M. Ferrari and V. Quaresima, J. Near Infrared Spectrosc. 20, 1–14 (2012)
Received: 27 July 2011 n Revised: 23 November 2011 n Accepted: 23 November 2011 n Publication: 31 January 2012

1

JOURNALOF
NEAR
INFRARED
SPECTROSCOPY
Special Issue on Medical Applications

Review

Near infrared brain and muscle oximetry:from the discovery to current applications
Marco Ferrari* and Valentina Quaresima
Department of Health Sciences, University of L’Aquila, L’Aquila, Italy. E-mail: marco.ferrari@univaq.it

In the early 1960s, Norris introduced near infrared (NIR) spectroscopy (700–2500 nm) as an analytical technique for agricultural products. In 1977, Jöbsis founded in vivo medical NIR spectroscopy, reporting that the relatively high degree of transparency of brain tissue
in the NIR spectral window (700–1000 nm) enables safe real-time non-invasive detection of regional haemoglobin oxygenation usingtrans-illumination spectroscopy. In order to place current medical NIR spectroscopy in its proper perspective, this review provides asnapshot of the roots of the discovery and the early years of medical NIR spectroscopy research and development. Starting in 1992, theopportunity of measuring quantitatively, by different NIR spectroscopy techniques, regional oxy-haemoglobin saturation by NIR oximetry, it is possible to monitor brain/muscle reserve capacity following tissue oxygen extraction in different pathophysiological conditions.
This review reports the status of the current commercial oximeters (including wireless instrumentation) and their main clinical andphysiological applications. In the last decade, NIR spectroscopy brain oximetry has obtained significant clinical relevance as suggestedby the more than 10,000 instruments sold and the high number of related scientific publications. The most relevant clinical applicationis represented by the evaluation of cerebral oxy-haemoglobin saturation during adult cardiac surgery and cardiopulmonary bypass.
Many commercial oximeters are presently available. However, their relatively poor precision and the lack of standardisation amongst
the different instruments suggest that further technological advances are required before NIR spectroscopy oximetry can be adopted
more widely under the “guidelines” of regulatory authorities.
Keywords: near infrared spectroscopy, oximetry, brain oxygenation, muscle oxygenation, spatially resolved spectroscopy

Introduction
In the early 1960s, Karl Norris and co-workers of the Agricultural
Research Service of the USA Department of Agriculture introduced NIR spectroscopy (700–2500 nm) as an analytical technique for agricultural products. They recognised the potential ofthe diffuse reflectance measurement for rapid analysis of grainsthat exhibit specific absorption bands due to proteins and moisture in the region. In the following years, Norris and co-workers
introduced the use of NIR instruments for measuring different
agricultural products. Since the 1970s, commercial companies
ISSN: 0967-0335 		
doi: 10.1255/jnirs.973 		have started to market NIR spectroscopy instrumentation foruse in different fields of application. In vivo medical NIR spectroscopy, using NIR light in the 700–1000 nm wavelength range,
goes back to 1977. In order to place current medical NIR spectroscopy in its proper perspective, this review provides a snapshot of the roots of the discovery and the early years of medical
NIR spectroscopy research and development. The status of thecurrent commercial oximeters and their more relevant medical­applications are discussed.
© IM Publications LLP 2012
All rights reserved

2

Review of NIR Brain and Muscle Oximetry

Methods
Papers were retrieved by the authors through different strategies. First, the databases PubMed, Scopus and Web of Science
were searched using the keywords: “near-infrared”, “nearinfrared oximetry”, “cerebral oximetry”, “muscle oxygenation”,
and/or “instrument”. In addition, newborn NIR spectroscopy,
functional NIR spectroscopy and NIR imaging were excluded
because these topics are reported in other papers of thisspecial issue of the Journal Near Infrared Spectroscopy dedicated to medical applications of NIR spectroscopy. Researchgroups known to be active in a specific field were contacted togather further information. The websites of commercial NIR
systems manufacturers were visited and searched to obtainthe specifications of the instruments.

The roots of medical NIR­
spectroscopy discovery andthe early years of research and­development of the technique
Medical applications of optical methods are very old. The majoradvantages of using optical methods include bio­chemical
specificity, temporal resolution in the millisecond range, thepotential of measuring intracellular/intravascular events
simultaneously, and the easy transportability of optical devices.
The effect of oxygenation to change the colour of haemoglobin (Hb) was observed in a human hand in 1875 by Karl vonVierordt, a German physician who developed techniques formonitoring oxy-haemoglobin (O2Hb) saturation of circulating
blood. O2Hb and de-oxygenated haemoglobin (HHb) preferentially absorb visible light and NIR of different wavelengths, asevidenced by the more reddish colour of oxygenated blood andthe more bluish colour of de-oxygenated blood. The spectraof O2Hb and HHb in the visible and NIR range are shown in
Figure 1. The extent of absorption by each type of haemoglobin
provides information about their relative concentrations andindirectly provides information about the vascularisation andmetabolic status of tissue.
In 1927, Millikan began studying blood oxygenation in vitro
using visible light (400–650 nm) in Cambridge (UK). In 1937, hedemonstrated muscle deoxygenation upon electrical stimulation in laboratory animals. This application was limited by thepoor penetration depth of the visible light (few millimetres) intissues. Early in World War II, there were reports of black-outs
in fighter pilots at high altitude. Then, Millikan developed thefirst portable human ear oximeter using red and NIR lightat the University of Pennsylvania (Philadelphia, PA, USA).1,2
This ear oximeter was lightweight and, with later modifications, was used in many pulmonary function laboratories forabout 30 years. It is worth noting that the word “oximeter” wascoined by Millikan.1
NIR light was also utilised in pulse oximetry, which was
discovered by Takuo Aoyagi at the Research Division of Nihon
Kohden Corporation (Tokyo, Japan) in 1972. Pulse oximetry is
an extremely simplistic version of reflectance spectroscopy.
From the red light signal he subtracted a NIR wavelength
signal which contained the same arterial pulses. Then, he
discovered that the cancellation failed if O2Hb saturation was

