OPTO−ELECTRONICS REVIEW 22(1), 55–67 DOI: 10.2478/s11772−014−0178−y
Time-resolved multi-channel optical system for assessment of brain oxygenation and perfusion by monitoring of diffuse reflectance and fluorescence D. MILEJ1*, A. GEREGA1, M. KACPRZAK1, P. SAWOSZ1, W. WEIGL2, R. MANIEWSKI1, and A. LIEBERT1 1Nalecz
Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, 4 Ks. Trojdena Str., 02–109, Warsaw, Poland 2Warsaw Praski Hospital, Department of Intensive Care and Anesthesiology, 67 Al. Solidarności Str., 03–401 Warsaw, Poland Time−resolved near−infrared spectroscopy is an optical technique which can be applied in tissue oxygenation assessment. In the last decade this method is extensively tested as a potential clinical tool for noninvasive human brain function monitoring and imaging. In the present paper we show construction of an instrument which allows for: (i) estimation of changes in brain tissue oxygenation using two−wavelength spectroscopy approach and (ii) brain perfusion assessment with the use of sin− gle−wavelength reflectometry or fluorescence measurements combined with ICG−bolus tracking. A signal processing algo− rithm based on statistical moments of measured distributions of times of flight of photons is implemented. This data analysis method allows for separation of signals originating from extra− and intracerebral tissue compartments. In this paper we present compact and easily reconfigurable system which can be applied in different types of time−resolved experiments: two−wavelength measurements at 687 and 832 nm, single wavelength reflectance measurements at 760 nm (which is at maxi− mum of ICG absorption spectrum) or fluorescence measurements with excitation at 760 nm. Details of the instrument con− struction and results of its technical tests are shown. Furthermore, results of in−vivo measurements obtained for various modes of operation of the system are presented.
Keywords: diffuse reflectance and fluorescence, time−resolved optical measurements, brain perfusion, brain oxygenation.
1. Introduction Near−infrared spectroscopy (NIRS) is an optical technique which was proposed for measurement and monitoring of oxyge nation changes in human brain [1]. The method is based on estimation of changes in oxy− and deoxyhemoglo− bin concentration by utilization of different spectral proper− ties [2] of these two forms of hemoglobin contained in blood. In numerous studies it was shown that this technique can be used as an effective tool for monitoring of changes in brain oxygenation during neurophysiological experiments and in assessment of brain perfusion insufficiencies [3–7]. In relation to the most popular brain imaging techniques (MRI [8], CT [9], SPECT [10–12] or PET [13]), NIRS tech− nique can be characterized by a relatively low cost, appli− cability at the bedside, and non−invasiveness. As an effect of technological development the NIRS technique underwent a serious evolution. Three modes of operation were proposed which differ in technical advance− ment, price and flexibility of use. Continuous wave NIRS *e−mail:
[email protected]
Opto−Electron. Rev., 22, no. 1, 2014
(cwNIRS) is based on assessment of changes in intensity of light diffusely reflected from the tissue at a distance of 1–5 cm. This technique and its modifications based on multi−distance detection [14–16] is most popular because of low cost and compactness of instrumentation [17–19]. Fre− quency−domain NIRS (fdNIRS) makes use of sub−GHz fre− quency modulation of intensity of the light delivered to the tissue and allows for estimation of pathlength of photons in the tissue by analysis of phase shift between the light waves emitted to the medium and diffusely reflected [20–22]. Most advanced NIRS technique, called time−resolved NIRS (trNIRS) [23–29], is based on emission of picosecond light pulses and analysis of distributions of times of flight of diffusely reflected photons. A methodology based on measurement of diffuse reflec− tance combined with optical contrast agent tracking was developed for assessment of cerebral perfusion [30–33]. In this respect indocyanine green (ICG) is considered as a va− luable contrast agent revealing high absorption in near infra− red wavelength region [34] which can be safely [35] used in clinical studies [36–38]. In some of these studies the time− −resolved optical systems were applied in order to eliminate
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Time−resolved multi−channel optical system for assessment of brain oxygenation and perfusion by monitoring... influence of changes in extracerebral tissue perfusion and oxygenation during recording of signals related to the inflow of the dye to the brain [39–41]. Moreover, it was reported that fluorescence light excited in the fluorophore circulating in the brain can be detected on the surface of the head [42–47]. Time−resolved NIRS was reported as a potentially valu− able tool allowing for depth−resolved analysis of changes in absorption of the tissue. A universal trNIRS instrument should allow for two modes of operation: (i) monitoring of tissue oxygenation or (ii) monitoring of inflow of the ICG. Such instrument may be effectively applied in clinical stud− ies on different categories of patients with brain perfusion and/or oxygenation disorders. In the present paper a construction and technical testing of a modular multichannel trNIRS instrument is presented. The system can be used for acquisition of distributions of times of arrival (DTA) of fluorescence photons and distribu− tions of times of flight (DTOF) of diffusely reflected pho− tons. Its construction is based on our earlier methodological studies in which we used trNIRS [41,48–50]. Most impor− tant advantage of the presented instrument is its compact design and ability to switch between different modes of operation in less than 5 min. The setup is optimized for acquisition of time−resolved data from 4 spots (related to 4 source−detector pairs) on each hemisphere of the brain, thus allowing for depth− and space resolved assessment of chan− ges in brain oxygenation or in brain perfusion. Results of technical tests of the system and examples of in−vivo measurements in clinical environment are presented.
