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Page 1: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

PDF hosted at the Radboud Repository of the Radboud University

Nijmegen

The following full text is a publisher's version.

For additional information about this publication click this link.

http://hdl.handle.net/2066/19136

Please be advised that this information was generated on 2020-07-11 and may be subject to

change.

Page 2: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

QUANTITATIVE NEAR-INFRARED SPECTROSCOPY

IN HUMAN SKELETAL MUSCLE

METHODOLOGICAL ISSUES AND CLINICAL APPLICATION

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Page 5: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

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Page 6: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

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Page 7: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

Page 8: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

CONTENTS

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Page 9: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

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Page 11: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

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Page 12: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

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Page 13: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

OUTLINE

Background Near-infrared spectroscopy

Quantitative NIRS measurements Venous occlusion method Arterial occlusion method Oxygen consumption Blood flow Venous oxygen saturation Half-recovery time Reoxygenation rate

NIRS measurements during exercise Sustained vs. rhythmic isometric exercise Arm vs. leg measurements

Aim of the thesis Thesis outline

Methodological issues Clinical application

Page 14: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

INTRODUCTION

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BACKGROUND

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Fig. 1 The electromagnetic spectrum. Both frequency and wavelength are presented together with the most common applications.

AM Radio Band

Short Wave

TV and FM Radio Band

Infrared

Millimeter Waves, Telemetry

Microwaves, Radar

Gamma Rays

X-Rays

Ultraviolet

VisibleLight

AM Radio Band: radio, maritime com-

munication, and aircraft navigation.

Short Wave: amateur radio, inter-

national broadcast, fixed and mobile

communications, government radio; in-

cluding police, fire, forestry, highway,

and railroad services.

TV and FM Radio Band: television,

radio, fixed and mobile communi-

cations, amateur broadcast, govern-

ment and non-government signals,

satelite communication and Global

Positioning System (GPS).

Microwaves, Radar: microwave ovens,

radio navigation.

Millimeter Waves, Telemetry: variety of

experimental, government and

amateur purposes in communication.

Infrared: near-infrared spectroscopy ,

pulse oximetry, Green-house effect,

radiation from hot objects, infrared ear

thermometers, photography.

Visible Light: these are the only

electromagnetic waves we can see.

Each color has a different wavelength.

Red the longest, violet the shortest. All

waves together make white light.

Ultraviolet: sunburn, UV-therapy, in-

volved in the production of vitamin D,

astronomy.

X-Rays: medical images, airport

security, astronomy.

Gamma-rays: cancer radiation therapy,

astronomy.

Wav

elen

gth

(m)

10-15

10-14

10-13

10-12

10-11

10-10

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

101

102

103

104

105

Fre

quen

cy (

Hz) 103

104

105

106

107

108

109

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

Page 15: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

CHAPTER 1

� 14

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Fig. 2 Schematic presentation of the set-up with the spectrophotometer emitting light of 3 wavelengths (770, 848, and 901 nm) The light is transported into the tissue by an optical fibre (optode). The light that is detected by the receiver is thought to describe a banana-shape travelling through the tissue [Cui et al. 1991]. Typically, the interoptode distance used in this thesis was 35 and 50 mm.

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INTRODUCTION

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Fig. 3 Changes in lactate and ammonia during the ischemic forearm test. Patients with myoadenylate deficiency (MAD) lacked ammonia production while patients with myophosphorylase deficiency (McArdle's disease) lacked lactate production. mitochondrial myopathies could not be discriminated from the controls.

∆lactate(mmol⋅l-1)

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CHAPTER 1

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INTRODUCTION

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Fig. 4 Extinction coefficients of adult oxyhaemoglobin (O2Hb) and deoxyhaemoglobin (HHb) as determined by Wray et al. [Wray et al. 1988]. Dotted lines represent the 3 wavelengths used (770, 848, and 901 nm).

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CHAPTER 1

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INTRODUCTION

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Fig. 6 A) Real-time NIRS tracings of oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb), and total haemoglobin (tHb) in response to 20 s of venous occlusion (VO) and 45 s of arterial occlusion (AO). Note that recovery after VO is very rapid while recovery from AO takes more than two minutes. B) Experimental set-up as used in the majority of our studies with the NIRS optodes placed on the forearm and a pneumatic cuff around the upper arm to apply occlusion. NIRS data were sampled at 10 or 20 Hz, displayed real-time on screen and stored on disk for off-line analysis.

[O2H

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CHAPTER 1

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Fig. 7 Quantitative NIRS measurements during A) venous occlusion and B) arterial

occlusion. During venous occlusion, blood flow (BF), muscle oxygen consumption

( 2OVm � ), and venous saturation (SvO2) can be calculated. Using arterial occlusion and its

recovery phase, it is possible to calculate 2OVm � , reoxygenation rate (∆O2Hb), and half-

recovery times (t50) of the signals. �

450 460 470 480 490 500 510-2

0

2

4

6

8

10

12

14

16

18

[O2H

b] (

µM)

Time (s)

tHb

O2Hb

HHb

mVO2 = δHHb/δt

BF = δtHb/δt

SvO2 = (δO2Hb/δt)/ (δtHb/δt)

A

540 560 580 600 620 640 660-20

-15

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0

5

10

15

20

25

30

35

[O2H

b] (

µM)

Time (s)

mVO2 = -δO2Hb/δt

∆reoxy = δO2Hb/δt (3 s)

t50 = t(O2Hb(max)-O2Hb(min)/2)

B

tHb

O2Hb

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Fig. 8 Half-time recovery, calculated as A) the time needed for half recovery of O2Hb from maximum deoxygenation at the end of arterial occlusion or exercise to maximum re-oxygenation during hyperaemia, and B) the tau value derived from a mono-exponential curve-fit of O2Hb recovery as is standard for calculation of PCr resynthesis with 31P-MRS.

660

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540 560 580 600 620 640-25

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Fig. 9 Individual NIRS O2Hb, HHb, and tHb signals during exercise, arterial occlusion, and recovery. Rhythmic isometric handgrip exercise was performed at 70% of the subject's maximum voluntary contraction force (MVC). Rhythmic changes, corresponding to muscle contraction and relaxation are clearly visible in the NIRS signals during exercise.

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CHAPTER 1

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INTRODUCTION

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CHAPTER 1

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SUMMARY

The aim of this study was to investigate local oxygen consumption ( 2OVm � ) and forearm blood flow (FBF) in resting and exercising

muscle by use of near-infrared spectroscopy (NIRS) and to compare the results with the global 2OVm � and FBF derived from the well-

established Fick-method and plethysmography. 2OVm � was derived

from 1) NIRS using venous occlusion, 2) NIRS using arterial occlusion, and 3) the Fick-method ( ( )Fick2 OVm � ). FBF was derived from

1) NIRS and 2) strain-gauge plethysmography. Twenty-six healthy subjects were tested at rest and during sustained isometric handgrip exercise. Local variations were investigated with two independent and simultaneously operating NIRS systems at two different muscles and two measurement depths. 2OVm � increased more than fivefold in the

active flexor digitorum superficialis muscle, and it increased 1.6 times in the brachioradialis muscle. The average increase in ( )Fick2 OVm � was

twofold. FBF increased 1.4 times independent of the muscle or the method. It is concluded that NIRS is an appropriate tool to provide information about local 2OVm � and local FBF because both place and

depth of the NIRS measurements reveal local differences that are not detectable by the more established, but also more global, Fick method.