Molar extinction coefficient (M-1 cm-1)

106
MEDICAL NIR
MEDICALNIRS
SPECTROSCOPY
RANGE
RANGE

10

5

104

HHb
103

102
250

O2Hb

350

450

550

650

750

850

950

Wavelength (nm)Figure 1. Absorption spectra of oxygenated (O2Hb) and deoxygenated (HHb) haemoglobin. Most commercial oximeters currently utilise
wavelengths in the 750–850 nm range to maximise the separation between O2Hb and HHb and minimise the overlap with the water peakabsorption centred around 980 nm.

M. Ferrari and V. Quaresima, J. Near Infrared Spectrosc. 20, 1–14 (2012)changing. In addition, he realised that this method could be
used to measure O2Hb saturation because the ratio of thepulsatile fractions of the red and NIR lights was a unique function of arterial O2Hb saturation, independent of Hb concentration, subject to skin colour, tissue thickness or other pigments.
In 1978, Minolta (Japan) marketed the first commercial pulse
oximeter. In 1995, fingertip oximeters, which are small enoughto accommodate a finger, first appeared on the market.
Typically, pulse oximeters have a pair of small light-emitting
diodes (LEDs) facing a photodiode through a translucent partof the patient’s body, usually a fingertip or an earlobe. One LED
is red, with a wavelength of 660 nm and the other is infrared,
905 nm, 910 nm or 940 nm. Absorption at these wavelengths
differs significantly between O2Hb and HHb. Pulse oximetry,
continuously measuring arterial O2Hb saturation in the index
finger or in other vascular districts, is considered the mostsignificant technological advance ever made in monitoring thesafety of patients during anaesthesia and critical care. The
introduction of pulse oximetry has reduced 90% of anaesthesia-related fatalities.
Another step in the usefulness of using NIR light in the
medical field is represented by the discovery of medical NIR
spectroscopy. The NIR spectroscopy technique, which noninvasively monitors brain/muscle oxygenation, exploits thechanges in the optical properties of haemoglobin at the microcirculation level associated with tissue activity (either in physiological or pathological conditions).
Frans Jöbsis, the founder of in vivo medical NIR spectroscopy, was Professor of Physiology at the Department of
Physiology of Duke University (NC, USA) and, in 1977, reported
that the relatively high degree of transparency of brain tissue
in the NIR range (“optical window”) enables real-time noninvasive detection of haemoglobin oxygenation using transillumination spectroscopy.3 NIR light scattering is a functionof tissue composition and the number of tissue interfaces,
while absorption is determined by the molecular properties ofsubstances within the light path, mainly haemoglobin. Above
1300 nm, water absorbs all photons over a pathlength of afew millimetres with a secondary peak between 950 nm and1050 nm whereas, below 700 nm, the increase of light scattering and the more intense haemoglobin absorption bands
prevent effective light transmission. The details of the discovery
have been reviewed.4 In his article, Jöbsis also described how
it is possible to monitor the redox state of the copper bandof cytochrome c oxidase, the terminal enzyme of the mithocondrial respiratory chain, responsible for about 90% of thecellular oxygen consumption. Oxidised cytochrome c oxidase
has a broad peak at 820–840 nm. Cytochrome c oxidase was
the target of several investigators during the first years of
medical NIR spectroscopy research. After almost 10 years ofstudies performed on the brain of haemoglobin-free anaesthetised laboratory animals, it was concluded that the redox
state of cytochrome c oxidase does not affect the haemoglobin oxygenation measurements because its absorption isless than 10% of haemoglobin absorption and it only starts
to reduce at very low levels of tissue oxygenation. In recent