2. Methods 2.1. Instrumentation The instrument for multi−channel time−resolved NIRS mea− surements is housed in a mobile 19” cabinet (Shroff, Ger− many) 120×60×60 cm (height, width and depth) (see Fig. 1). The constructed instrument consists of the following parts : in− dustrial PC with eight time−correlated single photon counting (TCSPC) cards (SPC−134, Becker&Hickl, Germany), pulse/ pattern generator (81110A, Agilent, US), power supply (HN7042−5, HAMEG Industries, Germany), multichannel controller (PDL 808 Sepia, PicoQuant, Germany) which deliv− ers current pulses to the laser heads (LDH−P 690, LDH−P 760, LDH−P 830, PicoQuant, Germany). These elements are grou− ped in two detection and one emission module which will be described below in detail.
2.1.1. Emission module Construction of the emission module is presented in Fig. 2. The setup is equipped with five picosecond semiconductor laser diodes (LD) operating at four wavelengths 687 nm, 760 nm, 780 nm and 832 nm. Each laser head generates light pulses at a frequency of 80 MHz with an average power of 6–8 mW. In order to obey safety limits (2 mW/mm2), the construction of the optode cause that the power of light
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Fig. 1. Schematic diagram of the universal multichannel NIRS system.
on the tips of the emitting fibres is lower than 1 mW. In the emission module the light is coupled into 2 m long step− −index optical fibres (M28L02 Thorlabs, Sweden, numerical aperture is NA = 0.39, diameter is of 400 μm) which are used for transmission of laser pulses to the studied medium. For assessment of cerebral oxygenation, laser diodes operating at 687 nm and 832 nm are used (LDH−P−690 and LDH−P−830, PicoQuant, Germany). Laser light from the two laser heads is coupled into two optical fibres with an adjustable optical setup equipped with a 50:50 broadband plate beam splitter (BSW27, Thorlabs, Sweden). Thus, each of the emitting fibres is used for transmission of laser pulses at two wavelengths. These pulses are shifted in time using the precision programmable delay line (Kentech Instru− ments Ltd., UK) and distributions of times of flight of pho− tons can be observed separately for both wavelengths. In order to perform measurements of diffuse reflectance and fluorescence, emission module was equipped with addi− tional two LDs operating at 760 nm and beam splitter same
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as described above. Pulses from one LD are delivered into both optical fibres. The pulses generated by one of the LDs are delayed in respect to the pulses generated by the other one using precision programmable delay line. This delay allows to differentiate distributions of times of flight of pho− tons originating from the defined laser heads as shown in Fig. 3. The IRF signals were measured using a scattering material sheet positioned in front of the detecting bundle according to procedure described in detail elsewhere . The FWHM of the IRF of the setup was 696 ±26 ps for all chan− nels of the setup. The DTOFs and DTAs shown in Fig. 3 were obtained during the experiment on a healthy subject. To provide stable measurements conditions for various modes of operation of the system, trigger laser head (780 nm, LDH−P−780, PicoQuant, Germany) is connected to the Sepia controller. Trigger signal is generated by high speed PIN photodiode module (PHD 400, Becker&Hickl, Germany) illuminated with the laser light and sent to the TCSPC electronics with 1.2 m long SMA cable (CA2948, Thorlabs, Sweden). Fig. 2. Schematic diagram of the emission module: 1. Synchroni− zation signal obtained from LD operating at l = 780 nm; 2,3. Pairs of optical fibres for diffuse reflectance and/or fluorescen− ce measurements (at l = 760 nm); 4. Pair of optical fibres used for measurements of changes in oxygenation (at l = 687 nm and l = 832 nm).