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NIRS PERFORMANCE IN HUMAN SKELETAL MUSCLE

� 33

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CHAPTER 2

� 34

R[LPHWU\�� DQG� SOHWK\VPRJUDSK\� DQG� ZKHWKHU� WKH� GHSWK� DQG� WKH� SODFH� RI� WKH� 1,56�

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MATERIALS AND METHODS

Subjects

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Near-infrared Spectroscopy (NIRS)

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NIRS PERFORMANCE IN HUMAN SKELETAL MUSCLE

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Blood sampling

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Protocol

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Page 37: PDF hosted at the Radboud Repository of the Radboud University Nijmegen · electromagnetic waves we can see. 19 Fig. 1 The electromagnetic spectrum. Both frequency and wavelength

CHAPTER 2

� 36

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NIRS PERFORMANCE IN HUMAN SKELETAL MUSCLE

� 37

Method NIRS NIRS NIRS Plethysmo

-graphy

POX Blood gas

analysis

Intervention Venous

occlusion

Arterial

occlusion

Venous

occlusion

Venous

occlusion

Arterial

pulse

Venous

samples

Variables: CaO2 CvO2

FBFNIRS FBFPleth (a-v)O2diff

( )VONIRS 2OVm �

( )AONIRS2OVm � ( )Fick2OVm �

Fig. 1. Protocol (A) and measurements (B) as performed by each subject. Venous and arterial occlusion (VO and AO, respectively) are applied at rest and during sustained isometric handgrip exercise at 10% of the subject’s maximal voluntary contraction force (10%MVC). BS = blood sample. See METHODS for a detailed description of the protocol. From this protocol, oxygen consumption was calculated with NIRS during VO

( ( )VONIRS2 OVm � ) and during AO ( ( )AONIRS2OVm � ). Forearm blood flow was calculated during

VO with NIRS (FBFNIRS) and with plethysmography (FBFPleth). Oxygen consumption

derived from Fick ( ( )Fick2OVm � ) was obtained by the combination of plethysmography,

pulse oximetry (POX) and blood sampling. CaO2 = arterial O2 content, CvO2 = venous O2 content, (a-v)O2diff = arterio-venous O2 difference.

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A

B

Rest 5 min Rec. 5 minRec. 5 min Rec. 3 minVO VOVOVORec. AO AORec. Rec. 10%MVC 10%MVC

BS

Wrist cuff Wrist cuff Wrist cuff

BS BS BS

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CHAPTER 2

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Table 1. Correlation between ATT and ( )AONIRS2OVm � in the FDS and BR

FDS IO35 FDS IO50 BR IO35

ATT (mm) 2.2 ± 0.8

(1.3-4.5)

2.2 ± 0.8

(1.3-4.5)

2.6 ± 0.5

(1.8-3.7)

Spearman r -0.13 0.11 -0.20

P 0.52 0.61 0.31

Values are mean ± SD (range) for adipose tissue thickness (ATT). Spearman correlation coefficient (r) and P values are given for the three

near-infrared spectroscopy (NIRS) local muscle O2 consumption ( 2OVm � )

measurements. FDS, flexor digitorum superficialis muscle; BR, brachio-radialis muscle; IO35 and IO50, interoptode distances of 35 and 50 mm, respectively.

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CHAPTER 2

� 40

Table 2. Reproducibility of 2OVm � and FBF during three consecutive venous occlusions

VO-1 VO-2 VO-3 Comparison P value CV (%)

( )VONIRS 2OVm � FDS IO35

n = 24

0.09 ± 0.04 0.08 ± 0.04 0.08 ± 0.04 Overall

VO-3 vs. VO-1

VO-3 vs. VO-2

VO-2 vs. VO-1

*

*

NS

**

P = 0.01

P < 0.05

P > 0.05

P < 0.01

30.6

FDS IO50

n = 20

0.08 ± 0.04 0.08 ± 0.04 0.07 ± 0.04 Overall NS 25.4

BR IO35

n = 26

0.14 ± 0.09 0.14 ± 0.11 0.13 ± 0.10 Overall NS 23.3

FBFNIRS FDS IO35

n = 25

0.76 ± 0.33 0.70 ± 0.39 0.71 ± 0.35 Overall NS 28.6

FDS IO50

n = 21

0.61 ± 0.28 0.59 ± 0.34 0.54 ± 0.28 Overall NS 30.3

BR IO35

n = 26

1.41 ± 1.01 1.40 ± 1.09 1.44 ± 1.11 Overall NS 20.4

FBFPleth n = 24 2.07 ± 0.86 2.01 ± 0.73 2.07 ± 0.71 Overall NS 16.7

Values are mean (±SD) for 2OVm � (mlO2⋅min-1⋅100g-1) and forearm blood flow (FBF; ml⋅min-1⋅100ml-1).

First, second, and third venous occlusions are represented by VO-1, VO-2, and VO-3, respectively. Number of subjects (n) varies due to missing values in either VO-1, VO-2 or VO-3. CV, coefficient of variation. *P ≤ 0.05; **P ≤ 0.01; NS, not significant.

NIRS 2OVm � measurements

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NIRS PERFORMANCE IN HUMAN SKELETAL MUSCLE

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Table 3. 2OVm � values measured by NIRS during arterial occlusion vs. venous occlusion

( )AONIRS2OVm � , ( )VONIRS2OVm � ,

mlO2⋅min-1⋅100g-1 mlO2⋅min-1⋅100g-1 P value

Rest FDS IO35 0.11 ± 0.03

FDS IO50 0.09 ± 0.03 0.08 ± 0.04 NS P = 0.04

BR IO35 0.13 ± 0.05 0.14 ± 0.10 NS P = 0.51

Exercise FDS IO35 0.58 ± 0.27 0.21 ± 0.12 ** P < 0.01

FDS IO50 0.55 ± 0.22 0.19 ± 0.10 ** P < 0.01

BR IO35 0.20 ± 0.09 0.24 ± 0.21 NS P = 0.30

Values are means ± SD; n = 22 for FDS IO35; n = 26 for FDS IO50 and BR IO35. No P value was

calculated for FDS IO35 at rest because ( )VONIRS2OVm � was not reproducible. ( )AONIRS2OVm � , 2OVm �

measured by arterial occlusion. To protect against a type I error, an α of 0.01 was chosen, **P ≤ 0.01.

Influence of depth

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CHAPTER 2

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Fig. 2. Average and SD for NIRS 2OVm � vs. NIRS FBF showing an increased 2OVm � in

the active flexor digitorum superficialis muscle (FDS) during isometric handgrip exercise with interoptode distances of 35 and 50 mm (IO35 and IO50, respectively) compared with the relative inactive brachioradialis muscle (BR). Circles represents resting values, and triangles represents values during exercise. Significant differences are shown in Table 4.

mVO2 (mlO2⋅min-1⋅100g-1)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

FB

F (

ml⋅ 1

00m

l-1⋅ m

in-1

)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

FDS IO35

FDS IO50

BR IO35

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NIRS PERFORMANCE IN HUMAN SKELETAL MUSCLE

� 43

Table 4. 2OVm � and FBF values at rest and during sustained isometric handgrip exercise at 10%

maximum voluntary contraction

2OVm � , mlO2⋅min-1⋅100g-1 FBF, ml⋅min-1⋅100ml-1

Rest Exercise Rest Exercise

NIRS FDS IO35 0.11 ± 0.03 0.59 ± 0.27 † 0.72 ± 0.32 0.98 ± 0.46 †

NIRS FDS IO50 0.09 ± 0.03 * 0.55 ± 0.22 † 0.57 ± 0.26 * 0.81 ± 0.47 *, †

NIRS BR IO35 0.13 ± 0.05 0.20 ± 0.09 *, † 1.42 ± 1.04 * 2.18 ± 1.98 *, †

Fick/pleth. 0.15 ± 0.06 * 0.30 ± 0.12 *, † 2.06 ± 0.70 * 2.98 ± 1.26 *, †

Values are means ± SD. *Significantly different (P ≤ 0.01) from FDS IO35; †significant difference

(P ≤ 0.01), rest vs. exercise.