3years, much work has been done on the refinement of NIR
spectroscopy hardware and algorithms (utilised to deconvolute the light absorption signal) for monitoring the cytochromec oxidase redox state that might be a potential intracellularmarker of tissue oxygenation. To improve the accuracy of themeasurement of this NIR spectroscopy parameter, most of
the recent animal and human NIR spectroscopy studies havebeen performed using broadband. At the present time, nocommercial system includes the cytochrome c oxidase redox
state measurement. Boxes 1 and 2 summarise the features,strengths, advantages, and limitations of medical NIR spectroscopy instruments for non-invasive monitoring of tissue
oxygenation according to present knowledge.
Interestingly, the first NIR absorption spectrum of humanmuscle was measured by Norris and co-workers in the same
year as Jöbsis’ discovery.5 The spectral features of haemoglobin, water and fat were identified by Norris and, later, achemometric algorithm was developed to quantify body fat.6
The possibility of measuring haemoglobin, cholesterol, total
proteins, albumin and urea concentrations in whole humanblood using NIR spectroscopy was demonstrated in various
papers by Kuensner and colleagues.7–10 Unfortunately, theseinteresting methods have never found application in commercial clinical chemistry instrumentation. In 2008, a non-invasive spectrophotometry-based technology (Radical-7; Masimo
Corp., Irvine, CA, USA), providing continuous online fingertip
haemoglobin concentration measurement, was introduced.
When compared with laboratory reference values, haemoglobin content measured by pulse oximetry has absolute andtrending accuracy similar to that measured by the more extensively used invasive methods.11
Following several demonstration studies about the applicability of NIR spectroscopy on laboratory animals,12 Jöbsis
and his colleagues used the technique for studying cerebral
oxygenation in newborn sick infants.13 In 1980, Marco Ferrari,at that time working at the “Istituto Superiore di Sanità” (Rome,
Italy) (before moving in 1988 to the University of L’Aquila, Italy),
started to utilise NIR spectroscopy instrumentation prototypes for measuring brain/muscle oxygenation changes inexperimental animal models14,15 and human adults.16,17 In
1985, data on the effects of carotid artery compression tests
on regional cerebral haemoglobin oxygenation and volume of
cerebrovascular patients were presented at the 13th Meetingof the International Society on Oxygen Transport to Tissue.18
Moreover, data collected on the brains of newborns were
presented at the same meeting.19
In 1984, Professor David Delpy (University College London,
UK), and colleagues, started to develop several NIR spectroscopy instruments and, three years later, reported thefirst quantitative measurements on sick newborn infantsof various oxygenation and haemodynamic parameters[including changes in O 2Hb, HHb and total haemoglobin(tHb; tHb = O2Hb + Hb) concentrations], cerebral blood volume,and cerebral blood flow. 20,21 A four-wavelength system,
described by Cope and Delpy,22 was used as the basis for the
single-channel continuous wave (CW) NIRO-1000, the first

4

Review of NIR Brain and Muscle Oximetry

Medical NIR spectroscopy is a non-invasive and safe optical technique which uses light emitting diodes or laser
diodes as light source, and different NIR detectors to measure regional tissue oxygenation. In the case of the adultbrain, the frontal lobes are the monitored area.



Human tissues are relatively transparent to light in the NIR spectral window (650–1000 nm).

The NIR light is either absorbed by pigmented compounds (chromophores) or scattered in tissues. NIR light is able
to penetrate human tissues because the dominant factor in its transport to tissue is represented by scattering, which
is typically about 100 times more probable than absorption.



The relatively high attenuation of NIR light in tissue is due to the main chromophore haemoglobin (the oxygen
transport red blood cell protein) located in small vessels (< 1 mm diameter) such as the capillary, arteriolar andvenular bed of the microcirculation. Blood vessels > 1 mm completely absorb light. Given the fact that 70–80% of theblood in the tissues is in the venous compartment, NIR spectroscopy technique offers information mainly about theoxygenation changes occurring at the venous blood level (NIR spectroscopy signal from venous, capillary and arterialside being approximately 70:20:10, respectively).



Haemoglobin absorption spectrum depends on its oxygenation status.



As a consequence of the complex light scattering effect by different tissue layers, the pathlength of NIR light throughtissue (optical pathlength) is longer than the physical distance between the source and the detector. The spatial
distribution of NIR light through the different tissue layers is a banana-shaped region.

Adequate NIR light penetration depth (almost half of the source–detector distance) can be achieved using a source–
detector distance of 2–3 cm and 4–5 cm on an infant’s and adult’s head, respectively, or 4–5 cm on muscle. The
selection of the optimal source–detector separation depends on NIR light intensity, the subject’s head/muscle region
and age, in the case of the brain.



NIR spectroscopy allows for semiquantitative/quantitative monitoring of important physiological measures: (i)oxyhaemoglobin (O2Hb); (ii) deoxyhaemoglobin (HHb); (iii) total haemoglobin (tHb), (tHb = O2Hb + HHb) (tHb is strictly
related to blood volume); (iv) O2Hb saturation (measurable only by NIR tissue oximeters). Parameters quantification
depends on the adopted NIR spectroscopy technology. NIR spectroscopy measurements are repeatable andreproducible.



NIR spectroscopy is characterised by a relatively high temporal resolution (typically between 1 Hz and 10 Hz)
enabling to measure the time course of cortical or muscle oxygenation changes. NIR spectroscopy instrumentationis relatively low/moderate costly, transportable or portable or wearable. NIR spectroscopy systems can beminiaturised and even made wireless.

Box 1. Features, strengths and advantages of medical near infrared spectroscopy.



Optode–skin coupling/sliding. A stable contact between light source and skin is critical for continuous wave-based
NIR spectroscopy instrumentation. The layering and dark colour of hair attenuate NIR light.



NIR spectroscopy measurements are restricted to outer cortex or superficial muscle(s). Depth sensitivity of NIR
spectroscopy signal depends on many factors (i.e. source–detector separation, source power, detector sensitivity,
optical properties of the skin/skull layers, degree of white matter myelination, adipose tissue thickness etc.). Typical
depth sensitivity of most NIR spectroscopy systems is ~1.5 cm.



The separation of NIR spectroscopy signals originating either from cerebral tissue or extracerebral
tissues/structures (scalp, temporal muscle, skull, frontal sinus, cerebrospinal fluid and dura) is difficult.



The determination of NIR spectroscopy parameters is influenced by skin blood flow/volume changes.

Continuous wave-based systems cannot measure optical pathlength, then do not provide absolute quantification
value of NIR spectroscopy parameters. Optical pathlength differences across diverse head/muscle regions should betaken into consideration for interpreting NIR spectroscopy data. Technological developments of time-domain andfrequency-domain-based instrumentations (being able to measure the spatial and temporal variations in optical
pathlength) would improve the NIR spectroscopy sensitivity and the quantification of NIR spectroscopy parameters.



