Near-infrared spectroscopy: does it function in functional activation studies of the adult brain?

Ž .International Journal of Psychophysiology 35 2000 125]142

Near-infrared spectroscopy: does it function infunctional activation studies of the adult brain?

Hellmuth ObrigU, Rudiger Wenzel, Matthias Kohl, Susanne Horst,¨Petra Wobst, Jens Steinbrink, Florian Thomas, Arno Villringer

Department of Neurology, Charite, Humboldt Uni ersitat zu Berlin, 10098 Berlin, Germany´ ¨

Received 23 March 1999; accepted 23 March 1999

Abstract

Ž .Changes in optical properties of biological tissue can be examined by near-infrared spectroscopy NIRS . Therelative transparency of tissues including the skull to near-infrared light is the prerequisite to apply the method tobrain research. We describe the methodology with respect to its applicability in non-invasive functional research ofthe adult cortex. A summary of studies establishing the ‘typical’ response in NIRS ¨ascular parameters, i.e. changesin the concentration of oxygenated and deoxygenated haemoglobin, over an activated area is followed by thevalidation of changes in the cytochrome-oxidase redox state in response to a visual stimulus. Proceeding from thesefindings a rough mapping of this metabolic response over the motion-sensitive extrastriate visual area is demon-

w xstrated. NIRS measures concentration changes in deoxygenated haemoglobin deoxy-Hb which are assumed to beŽ .the basis of fMRI BOLD contrast blood oxygenation level-dependent . The method is therefore an excellent tool to

validate assumptions on the physiological basis underlying the fMRI signal, due to its high specificity as to theparameters measured. Questions concerning the concept of ‘activation’r‘deactivation’ and that of the linearity of thevascular response are discussed. To challenge the method we finally present results from a complex single-trial motor

Ž .paradigm study testing the hypothesis, that premotor potentials contingent negative variation can be examined byfunctional techniques relying on the vascular response. Some of the work described here has been publishedelsewhere. Q 2000 Elsevier Science B.V. All rights reserved.

Ž .Keywords: Near infrared spectroscopy NIRS ; Motion sensitivity; Contingent negative variation; Cytochrome oxidase

U Corresponding author. Tel.: q49-30-28021331; fax: q49-30-28028480.Ž .E-mail address: [email protected] H. Obrig

0167-8760r00r$ - see front matter Q 2000 Elsevier Science B.V. All rights reserved.Ž .PII: S 0 1 6 7 - 8 7 6 0 9 9 0 0 0 4 8 - 3

( )H. Obrig et al. r International Journal of Psychophysiology 35 2000 125]142126

1. Introduction

In the course of the past few years near-in-Ž .frared spectroscopy NIRS has been increasingly

used in functional activation studies in adultsŽKato et al., 1993; Villringer et al., 1993; Hoshi etal., 1994; Meek et al., 1995; Hoshi and Tamura,1997; Tamura et al., 1997; Shiotsuka et al., 1998;

.Watanabe et al., 1998 . First described by JobsisŽ .1977 , the optical method of non-invasively as-sessing cerebral oxygenation changes has newlygained interest by the ever enlarging evidencethat haemodynamic changes evoked by functionalactivation of the brain are an excellent means to

Žimage functional cortical anatomy Ogawa et al.,.1990; Frahm et al., 1992; Belliveau et al., 1992 .

At present functional magnetic resonance imag-Ž .ing fMRI excels most other techniques in tem-

poral and spatial resolution challenging the ques-tion as to the necessity of developing yet anothertechnique. The strength of NIRS is the applicabil-ity at the bedside and its comparatively low ex-pense. This paper focuses on the method’s con-tribution to the more profound understanding ofthe mechanisms underlying the imaging tech-

niques. The first question addressed is whetherwe can monitor parameters filling the gap betweenthe vascular response and the allegedly mappedneuronal activity. The second issue is that ofsignal physiology and specificity. If neuronal activ-ity does translate into changes in blood flow howcan for example changes in susceptibility as mea-sured by BOLD-contrast fMRI be translated intoevidence of an increased blood flow.

Investigating the basis of functional imagingtechniques with NIRS is not an end to itself. Onthe contrary the relevance of clearly differentiat-ing between neuronal activation and focally in-creased blood flow, which by itself is often termed‘activation’, may become of supreme relevancewhen applying findings raised by fMRI or PET topatients with a disturbed neuro-vascular coupling.The goal is the applicability of functional diagnos-tic techniques relying on and assessing possible

Ždisturbances of neurovascular coupling for a re-.view see Villringer and Dirnagl, 1995 .

Proceeding from an introduction to the metho-dology we discuss the established and potentiallyuseful parameters of the method. The potentialof the method to describe metabolic changes in

Ž .Fig. 1. a Sketch of NIRS measurement of the adult head. Three possible photon paths are illustrated. Photon 1 undergoes anumber of scattering events to reach the detector, photon 2 is absorbed after a number of scattering events, photon 3 leaves the

Ž .head without being detected by the system. Changes in scatter and absorption in the banana like shaped sampling volume whiteŽ .will alter the amount of photons reaching the detector. b The spectra of oxy-Hb, deoxy-Hb and Cyt-ox in the near-infrared. The

lines denote the four wavelengths of the NIRO-500 monitor, the grey bar signifies the spectral region typically analysed in theCCD-approach.

( )H. Obrig et al. r International Journal of Psychophysiology 35 2000 125]142 127

response to functional activation of the cerebralcortex is demonstrated. To further explore theapplicability to findings by the functional imagingtechniques we then report on our latest experi-ments investigating the signal physiology in NIRSand fMRI, touching the issue of ‘activation’r‘deactivation’ and the linearity of the responseselicited. The method’s potential in functionalstudies is finally challenged by a complex single-trial paradigm investigating premotor potentialsin a Go-NoGo task.

2. Methodology

The method relies on a simple basic principle.Near-infrared light injected into the head by alight emitting probe will be multiply scattered andpartly absorbed. The scattered light, which is notabsorbed on its path, will leave the head after anumber of scattering events and can in part bedetected by a second optical probe some centime-

Ž .tres apart from the emitter see Fig. 1a . Sincebiological tissue is rather transparent to lightbetween 600 and 900 nm enough light can bedetected to allow for a spectroscopic analysis. Thedetermination of changes in chromophore con-centration follows a modification of the Beer-

ŽLambert law Cope and Delpy, 1988a; Cope et al.,.1988b :

Ž .A sc)a ) d)DPF qG 1l l l

where, A is the attenuation measured at thel

wavelength l; c is the concentration of the chro-mophore; a is the specific extinction coefficientl

of the chromophore at l; d is the distancebetween light source and detector; DPF is thel

differential pathlength factor at l accounting forthe fact that in scattering media the mean path-length of a photon will be longer than the dis-tance between emitter and detector and G is thegeometry factor accounting for the losses of pho-tons due to scatter.