DISCUSSION

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SUMMARY

The aim of this study was to investigate the performance of in vivo quantitative near-infrared spectroscopy (NIRS) in skeletal muscle at various workloads. NIRS was used for the quantitative measurement of O2 consumption ( 2OVm � ) in the human flexor digitorum superficialis

muscle at rest and during rhythmic isometric handgrip exercise in a broad range of work intensities (10-90% MVC = maximum voluntary contraction force). Six subjects were tested on three separate days. No significant differences were found in 2OVm � measured over different

days with the exception of the highest workload. The within-subject variability for each workload over the three measurements days ranged from 15.7 - 25.6% and did not increase at the high workloads. 2OVm �

was 0.14 ± 0.01 mlO2⋅min-1⋅100g-1 at rest and increased roughly 19 times to 2.68 ± 0.58 mlO2⋅min-1⋅100g-1 at 72% MVC. These results show that local muscle oxygen consumption at rest as well as during exercise at a broad range of work intensities can be measured reliably by NIRS, applied to a uniform selected subject population. This is of great importance since direct local measurement of 2OVm � during

exercise is not possible with the conventional techniques. The method is robust enough to measure over separate days and at various workloads and can, therefore, contribute to a better understanding of human physiology in both the normal and pathological state of the muscle.

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REPRODUCIBILITY OF NIRS DURING EXERCISE

� 51

INTRODUCTION

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CHAPTER 3

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MATERIALS AND METHODS

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REPRODUCIBILITY OF NIRS DURING EXERCISE

� 53

Near-infrared Spectroscopy (NIRS)

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CHAPTER 3

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Fig. 1. Raw NIRS signal during 1 min of rhythmic isometric handgrip exercise at 20% of the maximum voluntary contraction force (MVC) followed by 45 s of arterial occlusion. O2 consumption was calculated from the linear decrease in oxyhaemoglobin (O2Hb) immediately after the start of the occlusion and from the linear decrease in Hbdiff ([Hbdiff] = [O2Hb] – [HHb]) (not shown). The sum of [O2Hb] and [HHb] reflects the total amount of haemoglobin ([tHb]) and changes in tHb can be interpreted as changes in blood volume in the tissue.

700 720 740 760 780 800 820 840 860 880 900-50

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REPRODUCIBILITY OF NIRS DURING EXERCISE

� 57

Table 1. Mean (± SE) values for O2 consumption ( 2OVm � ) from Hbdiff at rest and during rhythmic

isometric handgrip exercise.

Rest 9% MVC 18% MVC 28% MVC 36% MVC 44% MVC 61% MVC 72% MVC

Day 1 0.14 ± 0.01 0.38 ± 0.07 0.84 ± 0.25 1.31 ± 0.44 1.52 ± 0.51 1.85 ± 0.63 2.45 ± 0.79 2.54 ± 0.73

Day 2 0.15 ± 0.02 0.43 ± 0.09 0.95 ± 0.23 1.48 ± 0.37 1.83 ± 0.43 2.16 ± 0.65 2.68 ± 0.71 3.13 ± 0.59

Day 3 0.15 ± 0.02 0.41 ± 0.07 0.88 ± 0.25 1.46 ± 0.45 1.97 ± 0.56 2.14 ± 0.68 2.36 ± 0.60 3.06 ± 0.59

Avg 0.15 ± 0.01 0.41 ± 0.07 0.89 ± 0.24 1.42 ± 0.41 1.77 ± 0.49 2.05 ± 0.64 2.50 ± 0.69 2.91 ± 0.63

P-value 0.99 0.32 0.34 0.49 0.10 0.24 0.49 0.02 *

day 1 < day 2 day 1 < day 3

CV (%) 17.6 16.3 21.1 23.2 23.0 20.3 20.0 20.6

2OVm � in mlO2⋅min-1⋅100g-1. MVC = maximal voluntary contraction force, CV = coefficient of variation, n

= 6. *P ≤ 0.05 for differences between the three days.

Table 2. Within-subject variability for 2OVm � from Hbdiff at rest and during isometric handgrip exercise at

9% and 72% of the maximal voluntary contraction force (MVC).

Rest 9% MVC 72% MVC

Subject I II III CV (%) I II III CV (%) I II III CV (%)

1 0.15 0.11 0.09 25.0 0.55 0.61 0.45 15.2 1.70 2.30 2.00 14.9

2 0.18 0.14 0.21 21.4 0.40 0.54 0.57 17.8 2.76 3.54 3.10 12.6

3 0.13 0.11 0.10 10.8 0.41 0.37 0.33 11.1 1.51 2.09 1.87 16.1

4 0.14 0.18 0.17 12.7 0.11 0.16 0.17 21.9 2.37 3.23 3.52 19.6

5 0.13 0.13 0.14 5.0 0.24 0.23 0.31 17.3 0.93 1.84 2.18 39.0

6 0.14 0.22 0.17 21.8 0.54 0.69 0.62 12.1 5.95 5.78 5.70 2.2

Avg 17.6 Avg 16.3 Avg 20.6

2OVm � in mlO2⋅min-1⋅100g-1. CV = coefficient of variation ((SD/mean)⋅100%), I = day 1, II = day 2, III = day 3.

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Fig. 3. Group mean (± SE) over three measurement days for muscle oxygen consumption

( 2OVm � ) values during arterial occlusion at rest and after isometric handgrip exercise at

various work intensities. Closed circles represent 2OVm � calculated from Hbdiff, open circles

represent 2OVm � calculated from O2Hb. *P ≤ 0.05, **P ≤ 0.01 and ***P ≤ 0.001 for differences

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CHAPTER 3

� 60

Table 3. Mean (± SE) values for resting O2 consumption ( 2OVm � ) from literature.

Method 2OVm �

Method 2OVm �

Holling 1939 Fick 0.11 De Blasi et al. 1992 NIRS 0.11 ± 0.02

Mottram 1955 Fick 0.23 ± 0.02 De Blasi et al. 1993 NIRS 0.05 ± 0.01

Hartling et al. 1989 Fick 0.14 ± 0.04 De Blasi et al. 1994 NIRS 0.10 ± 0.01

Van Beekvelt et al. 2001b Fick 0.15 ± 0.01 De Blasi et al. 1997 NIRS 0.06 ± 0.01

Wang et al. 1990 31P-MRS 0.17 Niwayama et al. 1999 NIRS 0.21 ± 0.01

Hamaoka et al. 1996 31P-MRS 0.16 ± 0.00 Van Beekvelt et al. 2001a NIRS 0.11 ± 0.01

Sako et al. 2001 31P-MRS 0.16 ± 0.00 Van Beekvelt et al. 2001b NIRS 0.11 ± 0.00

2OVm � data from various studies were converted to mlO2⋅min-1⋅100g-1 using 1.04 kg⋅L-1 for muscle

density and 22.4 L as the molar volume of gas assuming STPD conditions. 1 mol of O2 is assumed to synthesise 6 mol of ATP.