No standardisation is available for NIR spectroscopy instrumentations/signal processing/data analysis. Regulatory
authorities or network of research laboratories should provide “guidelines”.



NIR spectroscopy signal artefacts (due to head/muscle motion or reduction of the grip of the light source on the skin)are not automatically corrected by software.



Most of the commercial brain/muscle oximeters are not approved by the USA Food and Drug Administration.

Box 2. Limitations of medical near infrared spectroscopy.

M. Ferrari and V. Quaresima, J. Near Infrared Spectrosc. 20, 1–14 (2012)c­ ommercial system built in 1989 by Hamamatsu Photonics
K.K. (Hamamatsu City, Japan). This instrument represented
the first results of a long-lasting collaboration between the
University College London and Hamamatsu Photonics.
From 1980 to 1995, another nine companies were involved in
the development of NIR spectroscopy prototypes:■■ American Edwards Laboratories in collaboration with Duke
University (NC, USA)■■ Critikon (UK) and Johnson & Johnson (Bridgewater, NJ,
USA) with Zurich University (Switzerland)■■ ISS Inc. (Champaign, IL, USA) with the University of Illinois
at Urbana-Champaign (Urbana, IL, USA)■■ Near Infrared Imaging Inc. with the University ofPennsylvania (both in Philadelphia, PA, USA)■■ NIRSystems, Inc. (Laurel, MD, USA) and Edwards
Lifesciences Corp (Irvine, CA, USA) with Johns Hopkins
University (Baltimore, MD, USA)■■ Radiometer (Copenhagen, Denmark) with Copenhagen
University (Denmark)■■ Sclavo (Siena, Italy) with the “Istituto Superiore di Sanità”(Rome, Italy)■■ Shimadzu Co. (Kyoto, Japan) with Hokkaido University(Sapporo, Japan)■■ Somanetics Corporation (Troy, MI, USA)
Only four of these companies (Hamamatsu, ISS, Shimadzu andSomanetics) are still producing NIR spectroscopy instrumentations in 2011 (Table 1). Wahrt et al.23 reviewed the technicaland historical development of the instruments utilised up to1995 (including experimental and medical applications). In thecase of the adult brain, the frontal lobes, due to the lack of hair,represent the most convenient region to be monitored by NIR
spectroscopy.
Interestingly, in 1987–1990, Ferrari (during his stay at theJohns Hopkins University) collaborated with Norris (consultant
of NIRSystems company) in the construction of a prediction
algorithm of cerebral venous O 2Hb saturation. 24 The four
medical NIR spectroscopy pioneers (Delpy, Chance, Norrisand Ferrari) during the 32nd Annual Eastern Analytical
Symposium held in 1993 at Somerset (NJ, USA) are shown in
Figure 2.
In general, spectroscopy using the NIR region of the spectrum can be performed in a variety of ways. Although two
wavelengths are required to resolve the spectroscopic equations with two chromophores (O2Hb and HHb), some NIR spectroscopy instruments utilise more wavelengths to improve
the accuracy of the algorithms. The wavelengths of NIR lightused in the commercial devices are selected to be sensitive
to haemoglobin and generally utilise wavelengths between
700 nm and 850 nm where the absorption spectra of O2Hb andHHb are maximally separated and there is a minimal overlap
with H 2O. The isobestic point (wavelength at which O 2Hb
and HHb have the same molar absorptivity) for HHb/O2Hb isaround 810 nm. The isobestic wavelength has been utilised
in some of the early instrumentation used for measuring tHb.
Most of the first generation instruments used laser diodes
and flexible fibre-optic bundles to carry the light to (source)

5

and from (detector) the monitored area. The laser diodes were
switched on in sequence and, thus, a single detector could
have been used. Most of the present commercial systems use
LEDs, each providing a small range of wavelengths.

Near infrared brain/muscle­oximetry
The first generation of medical NIR spectroscopy instruments used a CW-based NIR spectroscopy approach which
only provided concentration changes in O2Hb and HHb (withrespect to an initial value arbitrarily set equal to zero) calculated by using the modified Lambert–Beer law and expressedin micromolar × centimetres.25 Somanetics (Troy, MI, USA) was
the first company to market a single-channel NIR spectroscopy brain oximeter (INVOS 3100) using two LEDs (725 nm
and 797 nm) and two diode detectors (in 1992). In May 1993,
the INVOS 3100 was the first cerebral oximetry device to beapproved by the USA Food and Drug Administration (FDA).
The oximeters provide a continuous measure of regional O2Hb
saturation on a scale from 0% to 100%. Unlike conventional
pulse oximetry, NIR spectroscopy tissue oximetry does notrely on a pulsating flow and measures a weighted average ofarterial, capillary and venous blood oxygenation. Therefore,
NIR spectroscopy tissue oximeters provide information on
the balance between oxygen supply and demand in capillary, arteriolar and venular beds of tissue (mainly at brain
cortex and superficial muscle levels). Regional O2Hb saturation represents the tissue reserve capacity following tissue
oxygen extraction.
The principles of the operation of the NIR spectroscopy
tissue oximeters differ among instruments. The three mainprinciples exploited in making the oximeters are: spatiallyresolved spectroscopy (SRS), phase modulation spectroscopy (PMS) and time resolved spectroscopy (TRS).25 SRS, also
called multi-distance spectroscopy, is based on light intensity being measured at several different source–detector
distances. SRS techniques assume that the coupling is thesame for the different source–detector distances and, by
measuring the intensity as a function of the distance, determine a parameter which is independent of the coupling. This
allows the determination of ratios of O2Hb to tHb and, thus,
tissue O2Hb saturation. Moreover, a scaled absolute value fortHb can also be obtained by the SRS method. The applicationof cerebral NIR spectroscopy in adults has been hampered byconcerns about contamination from extra-cerebral tissues.
Using SRS, the brain cortex was identified as the anatomic
source of the signal on the forehead of adult patients undergoing carotid endarterectomy. In Figure 3, an example of thechanges in prefrontal cortex O2Hb saturation (measured as
tissue oxygenation index (TOI %) by the brain oximeter NIRO300 (Hamamatsu Photonics, Japan) during elective carotid
surgery is reported. The compression of the external carotid
artery provoked a decrease in frontal cutaneous blood flow