When comparing two successive measurementsunder assumption of a constant DPF and G,changes in chromophore concentration can beassessed by changes in A:

Ž . Ž .DcsD A r a ) d)DPF 2l l l

It is important to note two major implicationsŽ .of this approach: 1 it is assumed that scatter

does not change significantly during the measure-ment and will, therefore, not contribute to thechanges in attenuation, which also applies for the

Ž .constant absorbers, e.g. melanin; and 2 a quanti-fication of the changes is only possible whenassuming a constant differential pathlength factorŽ . ŽDPF or when the DPF is measured Matcher et

.al., 1994 .Two set-ups used for the acquisition of the data

reported in this paper are described in moredetail:

2.1. Commercial discrete wa¨elengths monitor( )NIRO-500

Ž .The monitor NIRO-500 Hamamtsu, Japanmeasures changes in attenuation at four discrete

Ž .wavelengths 775, 825, 850 and 905 nm usingfour laser diodes as light sources and a photonmultiplier tube as detector. As the chromophoresof interest have different specific extinction co-efficients at these wavelengths they can be dif-ferentiated by solving the linear equation system

Žobtained up to four when using four wave-.lengths, see Fig. 1b :

Ž .D A s Dc1)a1 qDc2)a2 q . . .l1 l1 l1

) d)DPFl1

Ž .D A s Dc1)a1 qDc2)a2 q . . .l 2 l 2 l 2

) d)DPFl 2

Ž .D A s . . . 3l 3

The algorithm implemented in the monitorŽ .Cope and Delpy, 1988a calculates changes inoxygenated and deoxygenated haemoglobinŽ w x w x.D oxy-Hb and D deoxy-Hb as well as changes

Ž win the redox state of cytochrome-oxidase D Cyt-x.ox . The maximal sampling frequency is 2 Hz.

ŽThe system is described in detail elsewhere Cope.and Delpy, 1988a .


( )2.2. Whole spectrum approach CCD-approach

When using a halogen bulb as a light sourceand a CCD camera as a detector the NIRS sys-tem can collect continuous attenuation spectra inthe near-infrared. The system used in our experi-ments consists of one or two light guides from the

Ž .halogen bulb 600]1100 nm and up to four lightdetectors. The collected light is spectrally resolved

Ž .by a spectrograph SP-275; Acton Research andŽdetected by a CCD-chip 1024 = 256 pixel;

.Princeton Instruments . The light collected onthe chip contains the spectral information in thex-direction and can be partitioned so that the four

Ždetector probes are read out separately y-direc-.tion , allowing for a multi-ocular tissue spectros-

copy. The set-up typically used in our experimentsachieves an effective spectral resolution of 20 nmŽdue to binning and smearing effects of the finite

.entrance slit of the spectrograph , the spectralrange analysed extends from 725 to 940 nm. In-stead of the above mentioned algorithm, a linearmulti-component fit is performed allowing theintroduction of different components, assumingthat different numbers of chromophores con-tribute to the attenuation changes measured. Atwo-component fit respects the oxy-Hb and de-oxy-Hb changes, a three component fit also re-

Ž .spects potential changes in Cyt-ox see Section 4 .If scatter is introduced as a fourth ‘chromophore’information related to optical changes indepen-

Ždent of absorption may be obtained Kohl et al.,.1998b . The temporal resolution is limited by the

signal to noise ratio of the measurements and notŽby the monitor itself up to 50 Hz in our experi-

.ments . The spectral range typically analysed isdenoted by a grey bar in Fig. 1b.

3. NIRS-parameters

( )3.1. Vascular parameters oxy-Hb and deoxy-Hb

The first functional studies performed by ourgroup were designed to define a typical responsepattern of the two vascular parameters measuredby NIRS. Using a simple motor and a simple

w xvisual task an increase in oxy-Hb and a decrease

w xin deoxy-Hb was observed over the area acti-Žvated by the respective stimulus see Fig. 2a for

the motor, Obrig et al., 1996a and Fig. 2b for avisual stimulus, Wenzel et al., 1996; Ruben et al.,

. w x1997 . By adding the changes in oxy-Hb andw x w xdeoxy-Hb a third parameter tot-Hb is obtainedcorresponding to the corpuscular blood volume,which in most cases is increased during the stimu-lation though a number of experiments have re-vealed only small or no significant increases in

Žthis parameter Obrig et al., 1996a,b; Wenzel et.al., 1996 .

These experiments were carried out with theNIRO-500 monitor. For the motor study opticalprobes were located over the left precentral re-

U Žgion, C3 according to the 10-20 system cf. Sec-.tion 8 . The stimulus consisted of a finger opposi-

tion task, opposing the thumb to each remainingfinger. The results for the right hand that iscontralateral to the probes are shown in Fig. 2a.For the visual study, probes were positioned overthe occipital region guided by a three-dimen-sional-reconstructed high resolution MRI, per-formed previous to the NIRS measurement. Thecortical structure aimed at was the calcarine fis-sure. A moving dodecahedron presented on acomputer screen served as the stimulus, ns 44

Žsubjects for motor ns16 subjects for visual. Ž .study , stimulus duration was 10 s 30 s , resting

Ž .period was 50 s 30 s ; 10]15 stimulation]restcycles were performed per subject. Data wereaveraged across cycles and subjects.

w xThe finding of a decrease in deoxy-Hb issomewhat controversial in the literature. Somegroups also report increases or changing responsedirection, all considered a response to the stimu-

Žlus Fallgatter et al., 1998; Hoshi and Tamura,.1997; Kato et al., 1993; Okada et al., 1993, 1994 .

w xSince the focal decrease in deoxy-Hb in an acti-vated cortical area has been long assumed toaccount for the susceptibility changes resulting in

U Ž . Žan increased T2 BOLD-contrast fMRI Ogawa.and Lee, 1990 a combined fMRI and NIRS studyŽ .was performed Kleinschmidt et al., 1996 .

ŽSimultaneous NIRO-500 with special non-magnetic optical probes, so called optodes, long

.enough to measure inside the magnet and fMRIŽ w xradio frequency-spoiled FLASH TRrTE ras


w x w x Ž . Ž .Fig. 2. Changes in oxy-Hb and deoxy-Hb in response to a simple motor task left and a visual stimulus right . The optical probesŽ .were located over the respective brain areas precentral region for motor, occipital region for visual stimulus . During the

w x w x Žstimulation there is an oxy-Hb increase and a decrease in deoxy-Hb . Note the different stimulus duration 10 s for motor 30 s for.visual stimulation . Data acquired with NIRO-500 monitor and averaged across all subjects.

w x .62.5r30 r108 measurements were performed.Subjects performed a finger opposition task for 16s followed by 32 s of rest. Stimulation periodswith the hand ipsi- and contralateral to the probelocation alternated. The optical probes were lo-cated over the precentral region of the left hemi-sphere according to a modified 10-20 systemaiming at the hand region of the precentral sul-cus. Marked by vitamin E capsules the exactprobe position could be assessed in the MRIimages. The functional MRIs were performed inan oblique slice orientation parallel to the planein which the optical probes were located. Thus, itwas possible to exactly project the optical probelocation onto the fMRI images.