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REPRODUCIBILITY OF NIRS DURING EXERCISE

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CHAPTER 3

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SUMMARY

The influence of adipose tissue thickness (ATT) on in vivo near-infrared spectroscopy (NIRS) measurements was studied in the human flexor digitorum superficialis muscle at rest and during sustained isometric handgrip exercise. NIRS was used for the quantitative measurement of muscle O2 consumption ( 2OVm � ) and

forearm blood flow (FBF) in seventy-eight healthy subjects. Skinfold thickness ranged from 1.4 – 8.9 mm within the group. Resting 2OVm �

was 0.11 ± 0.04 mlO2⋅min-1⋅100g-1, and FBF was 1.28 ± 0.82 ml⋅100ml-1⋅min-1. There was a negative correlation (r = -0.70, P ≤ 0.01) indicating a decrease in 2OVm � with increasing ATT. 2OVm � in

the 10 leanest subjects appeared to be twice as high as that in the 10 subjects with the highest ATT. A poor correlation (r = 0.29, P ≤ 0.01) was found between ATT and FBF. The gender difference that we found for 2OVm � was due to the difference in ATT between female

and male subjects. No correlation was found between maximum voluntary contraction (MVC) force and 2OVm � nor between MVC and

ATT, indicating that the contraction force did not confound our results. These results show that ATT has a substantial confounding effect on in vivo NIRS measurements, and that it is essential to incorporate this factor into future NIRS muscle studies in order to justify comparisons between various groups. To facilitate such comparisons, upper and lower boundaries for normal values of 2OVm � and FBF in relation to

ATT are presented. �

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ADIPOSE TISSUE THICKNESS VERSUS NIRS

� 65

INTRODUCTION

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CHAPTER 4

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ADIPOSE TISSUE THICKNESS VERSUS NIRS

� 67

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CHAPTER 4

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Fig. 1 Distribution of ATT for the 78 subjects. ATT is defined as skinfold thickness / 2. Data from male and female subjects are presented as stacked bars.

ATT (mm)

0 1 2 3 4 5 6 7 8 9 10

Fre

quen

cy

0

2

4

6

8

10

12

14

16malefemale

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CHAPTER 4

� 70

Table 1. Reproducibility of NIRS FBF and 2OVm � measurements during three consecutive occlusions

I II III CV (%)

FBF (ml⋅min-1⋅100ml-1) 1.26 ± 0.88 1.23 ± 0.78 1.34 ± 0.96 22.4

2OVm � (mlO2⋅min-1⋅100g-1) 0.12 ± 0.05 0.11 ± 0.04 0.10 ± 0.04 16.2

FBF was measured during venous occlusion, and 2OVm � during arterial occlusion. Values are means

± SD, and the coefficient of variance (CV) is given in each case. The first, second, and third occlusion are represented by I, II, and III, respectively.

�Table 2. Correlation coefficients for the relationship between ATT and NIRS variables

ATT a b SE(a) SE(b) r P-value

Rest FBF 0.71 1.11 0.24 0.43 0.29 *

Rest 2OVm � 0.18 -0.14 0.02 0.01 -0.70 **

10% MVC 2OVm � 0.71 -0.54 0.10 0.18 -0.33 **

20% MVC 2OVm � 1.20 -0.99 0.14 0.26 -0.41 **

30% MVC 2OVm � 1.43 -1.18 0.19 0.36 -0.36 **

The relationship is defined by the equation: FBF or 2OVm � = a + b*log(ATT). Calculated values are

given for all variables; a, b, standard error (SE) of a and b, and r. *P ≤ 0.05; **P ≤ 0.01.

Table 3. Values for 2OVm � and FBF at rest and during sustained isometric handgrip exercise for

female and male subjects separately

Female (33) Male (44) P-value

Rest FBF 1.46 ± 0.74 1.14 ± 0.86 0.159

Rest 2OVm � 0.08 ± 0.03 0.13 ± 0.03 **

10% MVC 2OVm � 0.31 ± 0.18 ## 0.53 ± 0.41 ## **

20% MVC 2OVm � 0.48 ± 0.33 ## 0.87 ± 0.54 ## **

30% MVC 2OVm � 0.52 ± 0.40 1.07 ± 0.75 ## **

2OVm � values are given in mlO2⋅min-1⋅100g-1, and FBF values in ml⋅min-1⋅100ml-1. Values are means ±

SD. Significance of differences: **P ≤ 0.01 for male compared with female subjects; ##P ≤ 0.01 for

differences in 2OVm � between two consecutive workloads.

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ADIPOSE TISSUE THICKNESS VERSUS NIRS

� 71

Fig. 2 Correlation between log(ATT) and NIRS variables at rest. A) 2OVm � and B) FBF,

measured in 78 healthy subjects. Data from male (Ì) and female (Ä) subjects are shown separately.

Log(ATT)0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

mV

O2

(mlO

2⋅ min

-1⋅ 1

00g-1

)

0.00

0.05

0.10

0.15

0.20

0.25

ATT (mm)

1.0 1.3 1.6 2.0 2.5 3.2 4.0 5.0 6.3 7.9 10.0

Log(ATT)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

FB

F (

ml⋅ m

in-1

⋅ 100

ml-1

)

-1

0

1

2

3

4

5

6

ATT (mm)

1.0 1.3 1.6 2.0 2.5 3.2 4.0 5.0 6.3 7.9 10.0

FBF = 0.71 - 1.11*log(ATT)

r = 0.29

P = 0.01

mVO2 = 0.18 - 0.14*log(ATT)

r = -0.70

P ≤ 0.01

B

A

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CHAPTER 4

� 72

DISCUSSION

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ADIPOSE TISSUE THICKNESS VERSUS NIRS

� 73

Fig. 3 Simplified schematic presentation of NIRS light penetration in relation to ATT (+skin) and muscle tissue in our subject with the greatest ATT (8.9 mm) and in our leanest subject (ATT = 1.4 mm). The model does not take into account the different light-scattering properties of fat and muscle. The light travels in a 'banana shape' form from source to detector [Cui et al. 1991], and the maximum penetration depth is roughly half the interoptode distance. Approximately 49% of the measurement depth (17.5 mm) in our subject with the largest ATT comprises muscle tissue, while this value was 92% for our leanest subject.

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depth(17.5 mm)

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ATT (+ skin)

Light in Light out

ATT = 8.9 mm

ATT (+ skin)

Muscle

Light in Light out

ATT = 1.4 mm

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CHAPTER 4

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ADIPOSE TISSUE THICKNESS VERSUS NIRS

� 75

Fig. 4 Combined data supporting the confounding effect of ATT on NIRS 2OVm �

measurements. Data from the present study (black circles) are shown, along with data

from other studies in our laboratory (n=27; grey circles) and from Binzoni et al. 1998 (É),

Yamamoto et al. 1999 (*), and Niwayama et al. 1998 (Å). All data are presented in units

of mlO2⋅min-1⋅100g-1, except the data from Yamamoto et al. 1999, which are presented in

∆OD[O2Hb](min-1), where OD represents absorbance. �

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CHAPTER 4

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SUMMARY

Near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy (31P-MRS) have been used in this study as complementary methods for the investigation of in vivo skeletal muscle metabolism, measured simultaneously and within the same volume of interest. In order to investigate the differences and similarities between both techniques, we studied muscle function in normal controls and a group of Friedreich ataxia (FRDA) patients in which mitochondrial function is thought to be impaired. Eleven healthy subjects and fifteen FRDA patients were tested during 2 phases of 3 min aerobic and ischemic isometric exercise and subsequent recovery. Immediately after the start of both exercise phases, a rapid deoxygenation and depletion of phosphocreatine (PCr) was found, accompanied by a moderate increase in the intracellular pH (pHi). Subsequently, pHi decreased indicating lactic acid formation during anaerobic glycolysis, while the rate of deoxygenation and PCr depletion slowed down. The results show that oxidative phosphorylation during exercise was present, even during ischemia when O2 stores were thought to be depleted. Similar responses in NIRS and 31P-MRS were found for FRDA patients and controls. Although PCr recovery after cessation of exercise was significantly delayed in FRDA, NIRS showed no indication for an impaired oxygen consumption. Our data are suggestive for either partial uncoupling of the electron-transport chain or reduced ATP synthesis at the level of complex V (ATPsynthase), the adenine nucleotide translocator (ANT), or mitochondrial creatine kinase. The results of this study demonstrated the additional value of NIRS in the complementary use with 31P-MRS for the investigation of in vivo muscle metabolism enabling both oxidative and anaerobic processes to be measured noninvasively and simultaneously within the same muscle area.