Multi-distance FD

OxiplexTS

TRS-20d

PortaMona,b,iPortaLite

TD

Multi-distance CW

Oximeter for muscle studies only;b
wireless system;coximeter with fat-layer compensation in real time;dcommercially available only in Japan;e
USA Food and Drug Administration’s approval;foximeter for brain studies only;gcapable of microcirculation blood flow measurement by ultrasounds;hfor thenar muscle only;ian accelerometer is available on request
CW, continuous-wave spectroscopy;
FD, frequency-domain spectroscopy;
LD, laser diode;LED, light-emitting diode;TD, time-domain spectroscopy.

aMulti-distance CW

Oxymon-II A

Multi-distance CW

Multi-distance CWb,fMulti-distance CW

NIMO

NIRO-200NX

Multi-distance CW

Multi-distance CW

Multi-distance CW

Multi-distance CW

Multi-distance CW

Multi-distance CW

Multi-distance CW

Techniquec

INVOS 5100Ce,f

e,h

e,f

InSpectra StO2 650

Fore-sight 2040e,f

EQUANOX 8004CA

EQUANOX 7600e,f

CerOx 3210F

e–g

Astem Hb-12c, a–dInstrument

2009

2006

2011

1998

2003

2010

2008

2006

2003

2006

2011

2009

2007

2010

Year ofrelease3 LDs, 2

2 LEDs, 1

2 LEDs, 1

2 LDs, 2

2-6 LDs, 2

3 LDs, 2

3 LD, 22 LEDs, 1–4

4 LEDs, 44 LDs, 2

4 LEDs, 4

2 LEDs, 2

3 LDs, 2

2 LEDs , 2

N° and type of sources,
N° of channels

Table 1. Main current commercial near infrared spectroscopy brain and/or muscle oximeters.

Hamamatsu, Japan

Artinis, Netherlands

Artinis, Netherlands

ISS, USA

Artinis, Netherlands

Hamamatsu, Japan

Nirox, Italy

Somanetics, USA

Hutchinson, USA

Casmed, USA

Nonin, USA

Nonin, USA

Ornim, Inc., USA

Astem, Japan

Company

www.hamamatsu.com

www.artinis.com

www.artinis.com

www.iss.com

www.artinis.com

www.hamamatsu.com

www.nimoworld.com

www.somanetics.com

www.htibiomeasurement.com

www.casmed.com

www.nonin.com

www.nonin.com

www.ornim.com

www.astem-jp.com

Website6
Review of NIR Brain and Muscle Oximetry

M. Ferrari and V. Quaresima, J. Near Infrared Spectrosc. 20, 1–14 (2012)

7

Figure 2. The medical NIR spectroscopy pioneers at the 32nd Annual Eastern Analytical Symposium, 16 November 1993, Somerset, NJ,
USA. From the left: David Delpy (UK), Britton Chance (USA), Karl Norris (USA), Marco Ferrari (Italy).

(measured by a skin laser Doppler flowmeter) without changes
in TOI. Conversely, the compression of the internal carotid
artery provoked a prompt decrease in mean ipsilateral middle
cerebral artery blood flow velocity (measured by intracranial
laser Doppler) accompanied by a concomitant decrease of TOI.
After insertion of the shunt, TOI promptly started to recover.
Therefore, a change in brain O2Hb saturation was associatedonly with the internal carotid artery clamping. The reason isthat using the SRS approach, the superficial layers of tissue
have an effect on all the light bundles similarly. Therefore,
their influence is cancelled out. Only deeper tissue layers havean effect on the values.
TRS, also known as time-domain spectroscopy, is a technique that measures the time of flight in addition to the lightintensity. It does so by emitting a short (~100 ps) pulse oflight into the tissue and measuring the time point spreadfunction of the light after it has passed through the tissue.
Due to the scattering process, the pulse will broaden and,due to absorption, the intensity will be reduced. The resultof such a measurement is a histogram of the number ofphotons on the y-axis and their arrival times on the x-axis.
The histogram also contains information about the depth ofthe photonic path, because photons that arrive later have ahigher probability of having travelled deeper. The absorption
and the reduced scattering coefficients are calculated fromthe histogram and the absorption coefficients are utilised
to calculate the absolute values of O2Hb and HHb. The NIR
TRS-based approach requires sophisticated and expensive
instrumentation; so far, only one system has been commercially available (Table 1).
PMS is also called frequency-domain spectroscopy. This
technique is, in principle, equivalent to TRS, except that it
operates in the Fourier domain. This means that the lightsources are intensity modulated at radio frequencies (50 MHz
to 1 GHz). After passing through the tissue, the mean intensity,
amplitude and phase of the emerging wave are measured.
The phase contains information about the time of flight. Mostof the instruments are single frequency instruments and use
multi-distance or SRS geometry. It has been shown that thelatter type of instrument is, technically, much simpler thanthe one using the TRS-based approach, and provides measurements with a good signal-to-noise ratio and a high time
resolution. NIR PMS-based approach requires sophisticatedinstrumentation; so far, one system has been commerciallyavailable (Table 1). In ascending order of cost and technological complexity are the CW-, PMS- and TRS-based instruments. On the other hand, only the PMS and TRS techniques
offer absolute characterisation of the tissue optical properties(absorption and reduced scattering coefficients) from which it
is possible to retrieve absolute concentration values of O2Hb
and HHb.
The different types of NIR spectroscopy instruments, with therelated key features, advantages and disadvantages and all theparameters measurable by using different NIR s­ pectroscopy
techniques, have been reviewed in detail.25–29 In addition, someaccompanying articles will cover the most recent technicalaspects of medical NIR spectroscopy i­nstrumentation.
The first commercial single-channel SRS oximeter was
introduced in 1997 (the OM-200, Shimadzu Co., Japan). In 1998,
the two-channel SRS oximeters (the NIRO-300 by Hamamatsu,
Japan, and the INVOS-4100 by Somanetics) were introduced
onto the market. In 1999, the Shimadzu Company introduced
the two-channel SRS oximeter OM-220. Table 1 shows themain commercial brain and/or muscle oximeters which are
currently available. The details of each system can be foundon the websites of the related companies. Commercial NIRFIGURE 38

