a v e l e n g t h p h o t o n s . For t h e case o f low i n t e n s i t y laser l i g h t i n t e r a c t i o n w i t h tissue, t h e i l l u m i n a t e d l i g h t is i n c i d e n t along a c e r t a i n d i r e c t i o n , b u t soon t h e d i r e c t i o n is lost due t o r e f l e c t i o n a n d scat-t e r i n g i n scat-t h e sub-layers. T h e l i g h scat-t scat-t h a scat-t penescat-trascat-tes scat-t h e scat-tissue undergoes m u l scat-t i p l e s c a t t e r i n g t i l l i t is e v e n t u a l l y absorbed. C h r o m o p h o r e s are t h e m a i n absorbers and t h e most c o m m o n ones k n o w n i n s k i n are h e m o g l o b i n , m e l a n i n a n d w a t e r i n d i f f e r e n t a b s o r p t i o n wavelengths. T h e p r o b a b i l i t y o f a b s o r p t i o n varies b y t h e c o n c e n t r a t i o n o f absorbers w h i c h is expressed i n t e r m s o f t h e a b s o r p t i o n coefh-cient. T h e a b s o r p t i o n coefficient (fia) is defined as t h e s u m o f c o n t r i b u t i o n s f r o m a f l a b s o r b i n g chromophores w i t h i n t h e tissue, w h i c h is expressed as [28]:

w h e r e Cj is t h e absorber c o n c e n t r a t i o n o f t h e c h r o m o p h o r e , [M], and e.;. is t h e m o l a r e x t i n c t i o n coefficient [ M ~ - ^ c m " ^ ] at t h e specific w a v e l e n g t h . T h e p r o d u c t of these t w o f a c t o r s is i n [cm~-^] u n i t w h i c h indicates t h e w a v e l e n g t h dependency of t h e a b s o r p t i o n c o e f f i c i e n t . T h e changes i n o p t i c a l a b s o r p t i o n as a f u n c t i o n w a v e l e n g t h is shown i n F i g . 2.1 f o r a v a r i e t y o f i m p o r t a n t chromophores, i n c l u d i n g m e l a n i n , oxy-{Hb02) a n d d e o x y h e m o g l o b i n (Hb). T h e l i g h t a b s o r p t i o n i n b l o o d is dependent o n t h e o x y g e n a t e d {Hb02) and deoxygenated {Hb) h e m o g l o b i n , where t h e difference i n t h e i r a b s o r p t i o n spectra can be seen i n t h i s p l o t . T h e tissue o p t i c a l w i n d o w is r e f e r r i n g t o a l o w a b s o r b i n g range where t h e l i g h t p e n e t r a t i o n i n t h e tissue is at i t s m a x i m u m .

Nevertheless, s c a t t e r i n g is t h e d o m i n a n t p h e n o m e n o n w h i c h originates due t o r e f r a c t i v e i n d e x inhomogeneities w i t h i n t h e tissue. S c a t t e r i n g influences t h e d e p t h of l i g h t p e n e t r a t i o n b y spreading i t o u t . T h e r e are t w o k i n d s of (elastic) scat-t e r i n g processes k n o w n as R a y l e i g h and M i e s c a scat-t scat-t e r i n g (dependenscat-t o n scat-t h e laser w a v e l e n g t h and size of t h e scatterers). W h e n t h e o b j e c t s are of t h e same size or smaller t h a n t h e i n c i d e n t w a v e l e n g t h , t h e n R a y l e i g h s c a t t e r i n g occurs w h e r e t h e i n t e n s i t y o f scattered l i g h t is p r o p o r t i o n a l t o A"'*. However, f o r o b j e c t s t h a t are larger t h a n t h e i n c i d e n t w a v e l e n g t h M i e s c a t t e r i n g occurs w i t h t h e i n t e n s i t y o f

Figure 2.1: Absorption spectra of some o f t h e important chromophores In the body,

adapted from [29].