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NIRS AND MRS

� 79

INTRODUCTION

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CHAPTER 5

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NIRS AND MRS

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CHAPTER 5

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NIRS AND MRS

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Fig. 1. Individual, simultaneously measured signals for near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy (31P-MRS) during aerobic and ischemic exercise and its recovery in a healthy volunteer. A) NIRS. Oxyhemoglobin (O2Hb), deoxyhaemoglobin (HHb), and total haemoglobin (tHb) signals measured at 20 Hz and displayed real-time on screen. B) 31P-MRS. Simultaneously measured phosphocreatine (PCr) tracing at 0.1 Hz. The grey bar represents the periods of sustained isometric exercise at 30% of the individual maximum voluntary contraction force (MVC). The black bar represents the period of arterial occlusion.

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CHAPTER 5

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NIRS AND MRS

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Fig. 3. Mean (±SD) values for NIRS and 31P-MRS tracings in Friedreich ataxia (FRDA) patients and healthy controls. A) O2Hb signals, B) PCr signals, and C) intracellular pH (pHi). The grey bar represents the periods of sustained isometric exercise at 30% MVC. The black bar represents the period of arterial occlusion.

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NIRS AND MRS

� 87

Table 1. Mean (± SD) values for phosphorus magnetic resonance spectroscopy (31P-MRS) and near-infrared spectroscopy (NIRS) variables in Friedreich ataxia (FRDA) and healthy controls.

Healthy subjects (11) FRDA patients (15)

Mean ± SD Range Mean ± SD Range P-value

Initial values

Pre-exercise intracellular pH 7.02 ± 0.03 6.96-7.11 7.01 ± 0.03 6.96-7.06 0.44

End-occlusion O2Hb deoxygenation (µM) -17.9 ± 4.9 -23.9 - -7.5 -15.7 ± 9.3 -38.0 - -5.9 0.45

2OVm � during AO (mlO2⋅min-1⋅100g-1) 0.05 ± 0.02

(10)

0.02-0.07 0.05 ± 0.04

(14)

0.01-0.14 0.85

Aerobic exercise

2OVm � (mlO2⋅min-1⋅100g-1) 0.26 ± 0.18

(10)

0.10-0.57 0.27 ± 0.33

(8)

0.03-1.04 0.92

End-exercise O2Hb deoxygenation (µM) -25.1 ± 13.3 -46.8-3.3 -20.7 ± 14.1 -51.9-1.3 0.44

End-exercise [PCr] (%[PCr]) 75.8 ± 10.7 59.6-90.4 74.4 ± 14.7 45.3-92.6 0.78

End-exercise pH 6.98 ± 0.09 6.77-7.08 6.97 ± 0.05 6.86-7.05 0.90

τ-value of O2Hb recovery (s) 29.9 ± 23.2 6.1-73.5 22.7 ± 5.8 13.9-33.1 0.36

τ-value of PCr recovery (s) 52.6 + 22.5 19.5-94.3 82.6 + 40.8 39.8-178.6 0.04

Ischemic exercise

2OVm � (mlO2⋅min-1⋅100g-1) 0.16 ± 0.09

(7)

0.05-0.29 0.17 ± 0.14

(7)

0.04-0.44 0.96

End-exercise O2Hb deoxygenation (µM) -37.4 ± 9.6 -59.5-15.4 -32.5 ± 18.6 -64.6-8.5 0.44

End-exercise [PCr] (%[PCr]) 61.0 ± 15.7 29.7-79.7 66.3 ± 18.7 20.3-98.0 0.45

End-exercise pH 6.94 ± 0.08 6.77-7.00 6.93 ± 0.06 6.79-7.01 0.90

τ-value of O2Hb recovery (s) 41.7 ± 28.2 17.2-116.3 30.6 ± 13.3 10.1-52.1 0.25

τ-value of PCr recovery (s) 57.1 ± 25.2 26.0-105.3 86.3 ± 28.6 46.7-161.3 0.01

2OVm � = muscle oxygen consumption, AO = arterial occlusion, O2Hb = oxyhaemoglobin, PCr =

phosphocreatine, (n) = number of subjects included in calculation. P ≤ 0.05 is considered statistically significant.

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CHAPTER 5

� 88

DISCUSSION

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Fig. 4. Strongly simplified scheme of the pathway of oxidative phosphorylation (OXPHOS) from blood born substrates to adenosine triphosphate (ATP) with a final role for oxygen at complex IV. The respiratory chain is presented by the roman-numbered squares, existing of five complexes. Electrons (e-) are transported from complex I to complex IV where they are adopted by O2 to form H2O. ATP then, is formed from adenosine diphosphate (ADP) by complex V, (ATPsynthase). Subsequently, phosphocreatine (PCr) can be resynthesised from creatine (Cr) by the adenine nucleotide translocator (ANT) and mitochondrial creatine kinase (CKm). MO; mitochondrial outer membrane, MI; mitochondrial inner membrane.

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Capillaries

Muscle cell

Glycolysis overall:

glucose + 2NAD + 2ADP + 2Pi → 2pyruvate + 2ATP + 2NADH

Glycolysis, citric acid cycle, and respiratory chain overall:

glucose +6O2 + 36Pi + 36ADP → 6CO2 + 36ATP + 42H2O

Fatty acid oxidation, citric acid cycle, and respiratory chain overall:

palmitate(C16) + 23O2 + 129Pi + 129ADP → 16 CO2 + 145H2O + 129ATP

MitochondriaCitric acidcycle

AcetylCoA

NADH

FADH2

Respiratory chain and OXPHOS (complex I-V)

e-

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O2 ADP

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CHAPTER 5

� 92

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OUTLINE

Introduction Methods Subject population Quantitative NIRS measurements

Oxygen consumption Blood flow Venous oxygen saturation Half-recovery time Reoxygenation rate

Conclusion

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QUANTITATIVE NIRS VARIABLES

� 95

INTRODUCTION

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CHAPTER 6

� 96

METHODS

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QUANTITATIVE NIRS VARIABLES

� 97

Fig. 1 Distribution and mean (±SD) values for the physical characteristics of the 139 healthy volunteers. Distribution is plotted as bars, mean as straight lines, and standard deviation as dotted lines. The median, instead of mean, is shown when distribution failed normality. Male (black bars) and female (white bars) subjects are presented separately. A) Distribution of age with median. B) Distribution of height with mean ± SD. C)

Distribution of weight with mean ± SD. D) Distribution of arm circumference with mean ± SD. E) Distribution of adipose tissue thickness (ATT) with median. F) Distribution of maximal voluntary contraction force (MVC) with mean ± SD.

MVC (N)

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n = 139 n = 138

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CHAPTER 6

� 98

Fig. 2 Real-time NIRS tracings of oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb), and total haemoglobin (tHb) in response to 20 s of venous occlusion (VO) and 45 s of arterial occlusion (AO). Note that recovery after VO is very rapid while recovery from AO takes more than two minutes.