ECA onICA on

Review of NIR Brain and Muscle Oximetry

Shunt inserted

ABP(mmHg)

LDF
(%)

FVm
(cm/s)TOI(%)

Time (min)Figure 3. Graphic display of data obtained from a patient during elective carotid endarterectomy. The vertical lines demonstrate time of
application of vascular clamps. The NIR spectroscopy oximeter NIRO-300 (Hamamatsu Photonics, Japan) provided a continuous online
measurement of the changes in prefrontal cortex O2Hb saturation, measured as tissue oxygen index (TOI) using spatially resolved spectroscopy. ECA, external carotid artery; ICA, internal carotid artery; ABP, mean arterial blood pressure; LDF, frontal cutaneous laser
Doppler flow (Moor Instruments, UK); FVm, mean ipsilateral middle cerebral artery flow velocity (Scimed, UK), TOI, tissue oxygenationindex. (Unpublished data from Professor P.G. Al-Rawi, University Department of Neurosurgery, Addenbrooke’s Hospital, Cambridge,
UK.).

spectroscopy oximeters with USA FDA approval are shown in
Figure 4. Adhesive pads are used to fix the optical probes tothe hairless skin of the forehead or the skin over the monitored muscle group. The overall chronology of the introductionof the main brain and muscle commercial NIR spectroscopybased oximeters is reported in Table 2.
Since it was first launched in 1992, the INVOS oximeterhas constantly been evolving and improving. Now in its sixth
generation, the four-channel INVOS 5100C (Figure 4) is acommercially available cerebral/somatic oximeter indicated also for use on neonates. There are currently four

FDA approved devices that are marketed to assess cortical
oxygenation (Figure 4, Table 1). It is worth mentioning that
Ornim’s oximeter only provides a simultaneous, yet independent, measure of HbO2 saturation and blood flow measured by a small ultrasound transducer. Miniturised oximeters are now being manufactrured. Wireless oximetry isparticularly useful for measuring muscle oxygenation during
exercise.30,31 It is estimated that approximately 10,000 brain
oximeters (almost two-thirds made by Somanetics) have beenutilised worldwide, mostly for adult medical applications. In
addition, several more quantitative oximeter p­ rototypes areM. Ferrari and V. Quaresima, J. Near Infrared Spectrosc. 20, 1–14 (2012)

9

FIGURE 4CerOX

EQUANOX 7600

Fore-sight 2040

INVOS 5100C

Figure 4. Commercial brain NIR oximeters with USA Food and Drug Administration approval: CerOx 3210F (Ornim, Inc., USA);
EQUANOX 7600 (Nonin, USA); Fore-sight 2040 (Casmed, USA); INVOS 5100C (Somanetics, USA). The oximeters are equipped with two
or four optical probes for monitoring the tissue oxygenation over the forehead.

under development in several university research groups.25
Because each oximeter uses a unique processing algorithm
to calculate O2Hb saturation, it is not possible to compare
the clinical results obtained by different instrumentations.
However, in the majority of publications, the Somanetics
brain oximeters have been used.
The importance of the introduction of the NIR spectroscopy
oximeters is also witnessed by the fact that the JapaneseSociety on Medical NIR Spectroscopy, founded in 1994, isholding regular annual meetings.
Laboratory and clinical validation studies are required todemonstrate the utility of any monitoring modality. Whilearterial O2Hb saturation, measured by pulse oximetry, can beeasily validated by collecting arterial blood samples, tissue
O2Hb saturation, measured by NIR spectroscopy, is a newparameter for which no “gold standard” method, invasive
or non-invasive, is available. Therefore, the accuracy of NIR

spectroscopy tissue oximetry cannot be assessed. So far,tissue NIR spectroscopy oximetry has been compared with the
O2Hb saturation measured in jugular vein blood considering aweighted average of venous and arterial blood. The weighted
factor is impossible to determine precisely and it changes inpathological conditions.
Unfortunately, the optical probes and the algorithms ofcommercial NIR spectroscopy oximeters are different and no
standardisation is available yet. In particular, (i) the operating
range (i.e. the interval within which the instrument works
reliably) of the oximeters should be recognised and indicated,and (ii) the comparison between oximeters at rest and duringphysiological changes such as muscle exercise should be
performed. Commercial NIR spectroscopy-based oximeters
can also measure a brain blood flow index by measuring thetime course of the NIR dye indocyanine green injected into aperipheral vein.