s c a t t e r i n g l i g h t is p r o p o r t i o n a l t o A ^ ^ , I n case o f v i s i b l e l i g h t , f o r most of t h e tissues, a c o m b i n a t i o n of b o t h , R a y l e i g h a n d M i e s c a t t e r i n g takes place, a l t h o u g h M i e s c a t t e r i n g is d o m i n a n t . T h i s is m a i n l y due t o d i f f e r e n t cell size (lysosomes, vesicles, m i t o c h o n d r i a ) a n d cell spacing. A l l other sub-cellular components a n d molecules lead t o R a y l e i g h s c a t t e r i n g [30,31]. I n c o n t r a s t t o a b s o r p t i o n where l i g h t travels i n t o t h e tissue a n d loses i t s energy, l i g h t diffuses due t o s c a t t e r i n g . Elas-t i c s c a Elas-t Elas-t e r i n g can be considered as process of p h o Elas-t o n a b s o r p Elas-t i o n a n d re-emission w i t h o u t loss of energy b u t p o s s i b l y associated w i t h a change i n p h o t o n d i r e c t i o n . T h e m a i n p r o p e r t i e s o f tissue are described i n t e r m s o f a b s o r p t i o n coefficient {fia)t s c a t t e r i n g and reduced s c a t t e r i n g coefficients (/j.s,/i(,) and a n i s o t r o p y f a c t o r (g). However, t h e s t r u c t u r a l c o m p o s i t i o n o f tissue w i t h d i f f e r e n t m a t e r i a l p r o p e r t i e s , requires a new d e f i n i t i o n of t r a n s p o r t coefficient w h i c h is t h e s u m o f reduced scat-t e r i n g {fi'J a n d a b s o r p scat-t i o n (fia) coeflicienscat-t: pscat-t = l-^'s+f^a- T h e scat-t e r m / i ^ is i n c l u d i n g t h e a n i s o t r o p y (g) f a c t o r w h i c h is a d i r e c t i o n a l l y dependent. These parameters can be e s t i m a t e d using a n inverse m e t h o d , where t h r o u g h an i t e r a t i o n m e t h o d these parameters are i n i t i a t e d a n d a p p l i e d i n a l i g h t p r o p a g a t i o n m o d e l [32]. These pa-rameters need t o be c o n t i n u o u s l y a d j u s t e d t i l l t h e r e f l e c t i o n or t r a n s m i s s i o n values are t h e sanies as t h e ones r e q u i r e d f r o m measurements. One o f t h e m e t h o d is using t h i n slices o f d i f f e r e n t thicknesses a n d a n a r r o w b e a m geometry, so i n t h i s case t h e a b s o r p t i o n i n tissue is based o n t h e L a m b e r t - B e e r L a w , so t h e i n t e n s i t y measured at a c e r t a i n d e p t h (z) is:

I{z) = {1- B.)Ioexp{-kz) (2.2)

w h e r e R is t h e R-esnel r e f l e c t i o n coefficient w h i c h is k n o w n f r o m t h e r e f r a c t i v e indices, t h e i n c o m i n g angle and t h e r e f l e c t i o n angle. IQ is t h e i n t e n s i t y of t h e i n c i d e n t l i g h t a n d k is the a t t e n u a t i o n coefficient w h i c h is s u m of t h e coefficient of a b s o r p t i o n a n d loss due t o s c a t t e r i n g . I n t h i s approach, t h e s c a t t e r i n g is

ne-glected as we o n l y considered t h i n slices o f sample. I n t h e case o f t h i c k samples, t h e m u l t i p l e s c a t t e r i n g effect need t o be t a k e n i n t o c o n s i d e r a t i o n . Moreover, t h e r e l i a b i l i t y o f t h i s m e t h o d is dependent o n t h e n u m e r i c a l a p e r t u r e set i n t h e mea-surements. I n case o f h a v i n g s m a l l r e c o r d i n g angle, i t can be assumed t h a t all t h e scattered l i g h t w i l l n o t be measured b y t h e detector [33]. A n o t h e r c o m m o n tech-nique t o e x t r a c t o p t i c a l p r o p e r t i e s is using t h e I n t e g r a t i n g Sphere m e t h o d . T h i s a p p r o a c h is o f t e n used f o r tissue p h a n t o m s where t h e ps, IJ-a a n d g parameters can be e x t r a c t e d . T h e i n t e g r a t i n g sphere is made o f h i g h l y r e f l e c t i n g m a t e r i a l , so t h a t t h e l i g h t passing t h r o u g h t h e sample w i l l be scattered h i g h l y t i l l i t reaches t h e detector. However due t o inconvenient sample p r e p a r a t i o n , f o r t h e in-vivo cases is m o r e c o m m o n t o use t h e t i m e or s p a t i a l l y resolved techniques. These are based on m e a s u r i n g t h e d i f f u s e reflectance or t r a n s m i t t a n c e f r o m t h e m e d i u m w h e r e a k n o w n source detector s e p a r a t i o n is used [34,35].