The results indeed confirmed that NIRS bestw xshowed the response pattern of a deoxy-Hb de-

w xcrease and an oxy-Hb increase when locatedover the area with the maximal BOLD-signal

Ž .increase see Fig. 3 .When optimally positioned the NIRS-parame-

ter changes were lateralised, thereby providinganother argument for their cerebral origin. Whenlocated in the vicinity of the BOLD-contrast max-imum, different patterns were observed in part

w xwith a non-lateralised increase in oxy-Hb . Thesefindings stress the importance of a clearly definedNIRS response pattern to focal cerebral haemo-dynamic changes since systemic haemodynamic

Ž .changes heart rate, blood pressure may occurduring a functional stimulation which will lead toextracerebral and global cerebral changes in oxy-Hb and deoxy-Hb. These are bound to be con-founded with the locally-induced cerebral stimu-lation signal.

w xTo sum up, the decrease in deoxy-Hb can bejudged as a robust marker of cerebral oxygena-tion changes in response to cortical activation. It

w xis usually associated with an increase in oxy-Hbw xand less consistently with an increase in tot-Hb .

It is, however, a big step from the activation ofa neuronal population, most directly measured by


Fig. 3.


intracellular recordings to the vascular responseas demonstrated by the different imaging tech-niques. Not only is the understanding of manyaspects of neuro-vascular coupling incomplete, itis also well known that a number of pharmacolog-ical or pathological conditions will severely inter-

Žfere with or alter this very coupling Villringer.and Dirnagl, 1995 . It seems, therefore, desirable

to obtain more knowledge about the differentsteps from the activated neurone to the vascularresponse elicited.

3.2. Cytochrome-oxidase

Changes in cytochrome-oxidase redox statehave been a controversial issue ever since first

Ždescribed in the pioneering work of Jobsis Jobsis,¨. Ž .1977 . The issue is twofold: 1 the in vivo absorp-

tion spectrum of the enzyme is still an issue ofsome debate, though a number of studies havedemonstrated the difference spectrum of the oxi-dised and reduced state in the bloodless fluoro-

Žcarbon perfused animal in the near-infrared inpart also reflecting other oxygen-dependent chro-

. Žmophores of the respiratory chain Ferrari et al.,.1995; Tamura et al., 1988; Wray et al., 1988 .

These animal studies used extreme oxygenationstates from hyperoxygenation to anoxia to de-monstrate changes in the redox state of the en-

Ž .zyme. 2 For the issue discussed in this paper asecond controversy concerning the possibility ofan overall change in Cyt-ox redox state due to thecomparatively small changes in oxygenation andenergy consumption as expected during physiolog-ical activation of neuronal populations is of even

Ž .more relevance Cooper et al., 1998 . Thoughfunctional activation studies are far from solving

those issues they may provide data explicablerather under assumption of either a change or nochange in the enzyme’s energy state.

[ ]4. Experiment 1: validation of D Cyt-ox

The experiment was performed to test whetherthe changes in attenuation elicited by a functionalcortical stimulation provide evidence for changesin the cytochrome-oxidase redox state. Increases

w xin Cyt-ox were seen regularly in the first stimula-tion studies with simple motor and visual stimuli,using the NIRO-500 monitor. The discrete wave-

Ž .lengths algorithm Cope and Delpy, 1988a com-w xprises changes in Cyt-ox but due to the low

spectral resolution of the monitor some doubt asto whether the changes might be caused bycross-talk of the other chromophores could notbe eliminated. The data presented here have been

Ž .published elsewhere Kohl et al., 1998a .

4.1. Methods

Five subjects were examined using the CCD-approach and they underwent 30 stimulation cy-cles with a visual stimulation paradigm consistingof a checkerboard pattern alternating at 8 Hz.The optodes were located over the occipital re-gion guided by previous MRI images and aiming

Žat the calcarine fissure optode spacing of 3 cm,.sampling frequency 50 Hz . The recorded spectra

were averaged across all 30 cycles and meanŽspectra for the resting state 3 s prior to stimulus

. Žonset and stimulation from the 9th to the 12th.second of the stimulation period were calculated

for each subject. The difference spectrum stimu-

Ž . Ž .Fig. 3. Comparison between BOLD-contrast fMRI a and NIRS b measurement in a single subject with optimal probeŽ . Ž .positioning. a The upper part of the graph shows the oblique slice orientation top left and the position of the optical probes

Ž . worange circles . Two slices are shown during performance of the motor task in the contralateral hand top right and bottom right inŽ .x Ž . Ž .a . There is a clear increase in BOLD contrast along the precentral gyrus scale from yellow to red denoting correlation value . b

w x w x w Ž .xThe NIRS measurements show a clear decrease in deoxy-Hb and an increase in oxy-Hb right graphs of b . During ipsilateralw Ž .performance no significant contrast change can be seen in the precentral gyrus left bottom in a , slice corresponding to right

xbottom, the other slice is not shown but did not show any stimulation correlated signal change either . The NIRS measurementw x w x wŽ . xshows no significant decrease in deoxy-Hb and oscillations not correlated to the stimulus in oxy-Hb b left graphs . Big white

circles in the functional MRIs denote probe position, small circles denote the Vitamin E capsules by which the position wasŽ .assessed. The grey bar in b denotes the stimulation period.


lation-rest was then subjected to a two- and athree-component fit.

4.2. Results

When only the spectra for oxy-Hb and deoxy-HbŽ .were considered two-component fit there was a

substantial residual which clearly exhibits a fea-ture similar to the extinction spectrum of cy-

Žtochrome-oxidase see Fig. 4 left-hand graph; also.see Fig. 1b . Using the three-component fit with

the haemoglobin and the cytochrome-oxidasespectra the difference spectrum between stimula-tion and rest is much better explained, as indi-

Žcated by the essentially featureless residual Fig..4, right hand side . The stimulation-induced

changes calculated for the three chromophoresŽ . w xamounted to y0.101 0.069 mM for D deoxy-Hb ,

Ž . w xq0.117 0.093 mM for D oxy-Hb and q0.03Ž . w x w Ž .0.016 mM for D Cyt-ox mean S.D. across

xsubjects . The robustness of the response withinthe individual subjects was tested by t-tests across

the 30 stimulation cycles in each subject compar-wing stimulation and rest. The decrease in deoxy-

x ŽHb was always highly statistically significant P-.0.01 as was with a lower significance level the

w x Ž . w xincrease in Cyt-ox P-0.05 . For oxy-Hb thechanges were greatest in amplitude but the latterstatistical analysis did not reach P-0.05 in twosubjects.

4.3. Conclusions

w xThe results confirm changes in Cyt-ox whichare smaller in amplitude but seem to be a ratherrobust marker of the stimulation-inducedmetabolic changes. It should be noted that theassumption of a wrong differential pathlength

Ž .factor DPF , will falsely mimic concentrationchanges. Especially small changes, such as that ofw xCyt-ox , will hence be prone to cross-talk effects.

ŽSince DPF varies between subjects Duncan et.al., 1996 the concentration changes reported here

were calculated on the basis of an individually

w xFig. 4. Validation of Cyt-ox changes in response to visual stimulation. The top two graphs show the difference spectrumŽ . Ž . Ž .‘stimulation-rest’ dots and the two-component line in left upper graph or three-component line in the right upper graph fit. The

residuals for either fit are given in the graphs below. The residual for the two-component fit resembles the spectrum of Cyt-ox,whereas the three-component fit residual is essentially featureless.


assessed DPF. The proposed method to de-termine the individual wavelength dependence of

the DPF on the basis of the pulse-induced changesŽ .is described in the publication Kohl et al., 1998a .