10

Review of NIR Brain and Muscle Oximetry

Table 2. Overall chronology of the introduction of the main brain and muscle commercial near infrared spectroscopy-based oximeters.

Year

Major events

1977

Jöbsis demonstrates the possibility to detect changes of adult cortical oxygenation during hyperventilation by
NIR spectroscopy

1985

First NIR spectroscopy clinical studies on newborns and adult cerebrovascular patients

1989

First commercial continuous wave one-channel clinical instrument: NIRO-1000 by Hamamatsu Photonics,
Japan

1992

First commercial continuous wave one-channel brain oximeter: INVOS 3100 by Somanetics (USA)1993

The oximeter INVOS 3100 gets the Food and Drug Administration approval

1994

First commercial continuous wave one-channel portable instrument for muscle studies: HEO-100 by Omron(Japan)1997

First commercial continuous wave one-channel spatially resolved spectroscopy brain oximeter: OM-200 by
Shimadzu (Japan)

1998

First commercial continuous wave two-channel spatially resolved spectroscopy brain oximeter: NIRO-300 by
Hamamatsu Photonics (Japan)
First commercial frequency-domain spectroscopy one-channel brain/muscle oximeter: OxiplexTS by ISS (USA)2003

First commercial time-resolved spectroscopy one-channel brain/muscle oximeter: TRS-10 by Hamamatsu
Photonics (Japan)
First commercial continuous wave one-channel oximeter for thenar muscle studies: InSpectra StO2 650 by
Hutchinson (USA)2006

First commercial continuous wave four-channel brain/somatic oximeter: INVOS 5100C by Somanetics (USA)First commercial continuous wave spatially resolved spectroscopy wireless and portable one-channel muscle
oximeter: PortaMon by Artinis (Netherlands)

2009

First commercial time-resolved spectroscopy two-channel brain/muscle oximeter: TRS-20 by Hamamatsu
Photonics (Japan)

2011

First commercial continuous wave spatially resolved spectroscopy wireless and portable one-channel brain
oximeter: PortaLite by Artinis (Netherlands)

Main applications of near­infrared brain/muscle oximetry
Brain oximetry
The application of NIR spectroscopy to the preterm andnewborn infant brain and its clinical value has been previously
reviewed32–34 and is also reviewed by Wolf et al. in this special
issue of Journal of Near Infrared Spectroscopy.35
The measurement of tissue O2Hb saturation by NIR oximetersoffers the great advantage of detecting clinical situations inwhich the oxygenation status of the adult brain can change
dangerously. Continuous real-time monitoring of the adequacyof cerebral oxygenation/perfusion can provide important therapeutic information in a variety of clinical settings. The current
clinical availability of several brain oximeters represents a
potentially important development for the detection of cerebral ischaemia. The most relevant applications of adult brain
oximetry are in: (i) surgery (for evaluating cerebral oxygenation during cardiac, renal or carotid artery surgery, as anindicator of shunting in carotid ­endarterectomy, balloon test
occlusion, aortic surgery, cardio­pulmonary bypass, venous
endovascular trombolysis, neurosurgical procedures etc.);(ii) anaesthesia (for e­ valuating cerebral oxygenation during

induction of general anaesthesia, drugs infusion, tracheal
extubation etc.); and (iii) stroke (stroke occurrence in intensive care, to follow effects of drugs, to evaluate cerebrovascular reactivity, to evaluate the post-stroke functional recoveryetc.). Different studies have demonstrated a close correlation
between changes in cerebral oxygenation by NIR spectroscopy
and other monitoring modalities under different conditions.
Increasing evidence suggests that a decrease in O2Hb saturation during surgery is associated with unwarranted neurological effects and postoperative complications.36–38
One retrospective 39 and three randomised controlled
trials 40–42 have examined the clinical value of cerebral
oximetry during cardiac surgery and cardiopulmonary bypass.
A ­relationship between cerebral hypoxia and post-operativecomplications was found, suggesting that brain oximetry–guided brain protection protocols might lead to reduced
neurological complications.37,43
The American Society of Thoracic Surgeons began collecting
cerebral oximetry data in its Adult Cardiac Surgery Databasein January 2008. In January 2010, the same society begancollecting cerebral and somatic oximetry data, including thosefor operating room and intensive care unit applications, in its
Congenital Heart Surgery Database.