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QUANTITATIVE NIRS VARIABLES

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Table 1. Quantitative NIRS variables in healthy subjects at rest

NIRS variable Normality Mean ± SD Median n P25 P75

Venous occlusion

Forearm blood flow (ml⋅min-1⋅100ml-1) No - 0.88 104 0.63 1.35

Venous saturation (%) Yes 59 ± 20 - 23 46 72

Oxygen consumption (mlO2⋅min-1⋅100g-1) Yes 0.12 ± 0.06 - 24 0.08 0.15

Arterial occlusion

Oxygen consumption (mlO2⋅min-1⋅100g-1) Yes 0.11 ± 0.04 - 138 0.08 0.14

Reoxygenation rate (µM⋅s-1) Yes 2.0 ± 1.0 - 33 1.3 2.8

Half-recovery time O2Hb (s) No - 3.8 33 3.4 4.8

Half-recovery time HHb (s) No - 6.7 34 5.5 7.9

Half-recovery time tHb (s) Yes 1.4 ± 0.8 - 29 1.0 1.8

Values are measured in the flexor digitorum superficialis muscle with an interoptode distance of 35 mm. Group values were tested for normality with the Kolmogorov-Smirnov test. SD: standard deviation, n: number of subjects, P25: 25th percentile, P75: 75th percentile.

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Table 2. Within-subject variability of in vivo quantitative NIRS variables in healthy subjects at rest

NIRS variable CV (%) nCV

Venous occlusion

Forearm blood flow (ml⋅min-1⋅100ml-1) 25.2 103

Venous saturation (%) 37.7 21

Oxygen consumption (mlO2⋅min-1⋅100g-1) 33.5 104

Arterial occlusion

Oxygen consumption (mlO2⋅min-1⋅100g-1) 16.3 83

Reoxygenation rate (µM⋅s-1) 23.4 6

Half-recovery time O2Hb (s) 16.9 6

Half-recovery time HHb (s) 16.1 6

Half-recovery time tHb (s) 53.9 6

CV: coefficient of variation, indicating the within-subject variability derived from repeated measurements. nCV: number of subjects in calculation of CV.

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QUANTITATIVE NIRS VARIABLES

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Table 3. Resting quantitative NIRS muscle oxygen consumption (in mlO2⋅min-1⋅100g-1) from literature.

Authors DPF IO Method Analysis Muscle n Mean ± SD

Van Beekvelt et al. 2002b 4.0 35 AO O2Hb FDS 6 0.14 ± 0.02

4.0 35 AO Hbdiff FDS 6 0.15 ± 0.03

Van Beekvelt et al. 2001a 4.0 35 AO Hbdiff FDS 78 0.11 ± 0.04

Van Beekvelt et al. 2001b 4.0 35 AO Hbdiff FDS 26 0.11 ± 0.03

4.0 50 AO Hbdiff FDS 26 0.09 ± 0.03

4.0 35 AO Hbdiff BR 26 0.13 ± 0.03

4.0 50 VO HHb FDS 26 0.08 ± 0.04

4.0 35 VO HHb BR 26 0.14 ± 0.10

Kragelj et al. 2000* ? 40 AO O2Hb Foot 6 0.08 ± 0.01

Van Beekvelt et al. 1999 4.0 35 AO O2Hb FDS 27 0.11 ± 0.03

Paunescu et al. 1999 ? 20-35 VO HHb GASTR 8 0.10

Niwayama et al. 1999 ? 30 AO O2Hb Forearm 15 0.12 ± 0.05

? 30 AO O2Hb Forearm 15 0.21 ± 0.03

Binzoni et al. 1998* 5.0 30 AO O2Hb GASTR 8 0.08 ± 0.05

5.0 30 AO O2Hb GASTR 8 0.16

5.0 30 AO O2Hb GASTR 8 0.04

De Blasi et al. 1997* 4.16 35 VO Hbdiff BR 10 0.07 ± 0.02

4.16 35 AO Hbdiff BR 10 0.06 ± 0.02

Colier et al. 1995* 4.3 45 AO O2Hb SOL 11 0.06 ± 0.03

De Blasi et al. 1994* 4.3 30-40 VO HHb BR 11 0.10 ± 0.03

De Blasi et al. 1993* 3.1-5.1 28-32 AO Hbdiff BR day 1 7 0.03 ± 0.01

3.1-5.1 28-32 AO Hbdiff BR day 2 0.05 ± 0.02

De Blasi et al. 1992* 3.59 30-35 AO Hbdiff BR 6 0.11 ± 0.06

Cheatle et al. 1991 5.4 30-50 AO O2Hb Calf 21 0.20

DPF: differential path-length factor, IO: interoptode distance in mm, AO: arterial occlusion, VO: venous occlusion, FDS: flexor digitorum superficialis muscle, BR: brachioradialis muscle, GASTR: gastrocnemius muscle, SOL: soleus muscle, n: number of subjects, ?: no data available. Values from studies marked with * are converted to mlO2⋅min-1⋅100g-1.

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Fig. 3 Muscle oxygen consumption ( 2OVm � ) in the flexor digitorum superficialis muscle,

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QUANTITATIVE NIRS VARIABLES

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Table 4. Forearm oxygen consumption measured by other methods.

Authors Method Flow measurement Localisation n Mean ± SD

Van Beekvelt et al. 2001b Fick Plethysmography Forearm 26 0.15 ± 0.06

Sako et al. 2001* 31P-MRS - FDS 12 0.16 ± 0.02

Hamaoka et al. 1996* 31P-MRS - FDS 5 0.16

Wang et al. 1990* 31P-MRS - Forearm 1 0.17

Hartling et al. 1989* Fick Dye dilution Forearm 5 0.14 ± 0.09

Wahren 1966 Fick Plethysmography Forearm 10 0.30 ± 0.09

Andres et al. 1956 Fick Dye dilution Forearm 8 0.26 ± 0.08

Mottram 1955 Fick Plethysmography Forearm 16 0.23 ± 0.07

Holling 1939* Fick Plethysmography Forearm 34 0.11

Mean (± SD) forearm oxygen consumption in mlO2⋅min-1⋅100g-1. Fick oxygen consumption is derived from the arteriovenous O2 difference (derived by blood gas analysis) times blood flow. 31P-MRS: phosphorus magnetic resonance spectroscopy, FDS: flexor digitorum superficialis muscle, n: number of subjects. Values from studies marked with * are converted to mlO2⋅min-1⋅100g-1.

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QUANTITATIVE NIRS VARIABLES

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Table 5. Resting quantitative NIRS blood flow values (in ml⋅min-1⋅100ml-1) from literature.

Authors DPF IO Muscle n Mean ± SD

Van Beekvelt et al. 2001a 4.0 35 FDS 78 1.28 ± 0.82

Van Beekvelt et al. 2001b 4.0 35 FDS 26 0.72 ± 0.32

4.0 50 FDS 26 0.57 ± 0.26

4.0 35 BR 26 1.42 ± 1.04

Van Beekvelt et al. 1999 4.0 35 FDS 27 0.72 ± 0.33

Paunescu et al. 1999 ? 20-35 GASTR 8 0.73

De Blasi et al. 1994 4.3 30-40 BR 11 1.9 ± 0.8

Edwards et al. 1993 # $ 3.59 Through Forearm 6 2.35 ± 1.11

DPF: differential path-length factor, IO: interoptode distance in mm, FDS: flexor digitorum superficialis muscle, BR: brachioradialis muscle, GASTR: gastrocnemius muscle, n: number of subjects, ?: no data available. # Blood flow measured by intravenous tracer instead of venous occlusion method. $ light detection through the arm instead of parallel optode placement.

Table 6. Forearm blood flow measured by other methods.

Authors Method Localisation n Mean ± SD

Van Beekvelt et al. 2001b Plethysmography Forearm 26 2.1 ± 0.7

De Blasi et al. 1994 Plethysmography Forearm 11 3.4 ± 1.3

Edwards et al. 1993* Plethysmography Forearm 7 2.2 ± 1.1

Hartling et al. 1989 Dye dilution Forearm 5 3.6 ± 2.2

Wahren 1966 Plethysmography Forearm 10 3.8 ± 1.1

Andres et al. 1956 Dye dilution Forearm 14 3.6

Mottram 1955 Plethysmography Total forearm 16 3.2

Estimation Forearm muscle 16 2.9

Mean (± SD) blood flow in ml⋅min-1⋅100ml-1. n: number of subjects. Values from studies marked with *

are converted to mlO2⋅min-1⋅100g-1.