Ž .Fig. 5. a The sketch demonstrates the probe array used to map the cortical response over the motion sensitive area MT. The greyŽ . Ž .symbols show the first position of the central light emitting probe star surrounded by the four detectors circles each 3 cm away

from the source. The black symbols show the position for the successive second measurement performed in 10 of the 14 s. TheŽ .whole array is shifted 1.5 cm laterally. b,c Rough mapping of the vascular and metabolic response over the motion sensitive

Ž . Ž .secondary visual area MT. b shows the results in all 14 subjects c gives an example of a subject in whom clear maxima could beŽ . Ž .seen for all three parameters. The grey-scale b and the bar scale c follow the r-values obtained by correlation of the recorded

data with a box car reference function respecting the vascular response latency.


It should be noted that the results of this studydo not solve the controversies mentioned above,we simply provide data which can be explainedbetter, when assuming changes in the redox state

Ž .of cytochrome-oxidase Heekeren et al., 1999 .We therefore currently investigate the issue in ananimal model.

Based on the findings validating the changes inw xCyt-ox we next examined the hypothesis thatmultilocular recording would allow for a spectros-copic ‘imaging’. Though the spatial resolution ofthe method is limited by the poorly defined pathof the photons, a number of imaging approacheshave been reported. First approaches performedsuccessive sampling of different optode locationsŽHirth et al., 1997; Hoshi and Tamura, 1993;

.Maki et al., 1995 which bears the possibility ofconfounding slow haemodynamic changes withspatial resolution. More recent multi-probe array

Žimaging approaches Benaron et al. 1994a; Be-naron and Stevenson, 1994b; Watanabe et al.,1996; Nioka et al., 1997; Villringer and Chance,

.1997; Shinohara et al., 1993 on the other handmostly trade the number of detectors for spectralresolution and do not allow for a clear spectros-copic differentiation of the vascular and metabolicparameters. It was, therefore, of special interestto investigate the feasibility of a multilocular de-

w xtection of D Cyt-ox .

5. Experiment 2: simultaneous mapping of(haemodynamic and metabolic response Wenzel

)et al., 1998

MT, an area of the extrastriate visual cortex, issensitive to movement of an object presented tothe observer. It has been broadly examined in the

Ž .monkey Zeki, 1980 and fMRI studies confirmedmany of the electrophysiological findings non-

Ž .invasively in the adult. Tootell et al. 1995 used astimulus of low contrast expanding and contract-ing rings, which resulted in a localised activationof the movement sensitive area. This stimulus wasused in the present study.

5.1. Methods

Fourteen subjects underwent 20 cycles of sti-mulation and rest while multilocular recordingswere acquired over their occiput. The CCD ap-proach was used with one light source and fourdetectors each 3 cm distant from the emitterwhich was placed 2 cm above and 3 cm lateral tothe inion. In 10 subjects a second recording wasperformed, with the array being located 1.5 cm

Ž .more lateral see Fig. 5a . Chromophore concen-tration changes in oxy-Hb, deoxy-Hb and Cyt-oxwere calculated according to the three-compo-nent linear fit model described above. Since themagnitude of the changes varied between subjectsand localisations, the response was analysed by

Žcorrelation with a simple box-car reference re-.specting the vascular response latency in analogy

Žto fMRI analysis strategies Bandettini et al.,.1993; Kleinschmidt et al., 1995 . The r-value

Ž .Pearson product coefficient was used to map theresponse.

5.2. Results

Fig. 5b shows the distribution of different r-value levels for all three parameters in all sub-jects. In 10 subjects at least one area was demon-strated to show a stimulus correlated increase inw x w xoxy-Hb , decrease in deoxy-Hb and increase inw xCyt-ox with a significant correlation with the

Žreference box-car function for ss 3, 9, 10 and 13there are no pixels in which all three parameters

.show the typical response . These changes arelocalised. Fig. 5c gives an example of one subjectwith clear maxima for each parameter.

5.3. Conclusions

The experiment demonstrates that spectros-copic imaging is possible with NIRS. It is the first

w xreport to demonstrate a rough imaging of Cyt-oxchanges. The distribution of these changes gener-ally coincides with those of the vascular parame-ters. The study opens up the perspective of acoregistration with fMRI to find out about poten-


tial spatial differences between vascular andmetabolic changes. The parameter might also beof relevance in, patients with a compromised vas-cular response, whose metabolic response may bepreserved.

To sum up we demonstrated the validity of thew xmetabolic parameter of Cyt-ox and showed the

feasibility of spectroscopic imaging.

6. Other potential parameters: scatter and fastoptical changes

Ž .The continuous wave CW approaches de-scribed above assume that the mean pathlengthof the photons does not change over the course ofthe experiment. However, this cannot be directlymeasured, a pure change in scatter will changethe pathlength and also alter the intensity of thelight detected. Changes in pathlength can, how-ever, be detected by measuring the mean time offlight of the light or the phase shift of an inten-sity-modulated light wave. The changes in attenu-ation due to scatter are small when compared tothe changes in attenuation caused by absorptionchanges due to the changes in chromophore con-centration. Hence, for the assessment of the vas-cular response these changes in scatter introducebut a negligible error to the oxygenation changesmeasured. On the other hand, changes in scatterindependent or temporally clearly distinct fromthe vascular response may contain additional in-formation about the tissue illuminated. One ofthe most intriguing hypothesis is that fast changeswithin the first few hundreds milliseconds afterstimulus onset reflect changes related to the elec-trophysiological activation of neuronal popula-tions. It is established, that the analysis of re-flectance from exposed single cells reveals changesin the optical properties of the cells simultaneousto the DC-changes evoked by the electrical dis-

Žcharge of the neurone Stepnoski et al., 1991;.Rector et al., 1997 . Lately, the group of Gratton

Ž .Gratton et al., 1995b, 1997a,b has reportedsimilar observations non-invasively in the adultwith an intensity-modulation system. So far ourgroup could not reproduce the reported data of aphase shift within the first 200 ms after checker-

board reversal. We, therefore, performed aMonte-Carlo simulation based on the reported

Ž .changes in the animal Rector et al., 1997 as wellas the multi-layer model of the adult head pub-

Ž .lished by Okada et al. 1997 to estimate theexpected range of changes for the adult head.According to this estimation the magnitude of theeffect is so small that the noise level of themeasurements with the monitor used in the publi-cation is greater than the effect itself. The noiselevel of the DC- and Phase-signal were approxi-mately 0.5‰ and 0.028, respectively. The theoret-

Ž .ically estimated signal Monte-Carlo simulationis in the order of 0.1‰ for DC and 0.00058 forthe phase signal. An altered technology is, there-fore, required to detect the signal non-invasivelyin the adult.

The potential, however, of a possible co-reg-Ž .istration of neuronal activity, metabolic Cyt-ox

Ž .and heamodynamic oxy-Hb, deoxy-Hb changesseems tantalising enough to further investigatethe field.

7. Signal physiology

Besides the perspective of supplying informa-tion about additional parameters of neurovascu-lar coupling non-invasively in the human, NIRShas already proven its potential to help confirmassumptions underlying the use of BOLD-con-

Ž .trast imaging see Fig. 3 . The method’s spatialresolution is poor but temporal resolution andmore important the specificity as to the vascular

w x w xparameters of D oxy-Hb andD deoxy-Hb arehigh, which offers the perspective of combiningthe complimentary strengths of either method.