M. Ferrari and V. Quaresima, J. Near Infrared Spectrosc. 20, 1–14 (2012)

Some articles have raised questions regarding the clinicalutility of cerebral oximetry monitoring.44–47 However, a numberof clinical studies and case reports have demonstrated that,
despite some limitations, the ability of cerebral oximetry
monitoring to detect otherwise clinically silent episodes of
cerebral ischaemia in a variety of clinical settings renders it
an important safeguard for cerebral function.
The proper management of brain oxygenation is one of theprincipal endpoints of all anaesthesia procedures. However,the brain remains one of the least monitored organs during
clinical anaesthesiology. There are some medical procedures
where iatrogenic brain ischaemia is present, including carotid
endarterectomy in patients with high-grade carotid arterystenosis, temporary clipping in brain aneurysm surgery, hypothermic circulatory arrest for aortic arch procedures andothers in which the pathology itself generates brain ischaemia,
such as traumatic brain injury and stroke. One of the mostcommon limitations seen in studies assessing the impactof cerebral oximetry monitoring has been the absence of adefined protocol based on physiologically derived interventions to treat decreases in O2Hb saturation.
Considering the poor reliability of absolute O2Hb baseline
values (coefficient of variation of about 10%), some researchers
suggest using O2Hb saturation trends instead of absolute values.
Moreover, no reliable absolute O2Hb saturation threshold for
inadequate cerebral perfusion has been determined to date. In
addition, it is not clear how changes in cortical oxygenation canbe interpreted. This suggests that oximetry should be accompanied by other neuromonitoring tools.
Although there are some limitations, the clinical results andthe ongoing technological advances suggest that NIR spectroscopy oximeters could represent a unique, very useful and noninvasive tool for diagnosing neural and vascular diseases andfor monitoring the effects of therapy/rehabilitation on the brain.

Muscle oximetry
Since the end of the 1980s, NIR spectroscopy has been utilised
to investigate local muscle oxidative metabolism at rest andduring different exercise modalities. The unique advantage
of using NIR spectroscopy is that, when proper care is taken
to minimise movement artefacts, it can yield acceptablesignal-to-noise ratios during exercise. Several review articles reported the methodological issues of NIR spectroscopy
for monitoring muscle oxygenation and haemodynamics inhealthy and diseased humans.48–52 The first low-cost CW-NIR
spectroscopy instrument dedicated to muscle studies wasmade by Chance (Pennsylvania University, USA) in 1990. In
1994, Nakase and Shiga (Omron Institute of Life Science Co.
Ltd., Kyoto, Japan) developed, in collaboration with Chance,
the first single-channel portable NIR spectroscopy instrument
for muscle studies (HEO-100, Omron Ltd. Inc., Japan) that wascommercialised worldwide up to 2003.53,54
Different NIR spectroscopy techniques (for example, CW,
SRS, TRS and PMS) have been utilised for measuring muscle
oxygenation during exercise. In the last decade, approximately 300 articles relating to muscle NIR spectroscopy have11

been published on different physiological aspects (primarily
muscle oxygenation and haemodynamics) of several upperand lower-limb muscle groups investigated by using mainly
two-channel CW and SRS commercial instruments. A
recently published review provides a snapshot of muscle
NIR spectroscopy at the end of 2010 summarising the recent
literature, offering the present status and perspectives of
NIR spectroscopy instrumentation and methods, describing
the main NIR spectroscopy studies on skeletal muscle physiology, posing open questions and outlining future directions.55
So far, only about 20 of the ~600 skeletal muscles have been
investigated by NIR spectroscopy. Specifically, lower limb
muscles (i.e. biceps femoris, gastrocnemius, rectus femoris,
tibialis anterior, vastus lateralis, vastus medialis) have beenstudied during diverse conditions (cycling, upon electricalstimulation, during knee extension exercise, leg press exercise, plantar flexion exercise, running, squatting, Wingatetest) and upper limb muscles (i.e. biceps brachii, brachioradialis, deltoid, forearm flexors, triceps brachii) during diverse
conditions (arm abduction exercise, bench press exercise,
cycling, elbow flexion exercise, upon electrical stimulation, handgrip, rowing, Wingate test). The trunk muscles(i.e. erector spinae, intercostal, multifidus, paravertebral,
serratus anterior) were also investigated during cycling, backextension and bending forward.
NIR spectroscopy has also been utilised as a non-invasive
method to assess O2 delivery, O2 consumption, blood flow, O2
re-saturation and recovery times in diverse muscle groups
at rest, during exercise and in the recovery phase in peripheral vascular disease patients and neuromuscular disease
patients.25,51
So far, NIR spectroscopy has been applied for studying exercise-induced muscle damage,56,57 ergonomics/biomechanics,58
heterogeneity of muscle O2 supply/demand,59,60muscle activation,57,61 priming exercise,62,63 respiratory muscle blood flow/
fatigue,64,65 the role of the brain in muscle fatigue,66,67the timecourse of oxidative metabolism68,69 and the effect of exercise
training.70 Unfortunately, NIR spectroscopy has rarely beenutilised in clinics.46 There are still several open questionsin the application of NIR spectroscopy in muscle studies: (i)whether NIR spectroscopy can be used in subjects with a thickfat layer and (ii) the effect on NIR spectroscopy measurements
due to scattering which may vary during exercise.55
The most exciting prospect of muscle oximetry studies
is the full understanding of skeletal muscle biochemistry/­
physiology/pathology for improving human health care,athletic p­ erformance and rehabilitation monitoring.

Conclusions
In the last decade, NIR brain and muscle oximetry has
obtained significant patho-physiological relevance assuggested by the high number of instruments sold and thehigh number of scientific publications. The most relevant
clinical application is the evaluation of cerebral oxygenation

12

during adult cardiac surgery and cardiopulmonary bypass.
Many commercial oximeters are available. However, theirrelatively poor precision and the lack of standardisation
amongst the different instruments suggest that further technological advances are required before NIR spectroscopy
oximetry can be adopted more widely under the “guidelines”
of regulatory authorities.

Acknowledgements
The authors wish to thank all the companies mentioned
throughout the text for providing the data (including themarket) about their instruments. The authors would like tothank Rosanna De Carolis for the technical support.

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