Fig. 4 Forearm blood flow (FBF) in the flexor digitorum superficialis muscle, A) calculated during venous occlusion. B) distribution of individual values. The straight line represents the median.

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CHAPTER 6

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QUANTITATIVE NIRS VARIABLES

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Table 7. Resting quantitative NIRS venous oxygen saturation (in %) from literature.

NIRS Co-oximeter

Authors n Localisation Median Range Median Range

Yoxall et al. 1997 19 adults Forearm 71.3 50.1 – 80.0 71.9 50.4 – 92.0

Yoxall et al. 1996 16 infants Forearm 71.6 50.7 – 79.7 75.9 60.8 – 90.7

n: number of subjects.

Fig. 5 Venous oxygen saturation (SvO2) in the flexor digitorum superficialis muscle, A) calculated during venous occlusion. B) distribution of individual values. Mean is presented as a straight line, SD as dotted lines.

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QUANTITATIVE NIRS VARIABLES

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Fig. 6 Half-time recovery, calculated as A) the time needed for half recovery of O2Hb from maximum deoxygenation at the end of arterial occlusion or exercise to maximum re-oxygenation during hyperaemia, and B) the tau value derived from a mono-exponential curve-fit of O2Hb recovery after exercise as is standard for calculation of PCr resynthesis with 31P-MRS.

�Table 8. Half-recovery time (s) after exercise from literature.

Authors Exercise protocol Muscle n Mean ± SD

McCully et al. 1994a Submax PF, incremental, 5 min GASTR 5 28 ± 6

Max PF, 64 s GASTR 5 29 ± 6

McCully et al. 1994b PF, 3.4-9.1 kg, 1 min GASTR 6 22 ± 9

Chance et al. 1992 100% MVC QUADRI 7 36 ± 4

n: number of subjects, PF: plantar flexion, GASTR: gastrocnemius muscle, QUADRI: quadriceps muscle.

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Fig. 7 A) Calculation of half-recovery time (t50) in the flexor digitorum superficialis muscle, after cessation of arterial occlusion at rest. Distribution (bars), mean (straight line), and SD (dotted lines) for half-recovery time of B) oxyhaemoglobin (O2Hb), C) deoxyhaemoglobin (HHb), and D) total haemoglobin (tHb).

t50(tHb) (s)

0 1 2 3 4 5

Fre

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0

1

2

3

4

5

6

t50(HHb) (s)

0 5 10 15 20

Fre

quen

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0

2

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6

8

10DC

n = 34 n = 29

Time (s)

0 25 50 75 100 125 150

Con

c. c

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-20

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t50(O2Hb) (s)

0 3 6 9 12 15

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0

2

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n = 33

A

O2Hb

HHb

tHb

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QUANTITATIVE NIRS VARIABLES

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CHAPTER 6

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QUANTITATIVE NIRS VARIABLES

� 113

Fig. 8 Rate of reoxygenation (∆O2Hb) in the flexor digitorum superficialis muscle, calculated immediately after cessation of arterial occlusion at rest. A) Concentration changes of oxyhaemoglobin (O2Hb). B) Distribution, mean (straight line), and SD (dotted lines) for the individual values.

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CHAPTER 7

� 118

NIRS IN NEUROMUSCULAR METABOLIC DISORDERS

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CLINICAL APPLICATIONS

� 119

�Table 1. Near-infrared spectroscopy in metabolic/mitochondrial myopathies.

Authors n Patients

Bank et al. 1994 1 Cytochrome c oxidase deficiency

3 Myophosphorylase deficiency (McArdle)

3 Phosphofructokinase deficiency

2 Carnitine palmitoyl transferase deficiency

Bank et al. 1995 2 Cytochrome c oxidase deficiency

3 Myophosphorylase deficiency (McArdle)

3 Phosphofructokinase deficiency

Abe et al. 1997 3 Chronic progressive external ophthalmoplegia (CPEO)

1 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like

episodes (MELAS)

Gellerich et al. 1998 1 Exercise induced myalgia

1 Proximal weakness + pseudohypertrophy

1 External ophthalmoplegia

Wariar et al. 2000 1 Coenzyme Q10 deficiency

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CHAPTER 7

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CLINICAL APPLICATIONS

� 121

MITOCHONDRIAL MYOPATHIES

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Fig. 1. Strongly simplified scheme of the pathway of oxidative phosphorylation (OXPHOS) from blood born substrates to adenosine triphosphate (ATP). The respiratory chain is presented by the roman-numbered squares, existing of five complexes. Electrons are transported from complex I to complex IV where they are adopted by O2 to form H2O. ATP then, is formed from adenosine diphosphate (ADP) by complex V, (ATPsynthase). Subsequently, phosphocreatine (PCr) can be resynthesised from creatine (Cr) by the adenine nucleotide translocator (ANT) and mitochondrial creatine kinase (CKm). MO; mitochondrial outer membrane, MI; mitochondrial inner membrane.

Capillaries

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CHAPTER 7

� 122

Neuromuscular disorders

Chronic Progressive External Ophthalmoplegia (CPEO):

CPEO is the most frequent form of adult mitochondrial myopathies. Ptosis and external

ophthalmoplegia are usually the first clinical signs because mitochondrial volume of the extraocular

muscles is several times greater than that of other skeletal muscle. Bindoff et al. 1997: in addition to

ophthalmoplegia, most patients have mild proximal myopathy. Patients might have pigmentary

retinopathy, ataxia, sensory neural deafness, mild pyramidal or extrapyramidal features. The onset

might be as late as the fifth or sixth decade. Muscle biopsy shows cytochrome oxidase (COX)

negative fibres and ragged red fibres (RRF). Mitochondrial DNA (mtDNA) analysis will show a single

large scale rearrangement in approximately 50% (sporadic cases). In a significant proportion of the

other patients, point mutations of mtDNA can be defined.

Dermatomyositis:

Dermatomyositis is an inflammatory muscle disease with the identifying clinical features of erythema

of the skin in combination with muscle weakness and pain (Engel et al. 1990). It is a multisystem

disorder that can occur at any age from infancy to late adult onset. Apart from skin and muscle,

dermatomyositis is associated with many other organs and systems (e.g. heart and lungs) as well as

with malignancy (Hill et al. 2001). The cause of dermatomyositis is still unknown, but a strong

indication for autoimmune mechanisms exists (Dalakas 1998). Dermatomyositis is characterised by

complement mediated capillary necrosis, resulting in ischemia and hypoperfusion. The pathological

features consist of a decreased number of capillaries per muscle fibre and necrosis of single muscle

fibres or clusters of fibres at the periphery of the fasciculi (Engel et al. 1990). Although the mechanism

is not completely understood, it is thought that the muscle fibre injury could be secondary to ischemia

caused by the decrease in capillary density. Muscle fibre regeneration and an increased number of

capillaries were shown after intravenous immune globulin treatment (Dalakas et al. 1993), but

corticosteroids are still considered to be the first line of therapy.

Friedreich ataxia:

Friedreich ataxia (FRDA) is a progressive degeneration of the dorsal root ganglia, spinocerebellar

tracts, corticospinal tracts and Purkinje cells of the cerebellum. It is characterised by a gradual loss of

coordination, usually the earliest and most prominent characteristic of the disease. Increasing

impairment of balance and movement eventually lead to the loss of the ability to walk. It is also

associated with cardiomyopathy. Friedreich Ataxia is an autosomal recessive neurodegenerative

disorder characterised by an expanded (GAA)n trinucleotide repeat in intron 1 of the frataxin gene on

chromosome 9q13 (Campuzano et al. 1996). It is the most common hereditary ataxia occurring with a

frequency of 1 in 50 000 in the Caucasian population. Frataxin is associated with the inner membrane

of the mitochondria, and mutations in the frataxin gene are thought to lead to impaired mitochondrial

function. The actual function of Frataxin remains to be elucidated.