7.1. ‘ Acti ation’ and ‘deacti ation’

In a combined fMRI and NIRS study lately oneŽ .of the authors RW challenged the simple con-

cept of cortical ‘activation’ used in many functio-nal imaging studies. The current concept is

Ž .founded on the findings of Fox and Raichle 1986who were the first to describe the disproportionalaugmentation of oxygen supply and oxygen up-take in a functionally activated cortical area. The


Ž .Fig. 6. a Prediction of responses to longer stimulation periods from short durations. Responses to a visual stimulus of 3, 6, 12 and24 s were obtained. It was then tested whether the responses of the longer stimulation periods could be predicted by adding and

Ž .shifting the response to the respective shorter duration. The graphs show the predicted solid line and the actually measuredŽ . w x Ž .responses open circles in one subject for the changes in deoxy-Hb . The response to 3 s is not shown. b , Selective averaging of

responses, examining whether the response to short stimuli can be assumed to sum up in a linear fashion when following in briefŽ .succession. The short stimulus 1 s of a checkerboard reversing at 8 Hz was either presented once, twice or three times during a

Ž . Ž . Ž .30-s experimental run. The time of presentation is denoted by the black triplet , grey doublet and white single bars at thew x Žbottom of the left hand graph. The deoxy-Hb changes shown show the greatest and longest response for the triple stimulus black

. w x Ž .circles left hand graph . On the right hand graph the deoxy-Hb -responses to the single white and the predicted responsesŽ . Ž .obtained by subtraction of double minus single grey and triple minus double black are shown.


phenomenon termed ‘focal uncoupling’ implies aclearly defined resting state as the baseline forchanges evoked by the functional challenge.

Investigating a deactivation paradigm for thevisual cortex it was demonstrated that inversechanges for the vascular NIRS parameters, i.e. a

w x wdecrease in oxy-Hb and an increase in deoxy-xHb , as well as a decrease in BOLD contrast

occur. This finding implies that the transitionfrom ‘deactivation’ to ‘rest’ to ‘activation’ is a

Žcontinuous equilibrium. Data submitted for pub-.lication .

7.2. Linearity of the response

A related issue of relevance for the interpreta-tion and understanding of BOLD-contrast imag-

Žing, is the issue of linearity Buckner et al., 1996;.Friston et al., 1998; Dale and Buckner, 1997 .

This issue is of particular interest when examin-ing stimuli with a duration much shorter than theexpected latency of the vascular response or ifdifferent events of the stimulation protocol suc-

Žceed with a short latency Dale and Buckner,.1997; Josephs et al., 1997 . Only if the vascular

response adds up linearly the individual responseto each stimulus can be derived from the overallresponse allowing for ‘single-trial’ or ‘event-

Ž .related’ study designs Rosen et al., 1998 . Theother side of this issue addresses the question inhow far the response to a longer stimulationperiod, as used in the classical ‘block’-design stud-ies, can be predicted from the response to ashorter stimulus duration. Apart from potentiallyreducing examination time, such ‘single-trial’ de-signs are a prerequisite for the examination ofmany complex tasks, which consist of a succession

Ž .of brief events Dale and Buckner, 1997 .The results of the first experiment testing for

predictability of the response to longer, based onthat to short stimulation periods are shown in Fig.6a. For stimulus durations of 6]24 s a goodprediction could be obtained. The second experi-ment used short visual stimuli of 1-s duration,which were presented as a single- double- ortriple-trial within the stimulus epoch of 30 s. Thevascular responses to the different conditionsdiffered in latency and amplitude. By subtracting

the respective responses, however, single-trial andthe prediction from the double and triplet matchquite well.

The results of these two NIRS studies confirmwa roughly linear response for the changes in de-

x w xoxy-Hb . Interestingly the changes in Cyt-ox alsoŽ .show a roughly linear behaviour data not shown .

ŽData submitted for publication Wobst et al.,.1998 .

8. Application of the ‘single trial’ approach

ŽProceeding from the simple motor study see.Fig. 2a and with the knowledge of the applicabil-

ity of single trial designs we examined whethermore complex psychomotor tasks and their vascu-lar response can be examined by NIRS.

( )8.1. Experiment 3: premotor potentials CNV andtheir haemodynamic response

When subjects receive a warning stimulus be-fore a GorNoGo choice motor reaction task aslow negative potential can be detected by EEGover the premotor areas with a predominance

Žover the right hemisphere Brunia and Damen,. Ž1988; Roberts et al., 1994 ‘contingent negative

. Ž .variation’, CNV . Fallgatter et al. 1997 and Fall-Ž .gatter and Strik 1997 reported results of a NIRS

study using a similar paradigm to find a change inw xdeoxy-Hb with a right hemisphere predomi-nance. The study, however, did not examine thedifferential response to Go and NoGo trials, thus,only demonstrating a difference between taskperformance and rest. There may be some doubtas to the specificity of the cerebral origin of suchchanges since a systemic haemodynamic responseby a rather demanding task cannot be easily ex-cluded.

8.2. Methods

Ten subjects watched a computer screen onwhich the letters ‘X’, ‘O’, ‘L’, ‘H’, ‘Z’ and ‘T’appeared in a pseudorandom order every 3.5 s.The subjects were asked to briskly press a button


Ž .whenever an ‘X’ S1, warning stimulus was fol-Ž .lowed by an ‘O’ S2-‘Go’, response stimulus . If

Žany of the other letters followed S2-‘NoGo’ re-.sponse stimulus the prepared action had to be

suppressed. When the letter ‘L’ appeared an im-Ž .mediate button press was required CONTROL .

The order of the letters was such that each of theŽ .three conditions Go, NoGo, CONTROL oc-

curred 12 times per experimental session andcould not be foreseen by the subject. Also theconditions were separated by at least 14.5 s toprevent an overlap of the vascular responses. Allsubjects performed two sets of the protocol re-

Ž .sponding either with the ipsilateral right or withŽ .the contralateral left index finger. NIRS mea-

surements were performed over two sites simulta-neously, with one pair of optical probes over C4U

aiming at the hand area of the right precentralgyrus while the second pair was localised 4.5 cm

Ž .anteriorly F4rFp2 to sample from premotor ar-eas. The usual measures to minimise artefactswere taken. Spectra from both sites were simulta-neously recorded with a 4-Hz sampling frequency.

8.3. Data analysis

Concentration changes were calculated accord-ing to the above described linear fitting routine.

w x w xChanges in oxy-Hb and deoxy-Hb were aver-aged for each channel and condition and aver-aged separately for each subject. For statisticalanalysis mean changes of three temporal windowswere assessed in each subject and for each condi-

Ž .tion: 1 the last 2 s before presentation of S2Ž .s‘CNVmax’; 2 from second 4 to 6 after presen-

Ž .tation of S2s‘response’; and 3 from second 8 to10 after S2spost-stimulus ‘undershoot’.