I n t i m e - r e s o l v e d measurements, a series o f s h o r t pulses, i n picoseconds range, is a p p l i e d so t h e t e m p o r a l p o i n t spread f u n c t i o n can be measured at a c e r t a i n distance f r o m t h e source [36]. I n t h i s case t h e shape o f detected pulse measured w i t h absolute i n t e n s i t y value, carries t h e i n f o r m a t i o n a b o u t t h e o p t i c a l i n t e r a c t i o n coefficients. I n t h e s p a t i a l l y resolved technique, d i f f u s e d reflectance is measured versus d i f f e r e n t s e p a r a t i o n distance between source a n d detector, so t h a t each t i m e l i g h t probes d i f f e r e n t volumes a n d d i f f e r e n t depths. T h e o p t i c a l p r o p e r t i e s can be calculated by fitting t h e t r a n s m i t t a n c e or reflectance values measured f r o m any of t h i s approaches i n t o a n u m e r i c a l m o d e l i n g . These models w i l l be addressed s h o r t l y , since i t is essential t o first i n t r o d u c e d i f f e r e n t s c a t t e r i n g regimes where these models can be a p p l i e d .

I n t h e interest o f i n t r o d u c i n g d i f f e r e n t s c a t t e r i n g regimes and how p h o t o n s are t r a n s p o r t e d i n t h e m e d i u m , we need t o use t r a n s p o r t mean free p a t h . T h i s is defined as t h e r e c i p r o c a l o f reduced s c a t t e r i n g coefficient, I's = T h i s p a t h can be realized as a l e n g t h t h a t p h o t o n s forgets i t s i n i t i a l o r i e n t a t i o n . T h e regime where p h o t o n s experience no s c a t t e r i n g event is called t h e b a l l i s t i c regime, w h i l e i n case of f e w s c a t t e r i n g t h e t e r m quasi-baflistic w i l l be used. I n t h i s case, f e w s c a t t e r i n g happens and p h o t o n s w i l l be deflected b u t s t i l l t h e y have a s t r o n g m e m o r y o f t h e i r i n i t i a l o r i e n t a t i o n , w h i c h is a b o u t 1 t o 10 t r a n s p o r t mean free p a t h . I n t h e b a l l i s t i c regime, mean free p a t h {1^ = 1//Js) is an i m p o r t a n t f a c t o r t o describe t h e m e a n distance between t h e successive s c a t t e r i n g event. I f n u m b e r o f s c a t t e r i n g events goes h i g h , b e y o n d 10 t r a n s p o r t mean free p a t h , p h o t o n s experience m a n y s c a t t e r i n g events a n d t h e y have no m e m o r y a b o u t t h e i r o r i g i n a l o r i e n t a t i o n [37]. So i n t h i s case, t h e distance between successive collision is o f no i m p o r t a n c e . As m u l t i p l e s c a t t e r i n g happens, we need t o t a k e i n t o account t h e influence o f s c a t t e r i n g angle a n d t r a n s p o r t m e a n free p a t h . For instance, i n d i f f u s i o n regime, p h o t o n s are scattered i n a l l d i r e c t i o n s so t h e a m o u n t o f l i g h t reaching t h e d e t e c t i o n plane is p r o p o r t i o n a l t o t h e m e a s u r i n g solid angle w h i l e i n case o f ballistic, p h o t o n s s t i l l r e t a i n t h e i r o r i g i n a l d i r e c t i o n [38]. I n case o f d i f f u s e d l i g h t , energy i n t h e b a l l i s t i c c o m p o n e n t drops e x p o n e n t i a l l y as i t goes deeper i n t h e sample, and energy i n t h e scattered components increases. T h i s is a c o m m o n p r o b l e m w h e n i t comes t o d i r e c t i m a g i n g . I n d i r e c t i m a g i n g , t h e s p a t i a l o r i g i n o f t h e b a l l i s t i c c o m p o n e n t is o f