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CLINICAL APPLICATIONS

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SUMMARY

Five patients with chronic progressive external ophthalmoplegia (CPEO) and 27 healthy controls were examined by near-infrared spectroscopy (NIRS) for the noninvasive and direct quantitative measurement of muscle oxygen consumption and forearm blood flow. NIRS measurements were obtained at rest and during static isometric handgrip exercise at 10% of the maximum voluntary contraction (MVC) force. A significantly decreased oxygen consumption at rest as well as during exercise was found in patients with CPEO. Our results suggest that NIRS is able to discriminate between CPEO patients and healthy controls, which makes NIRS a valuable tool in the diagnostic workup of patients suspected to have a mitochondrial myopathy.

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NIRS IN CPEO

� 127

INTRODUCTION

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CHAPTER 8

� 128

�Table. Clinical characteristics of patients with sporadic chronic progressive external ophthalmoplegia

No Sex/age

(yr)

MVC

(N)

Disease

duration

(yr)

Fatiguea Prox. Muscle

Strength

(MRC)

Modified

Rankin

scaleb

Muscle

Biopsy

RRFc

Serum

lactated

(µmol/L)

1 M/54 132 28 - 4/5 2 + 1520

2 M/19 262 3 + 5/5 2 ++ 1586

3 F/36 168 4 - 5/5 2 ++ 1288

4 F/42 153 22 +++ 3/5 3 ++ 844

5 F/54 100 27 ++ 3/5 3 + 2660

a : - = not present; + = mild; ++ = moderate; +++ = severe b : Modified Rankin scale described by Swieten et al. [van Swieten et al. 1988] c : RRF = ragged red fibres; + = present; ++ = abundant d : Normal values: < 1700 µmol/L M = male; F = female; MVC = maximal voluntary contraction force; MRC = medical research council �

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RESULTS

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NIRS IN CPEO

� 129

Fig. 1. Representative raw NIRS data as displayed real time on screen. Oxyhemoglobin (O2Hb), deoxyhaemoglobin (HHb), and the sum of O2Hb and HHb, reflecting total haemoglobin (tHb), are shown during A) arterial occlusion (240 mmHg) and B) venous occlusion (50 mmHg). Oxygen consumption is calculated during arterial occlusion as the rate of decrease in O2Hb indicated by the straight line in Fig. A. Forearm blood flow is calculated during venous occlusion as the rate of increase in tHb indicated by the straight line in Fig. B.

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-15

-10

-5

0

5

10

15

Arterial Occlusion

∆Hb

(uM

)

540 560 580 600 620 640 660Time [s]

HHb

O2Hb

tHb

A

-10

-5

0

5

10

Venous Occlusion

∆Hb

(uM

)

320 330 340 350 360 370Time [s]

15

tHb

HHb

O2Hb

B

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CHAPTER 8

� 130

Fig. 2. Near infrared spectroscopy values for muscle oxygen consumption ( 2OVm � ) and

forearm blood flow (FBF) in patients with chronic progressive external ophthalmoplegia (CPEO) and healthy control subjects A) at rest and B) during static isometric handgrip exercise at 10% of the subject’s maximum voluntary contraction force (MVC). Individual

values of 2OVm � and FBF are shown for the patients with CPEO. Mean ± SD in both

directions are shown for the control group.

DISCUSSION

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Rest

mVO2 (mlO2⋅min-1⋅100g-1)

0.00 0.05 0.10 0.15

FB

F (

ml ⋅m

in-1

⋅100

ml-1

)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

CPEO

Controls

1

3

4

5 2

AExercise

mVO2 (mlO2⋅min-1⋅100g-1)

0.0 0.2 0.4 0.6 0.8 1.0F

BF

(m

l ⋅min

-1⋅1

00m

l-1)

0.0

1.0

2.0

3.0

4.0

5.0 CPEOControls

41

23

5

B

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NIRS IN CPEO

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POSTSCRIPTUM:

NEAR-INFRARED SPECTROSCOPY IN CPEO: ADIPOSE TISSUE

THICKNESS CONFOUNDS DECREASED MUSCLE OXYGEN CONSUMPTION

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CHAPTER 8

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rest, measured in 78 healthy controls and 5 CPEO patients. The straight lines represent regression line and 95% confidential interval.

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SUMMARY

Near-infrared spectroscopy (NIRS) is a direct, noninvasive optical method for the measurement of local oxygenation and haemodynamics in muscle tissue. Although it has recently been used for diagnosis of metabolic myopathies, it has until now never been used in inflammatory myopathies. Because dermatomyositis is a muscle disorder characterised by complement mediated capillary necrosis, resulting in ischemia and hypoperfusion, we have used NIRS to study the effect of corticosteroid treatment in dermatomyositis. Clinical improvement correlated with NIRS, showing an increase in local muscle oxygen consumption and reoxygenation rate, indicating normalisation of microvascular function. This study shows that NIRS is able to detect therapy effect; direct, noninvasively, and with relative ease.

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NIRS IN DERMATOMYOSITIS

� 135

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CHAPTER 9

136

Fig. 1 NIRS oxyhaemoglobin (O2Hb) and deoxyhaemoglobin (HHb) signal during exercise

and occlusion. Muscle oxygen consumption ( 2OVm � ) is calculated from the initial rate of

linear increase in HHb during arterial occlusion. Reoxygenation rate (∆O2Hb) is determined as the rate of increase in O2Hb over the initial 3 s after cessation of arterial occlusion.

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NIRS IN DERMATOMYOSITIS

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consumption ( 2OVm � ) and B) reoxygenation rate (∆O2Hb) measured noninvasively by

NIRS at rest and following exercise at various levels of the maximum voluntary contraction force (MVC). Mean ± SD values are shown for the controls

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OUTLINE

Thesis objectives Methodological considerations

Nature of signal Path-length factor Haemoglobin vs. myoglobin Skinfold thickness Venous vs. arterial occlusion method Increase tHb during arterial occlusion

Clinical considerations Sensitivity/specificity Quantitative measurement Clinical applicability

Future perspectives Bio-energetic characterisation Effect of therapy Multi-channel NIRS Pathophysiology of myopathies

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SUMMARY AND FUTURE PERSPECTIVES

� 141

THESIS OBJECTIVES

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CHAPTER 10

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SUMMARY AND FUTURE PERSPECTIVES

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CHAPTER 10

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SUMMARY AND FUTURE PERSPECTIVES

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This thesis is financially supported by:

Biomedical Engineering Department University Medical Centre Nijmegen.

The Biomedical Engineering Department specifies, designs and builds dedicated measurement devices for medical scientific research and is specialized in transforming research questions into technical solutions. The Oxymon system is an example of one of our sophisticated projects. Oxymon has enabled many scientists to perform leading research in the area of Near Infra Red Spectroscopy.

Characteristics The Biomedical Engineering Department is ISO 9001 certified and combines employees with different technical specialisms:

• Electronics

• Data acquisition software

• (fine) Mechanics

• Optics In case specific capacities are required we fall back on our network of sub-suppliers.

For any further information please contact: Biomedical Engineering Department tel: +31 (0)24 3614860 UMCN 171 Instrumentele Dienst fax: +31 (0) 24 354 1211 POBOX 9101 6500 HB Nijmegen E-mail: [email protected] The Netherlands Web-site: http://www.kun.nl/id

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