8.4. Results

Fig. 7a shows the results of the CONTROLŽ .condition across all subjects . There is a clear

w xdecrease in deoxy-Hb , peaking, 5 s after thebrisk single movement. This response is moreclearly seen in the channel overlying the primary

Ž . wmotor area open circles . The increase in oxy-xHb peaks with a similar latency but exhibits a

clear undershoot 10 s after the single movement.Fig. 7b shows the results for the ‘NoGo’ and ‘Go’

w xcondition. The decrease in deoxy-Hb clearlystarts at the presentation of the warning stimulusfor the NoGo condition over the premotor area,which can be judged as the haemodynamic equiv-alent to the CNV. The Go condition elicits a

w xdecrease in deoxy-Hb over the motor area, peak-ing, 5 s after the single response movement. Mean

Table 1w x Ž .Mean changes in deoxy-Hb for the experiment investigating the vascular response to premotor potentials ‘CNV’ . The table gives

Ž . Ž .the changes for both conditions GO and NoGo and both channels premotor and motor . Compare Fig. 7b

NoGo Go

Premotor Motor Premotor Motor

Subject Cnv Resp Cnv Resp Cnv Resp Cnv Resp

1 0.07 0.11 0.04 0.14 y0.28 y0.01 y0.15 0.102 0.05 y0.16 0.05 y0.38 y0.01 0.07 0.00 0.153 y0.10 y0.18 0.11 0.17 0.09 y0.22 0.03 0.024 y0.01 y0.22 y0.04 y0.18 y0.13 y0.13 y0.11 y0.245 0.24 0.10 0.20 0.13 0.00 y0.08 y0.17 y0.466 0.09 y0.03 y0.41 y0.19 0.06 y0.01 y0.57 y0.307 y0.21 y0.07 y0.10 0.02 0.16 0.06 y0.01 0.378 y0.13 0.18 y0.21 y0.04 y0.11 y0.13 y0.07 y0.659 y0.88 y1.25 y0.11 0.20 y0.53 0.19 y0.47 y0.61

10 y0.20 y0.11 y0.13 y0.21 0.01 0.20 0.05 y0.36Mean y0.17 y0.18 y0.10 y0.06 y0.07 y0.01 y0.15 y0.27S.D. 0.26 0.37 0.14 0.18 0.19 0.13 0.20 0.27P 0.04 0.09 0.03 0.18 0.14 0.44 0.03 0.01


Fig. 7. Response to a single brisk flexion of the left index finger. Data were recorded over the ‘motor’- and the ‘premotor’-areaŽ . w x w xlocalisation by 10-20 system . There is a clear decrease in deoxy-Hb and an increase in oxy-Hb with a maximum of 5 s after the

Ž .movement. Also note the greater changes over the ‘motor’ recording site compared to the ‘premotor’ recording site. b , Responsesw x w x w xfor ‘Go’ and ‘NoGo’ condition in deoxy-Hb and oxy-Hb . The decrease in deoxy-Hb clearly starts with the presentation of the S1

warning stimulus in both conditions. The difference between the ‘NoGo’ and the ‘Go’ condition is clearly seen in both parametersw x w x Ž .showing a pronounced decrease in deoxy-Hb and an increase in oxy-Hb followed by a large undershoot cf. Fig. 7a and Fig. 2 .

The shaded bar denotes the period between presentation of the warning stimulus S1 and the response stimulus S2 in whichŽ .electrophysiologically a contingent negative variation CNV is expected over right premotor areas.

w xdeoxy-Hb changes in the temporal windows andresults of paired one sided t-statistics againstbaseline are given in Table 1. In the course of the

w xexperiment changes in oxy-Hb showed oscilla-tions apparently independent of the stimuli, whichaccentuate the problem of relating the changes toa baseline. The only feature which could be re-producibly seen was a clear difference between‘Go’ and ‘NoGo’ condition with respect to the

w xpoststimulus undershoot. The increase in oxy-Hbduring the CNV period is not seen for the NoGocondition, in which the same change would beexpected.

8.5. Conclusions

The experiment demonstrates that the re-sponse to complex stimuli can be detected byNIRS. Though spatial resolution is low we alsosaw a differential response in the two channels,allowing for a rough differentiation between the‘motor’ and ‘premotor’ response to the differentconditions. The experiment also demonstrates thefeasibility and usefulness of the ‘single trial’ ap-proach for NIRS. This approach allows for theanalysis of events of the stimulation protocolwhose duration is much shorter than the latency


of the vascular response. The experiments wereperformed without MRI-guided positioning of theprobe positions. By a combined approach NIRSmight well provide temporal and parameter-specific information to disentangle the complex‘activation’r‘deactivation’ processes evoked bycomplex stimuli.

9. Summary and outlook

The data presented here allow for the conclu-sion, that NIRS does have its role in functionalresearch of the adult brain. Not only does themethod supply data compatible with the es-tablished imaging techniques, the assessment ofcellular metabolic changes in response to functio-nal challenge provides additional information onthe basis of functional imaging, i.e. neuro-vascu-lar coupling. We were not able to replicate results

Žof Gratton et al. Gratton, 1997; Gratton andCorballis, 1995a; Gratton et al., 1994, 1995b,

.1997a,b, 1998 indicating the feasibility of a tran-scranial monitoring of fast optical signals. Analtered technical approach may prove that theeffect is much smaller than the one reported byGratton, also it may be feasible only in subjects,whose extracerebral tissue is very permissive toNIR light. The perspective to simultaneously as-sess neuronal activity, metabolic and vascular re-sponse, however, is most intriguing and needs tobe further examined.

Relying on the presently established parame-w x w xters of D oxy-Hb and D deoxy-Hb only, the

method’s perspective lies in the investigation ofthe basis of functional imaging, especially fMRIsignal physiology. This will be of special interestwhen pathophysiological conditions, in whomneurovascular coupling is disturbed are examined.The method may thereby, and by its easy appli-cability at the bedside, become a valuable tool tocomplete and follow up functional diagnostics inpatients.

The major shortcoming of the method is itspoor spatial resolution. In part this can be over-come by multiple site recordings and the furtherdevelopment of imaging approaches. Since theexact path of the light can only be described in a

statistical manner there are, however, limitationsinherent to the methodology. We, therefore, con-sider combined experimental approaches withNIRS and fMRI to be valuable to analyse thecerebral response to complicated stimuli as de-scribed in the last experiment. Such an approachcan rely on the excellent spatial resolution offMRI and use NIRS’ signal specificity and goodtemporal resolution.

References

Bandettini, P.A., Jesmanowicz, A., Wong, E.C., Hyde, J.S.,1993. Processing strategies for time-course data sets infunctional MRI of the human brain. Magn. Reson. Med.30, 161]173.

Belliveau, J.W., Kwong, K.K., Kennedy, D.N. et al., 1992.Magnetic resonance imaging mapping of brain function.Human visual cortex. Invest. Radiol. 27 Suppl 2, S59]S65.

Benaron, D.A., Ho, D.C., Spilman, S., Van, H.J., Stevenson,D.K., 1994a. Tomographic time-of-flight optical imagingdevice. Adv. Exp. Med. Biol. 361, 207]214.

Benaron, D.A., Stevenson, D.K., 1994b. Resolution of nearinfrared time-of-flight brain oxygenation imaging. Adv. Exp.Med. Biol. 345, 609]617.

Brunia, C.H., Damen, E.J., 1988. Distribution of slow brainpotentials related to motor preparation and stimulus antici-pation in a time estimation task. Electroencephalogr. Clin.Neurophysiol. 69, 234]243.

Buckner, R.L., Bandettini, P.A., O’Craven, K.M. et al., 1996.Detection of cortical activation during averaged single tri-als of a cognitive task using functional magnetic resonanceimaging. Proc. Natl. Acad. Sci. U.S.A. 93, 14878]14883.

Cooper, C.E., Delpy, D.T., Nemoto, E.M., 1998. The relation-ship of oxygen delivery to absolute haemoglobin oxygena-tion and mitochondrial cytochrome oxidase redox state inthe adult brain: a near-infrared spectroscopy study.Biochem. J. 332, 627]632.

Cope, M., Delpy, D.T., 1988a. System for long-term measure-ment of cerebral blood and tissue oxygenation on newborninfants by near infra-red transillumination. Med. Biol Eng.Comput. 26, 289]294.

Cope, M., Delpy, D.T., Reynolds, E.O., Wray, S., Wyatt, J.,van, d.Z., 1988b. Methods of quantitating cerebral nearinfrared spectroscopy data. Adv. Exp. Med. Biol. 222,183]189.

Dale, A.M., Buckner, R.L., 1997. Selective averaging of rapidlypresented individual trials using fMRI. Hum. Brain Mapp.5, 329]340.

Duncan, A., Meek, J.H., Clemence, M. et al., 1996. Measure-ment of cranial optical path length as a function of ageusing phase resolved near infrared spectroscopy. Pediatr.Res. 39, 889]894.

Fallgatter, A.J., Strik, W.K., 1997. Right frontal activationduring the continuous performance test assessed with


near-infrared spectroscopy in healthy subjects. Neurosci.Lett. 223, 89]92.

Fallgatter, A.J., Brandeis, D., Strik, W.K., 1997. A robustassessment of the NoGo-anteriorisation of P300 micros-tates in a cued Continuous Performance Test. Brain To-pogr. 9, 295]302.

Fallgatter, A.J., Muller, T.J., Strik, W.K., 1998. Prefron-tal hypooxygenation during language processing assessedwith near-infrared spectroscopy. Neuropsychobiology 37,215]218.

Ferrari, M., Williams, M.A., Wilson, D.A., Thakor, N.V.,Traystman, R.J., Hanley, D.F., 1995. Cat brain cytochrome-coxidase redox changes induced by hypoxia after blood-flu-orocarbon exchange transfusion. Am. J. Physiol. 269,H417]H424.

Fox, P.T., Raichle, M.E., 1986. Focal physiological uncouplingof cerebral blood flow and oxidative metabolism duringsomatosensory stimulation in human subjects. Proc. Natl.Acad. Sci. U.S.A. 83, 1140]1144.

Frahm, J., Bruhn, H., Merboldt, K.D., Hanicke, W., 1992.Dynamic MR imaging of human brain oxygenation duringrest and photic stimulation. J. Magn. Reson. Imaging 2,501]505.

Friston, K.J., Fletcher, P., Josephs, O., Holmes, A., Rugg,M.D., Turner, R., 1998. Event-related fMRI: characterizingdifferential responses. Neuroimage 7, 30]40.

Gratton, G., 1997. Attention and probability effects in thehuman occipital cortex: an optical imaging study. Neurore-port 8, 1749]1753.

Gratton, G., Corballis, P.M., 1995. Removing the heart fromthe brain: compensation for the pulse artifact in the photonmigration signal. Psychophysiology 32, 292]299.

Gratton, G., Maier, J.S., Fabiani, M., Mantulin, W.W., Grat-ton, E., 1994. Feasibility of intracranial near-infrared opti-cal scanning. Psychophysiology 31, 211]215.

Gratton, G., Corballis, P.M., Cho, E., Fabiani, M., Hood, D.C.,1995. Shades of gray matter: noninvasive optical images ofhuman brain responses during visual stimulation. Psy-chophysiology 32, 505]509.

Gratton, G., Fabiani, M., Corballis, P.M., Gratton, E., 1997a.Noninvasive detection of fast signals from the cortex usingfrequency-domain optical methods. Ann. N.Y. Acad. Sci.820, 286]298.

Gratton, G., Fabiani, M., Corballis, P.M. et al., 1997b. FastŽ .and localized event-related optical signals EROS in the

human occipital cortex: comparisons with the visual evokedpotential and fMRI. Neuroimage 6, 168]180.

Gratton, G., Fabiani, M., Goodman-Wood, M.R., Desoto,M.C., 1998. Memory-driven processing in human medial

Ž .occipital cortex: an event-related optical signal EROSstudy. Psychophysiology 35, 348]351.

Heekeren, H.R., Kohl, M., Obrig, H. et al., 1999. NoninvasiveAssessment of Changes in Cytochrome-C-Oxidase Oxida-tion in Human Subjects during Visual Stimulation. J. Cereb.Blood Flow Metab. in press,

Hirth, C., Villringer, K., Thiel, A. et al., 1997. Towards brainmapping combining near-infrared spectroscopy and highresolution 3D MRI. Adv. Exp. Med. Biol. 413, 139]147.

Hoshi, Y., Tamura, M., 1993. Dynamic multichannel near-in-frared optical imaging of human brain activity. J. Appl.Physiol. 75, 1842]1846.

Hoshi, Y., Tamura, M., 1997. Near-infrared optical detectionof sequential brain activation in the prefrontal cortex dur-ing mental tasks. Neuroimage 5, 292]297.

Hoshi, Y., Onoe, H., Watanabe, Y. et al., 1994. Non-synchro-nous behavior of neuronal activity, oxidative metabolismand blood supply during mental tasks in man. Neurosci.Lett. 172, 129]133.

Jobsis, F.F., 1977. Noninvasive, infrared monitoring of cere-bral and myocardial oxygen sufficiency and circulatoryparameters. Science 198, 1264]1267.

Josephs, O., Turner, R., Friston, K., 1997. Event-related fMRI.Hum. Brain Mapp. 5, 243]248.

Kato, T., Kamei, A., Takashima, S., Ozaki, T., 1993. Humanvisual cortical function during photic stimulation moni-toring by means of near-infrared spectroscopy. J. Cereb.Blood Flow Metab. 13, 516]520.

Kleinschmidt, A., Hanicke, W., Requardt, M., Merboldt, K.D.,Frahm, J., 1995. Strategies for data analysis of brain activa-

Žtion studies with functional MR tomography Strategiender Datenanalyse in Hirnaktivierungsstudien mit funk-

.tioneller MR-Tomografie . Radiologe 35, 242]251.Kleinschmidt, A., Obrig, H., Requardt, M. et al., 1996. Simul-

taneous recording of cerebral blood oxygenation changesduring human brain activation by magnetic resonanceimaging and near-infrared spectroscopy. J. Cereb. BloodFlow Metab. 16, 817]826.

Kohl, M., Nolte, C., Heekeren, H. et al., 1998a. Changes incytochrome-oxidase oxidation in the occipital cortex duringvisual stimulation: Improvement in sensitivity by the de-termination of the wavelength dependence of the differen-tial pathlength factor. SPIE conference proceedings 18]27.

Kohl, M., Nolte, C., Heekeren, H.R. et al., 1998b. Determina-tion of the wavelength dependence of the differential path-length factor from near-infrared pulse signals. Phys. Med.Biol. 43, 1771]1782.

Maki, A., Yamashita, Y., Ito, Y., Watanabe, E., Mayanagi, Y.,Koizumi, H., 1995. Spatial and temporal analysis of humanmotor activity using noninvasive NIR topography. Med.Phys. 22, 1997]2005.

Matcher, S.J., Cope, M., Delpy, D.T., 1994. Use of the waterabsorption spectrum to quantify tissue chromophore con-centration changes in near-infrared spectroscopy. Phys.Med. Biol. 39, 177]196.

Meek, J.H., Elwell, C.E., Khan, M.J. et al., 1995. Regionalchanges in cerebral haemodynamics as a result of a visualstimulus measured by near infrared spectroscopy. Proc. R.Soc. Lond. B. Biol. Sci. 261, 351]356.

Nioka, S., Luo, Q., Chance, B., 1997. Human brain functionalimaging with reflectance CWS. Adv. Exp. Med. Biol. 428,237]242.


Obrig, H., Hirth, C., Junge-Hulsing, J.G. et al., 1996a. Cere-bral oxygenation changes in response to motor stimulation.J. Appl. Physiol. 81, 1174]1183.

Obrig, H., Wolf, T., Doge, C., Hulsing, J.J., Dirnagl, U.,Villringer, A., 1996b. Cerebral oxygenation changes duringmotor and somatosensory stimulation in humans, as mea-sured by near-infrared spectroscopy. Adv. Exp. Med. Biol.388, 219]224.

Ogawa, S., Lee, T.M., 1990. Magnetic resonance imaging ofblood vessels at high fields: in vivo and in vitro measure-ments and image simulation. Magn. Reson. Med. 16, 9]18.

Ogawa, S., Lee, T.M., Kay, A.R., Tank, D.W., 1990. Brainmagnetic resonance imaging with contrast dependent onblood oxygenation. Proc. Natl. Acad. Sci. U.S.A. 87,9868]9872.

Okada, F., Tokumitsu, Y., Hoshi, Y., Tamura, M., 1993. Gen-der- and handedness-related differences of forebrain oxy-genation and hemodynamics. Brain Res. 601, 337]342.

Okada, F., Tokumitsu, Y., Hoshi, Y., Tamura, M., 1994. Im-paired interhemispheric integration in brain oxygenationand hemodynamics in schizophrenia. Eur. Arch. PsychiatryClin. Neurosci. 244, 17]25.

Okada, E., Firbank, M., Schweiger Arridge, S.R., Cope, M.,Delpy, D.T., 1997. Theoretical and experimental investiga-tion of near-infrared light propagation in a model of theadult head. Appl. Optics 36, 21]31.

Rector, D.M., Poe, G.R., Kristensen, M.P., Harper, R.M.,1997. Light scattering changes follow evoked potentialsfrom hippocampal Schaeffer collateral stimulation. J. Neu-rophysiol. 78, 1707]1713.

Roberts, L.E., Rau, H., Lutzenberger, W., Birbaumer, N.,1994. Mapping P300 waves onto inhibition: GorNo-Godiscrimination. Electroencephalogr. Clin. Neurophysiol. 92,44]55.

Rosen, B.R., Buckner, R.L., Dale, A.M., 1998. Event-relatedfunctional MRI: past, present, and future. Proc. Natl. Acad.Sci. U.S.A. 95, 773]780.

Ruben, J., Wenzel, R., Obrig, H. et al., 1997. Haemoglobinoxygenation changes during visual stimulation in the occipi-tal cortex. Adv. Exp. Med. Biol. 428, 181]187.

Shinohara, Y., Takagi, S., Shinohara, N. et al., 1993. OpticalCT imaging of hemoglobin oxygen-saturation using dual-wavelength time gate technique. Adv. Exp. Med. Biol. 333,43]46.

Shiotsuka, S., Atsumi, Y., Ogata, S. et al., 1998. Cerebralblood volume in the sleep measured by near-infrared spec-troscopy. Psychiatry Clin. Neurosci. 52, 172]173.

Stepnoski, R.A., LaPorta, A., Raccuia-Behling, F., Blonder,G.E., Slusher, R.E., Kleinfeld, D., 1991. Noninvasive detec-tion of changes in membrane potential in cultured neuronsby light scattering. Proc. Natl. Acad. Sci. U.S.A. 88,9382]9386.

Tamura, M., Hazeki, O., Nioka, S., Chance, B., Smith, D.S.,1988. The simultaneous measurements of tissue oxygenconcentration and energy state by near-infrared and nu-clear magnetic resonance spectroscopy. Adv. Exp. Med.Biol. 222, 359]363.

Tamura, M., Hoshi, Y., Okada, F., 1997. Localized near-in-frared spectroscopy and functional optical imaging of brainactivity. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 352,737]742.

Tootell, R.B., Reppas, J.B., Dale, A.M. et al., 1995. Visualmotion aftereffect in human cortical area MT revealed byfunctional magnetic resonance imaging. Nature 375,139]141.

Villringer, A., Chance, B., 1997. Non-invasive optical spectros-copy and imaging of human brain function. Trends. Neu-rosci. 20, 435]442.

Villringer, A., Dirnagl, U., 1995. Coupling of brain activity andcerebral blood flow: basis of functional neuroimaging.Cerebrovasc. Brain Metab. Rev. 7, 240]276.

Villringer, A., Planck, J., Hock, C., Schleinkofer, L., Dirnagl,Ž .U., 1993. Near infrared spectroscopy NIRS : a new tool to

study hemodynamic changes during activation of brainfunction in human adults. Neurosci. Lett. 154, 101]104.

Watanabe, E., Yamashita, Y., Maki, A., Ito, Y., Koizumi, H.,1996. Non-invasive functional mapping with multi-channelnear infra-red spectroscopic topography in humans. Neu-rosci. Lett. 205, 41]44.

Watanabe, E., Maki, A., Kawaguchi, F. et al., 1998. Non-inva-sive assessment of language dominance with near-infraredspectroscopic mapping. Neurosci. Lett. 256, 49]52.

Wenzel, R., Obrig, H., Ruben, J. et al., 1996. Cerbral bloodoxygenation changes induced by visual stimulation in hu-mans. J. Cereb. Blood Flow Metab. 1, 399]404.

Wenzel, R., Horst, S., Obrig, H., Henning, C., Kohl, M. andVillringer, A., 1998. Localised cytochrome-oxidase redoxstate and haemoglobin oxygenation response over visualarea MT shown with a multioculor full-spectrum NIRS.

Ž .Neuroimage 7, S258 Abstract .Wobst, P., Wenzel, R., Kohl, M., Villringer, A., 1998. Assess-

ment of linearity of the oxygenation response to visualŽ .stimulation Abstract . Proc. Soc. Neurosci. 24, 432.

Wray, S., Cope, M., Delpy, D.T., Wyatt, J.S., Reynolds, E.O.,1988. Characterization of the near infrared absorptionspectra of cytochrome aa3 and haemoglobin for the non-invasive monitoring of cerebral oxygenation. Biochim. Bio-phys. Acta 933, 184]192.

Zeki, S., 1980. The response properties of cells in the middleŽ .temporal area area MT of owl monkey visual cortex. Proc.

R. Soc. Lond. B. Biol. Sci. 207, 239]248.

Near-infrared spectroscopy: does it function in functional activation studies of the adult brain?

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