2.1.2. Detection module The instrument is equipped with two independent detection modules of the same construction. Each module consists of four independent detection channels (see Fig. 4) which are connected with four TSCPC cards mounted in the indus− trial PC. Each of the detection modules is closed in an opti− cally tight box in order to provide optical separation bet− ween channels. This solution allowed for reduction of noise
Fig. 3. Distributions of times of flight of diffusely reflected photons (DTOF), distributions of times of arrival (DTA) of fluorescence photons and instrumental response function (IRF) for (a) diffuse reflectance measurements, (b) combined diffuse reflectance (channels 1–4) and flu− orescence (channels 5–8) measurements. Count rate for IRF and DTOF measurements was approximately 106 photons/s and for DTA mea− surements reached up to 5·104 photons/s. Opto−Electron. Rev., 22, no. 1, 2014
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Time−resolved multi−channel optical system for assessment of brain oxygenation and perfusion by monitoring...
Fig. 4. Schematic presentation of the construction of a single detec− tion channel: 1. Beam−forming optics: (a) symmetric convex lens, (b) and (c) aspheric condenser lenses; 2. Rotating filter wheel for se− lection of operation mode; 3. Rotating film filter; 4,5 Rotating filters are operated using knobs located on opposite sides of the detecting module; 6. Photomultiplier (PMT) module; 7. Fibre bundle moun− ting slot.
from ambient light and cross−emission of light between channels. Light reemitted from the tissue is delivered to the detec− tion channel with the use of optical fibre bundles. Eight fibre bundles (Loptek, Germany, NA = 0.54) with a 1.5 m length, a 4 mm diameter of active area, connected to each detection channel were used in oxygenation measurements. In simultaneous reflectance−fluorescence measurements four bifurcated fibre bundles in which the output fibres were selected by random mixing from set of input fibres were used. Bundles of a 1.5 m length and a 5 mm diameter of active input area and 4 mm diameter output area (NA = 0.54, Loptek, Germany) were used. This solution warranted that the light from the tissue was equally distributed into two detection channels for simultaneous diffuse reflectance and fluorescence detection. It was reported that the high NA and increase of the length of the detecting bundles leads to broadening of the DTOFs measured in turbid media [51]. However, the source and detection fibres/bundles must be at least 1.5 m long which allows for easy attachment of the optode to the head during in−vivo measurements. The detection bundles of a large NA were used in order to provide transfer of as many as possible of the photons reemitted from the tissue to the photodetector. This property of the setup is a trade−off bet− ween countrate (which influence the noise in the measured signals of moments of the DTOFs and DTAs) and temporal resolution of the measurement. Design of the fibre bundle mounting slot allows for an easy and fast exchange of the fibre bundles used in different kinds of experiments. In order to provide proper filtration of
the light which is transmitted onto the detector, a set of opti− cal elements was used which form a quasi−parallel beam from the wave front which exits the fibre bundle. Construc− tion of the optical detection setups is shown in Fig. 4. For the beam forming configuration of two lenses was used: symmetric convex lens a) (f = 16 mm, F = 22,4 mm, BK7, G06 3033, Linos, US) and aspheric condenser lenses (b and c) (f = 18 mm, F = 22,4 mm, B270, G06 3097, Linos, US). The distances between the surfaces of subsequent elements (a and b) are 5mm and between b and c 15 mm. The length of the whole optics setup is 5 cm. For selection of mode of operation of the instrument a rotating filter wheel was used. Four different positions of the filter wheel correspond to dif− ferent modes of operation: (i) for diffuse reflectance mea− surements at 760 nm, short−pass filters (NT47−586, Edmund Optics, USA) with a cut−off wavelength of 800 nm were mounted in order to block fluorescence light; (ii) for the flu− orescence measurements with excitation at 760 nm, long− −pass interference filters (800LP, TFI Technologies, USA) with a cut−off wavelength of 790 nm were applied; (iii) no filters were applied in detection channel for oxygenation changes measurements in which wavelengths of 687 nm and 832 nm were used; (iv) for safety of the detectors during transportation of the instrument or stand−by periods the de− tection channel is completely blocked. For every detecting channel photomultiplier (PMT) module was constructed which is composed of: a small−size (8 mm in diameter) photomultiplier tube detector (R7400U−02, Hamamatsu Photonics, Japan), high−voltage power supplier (C4900−01, Hamamatsu Photonics, Japan) and a preamplifier (HFA−D, Becker&Hickl, Germany). For adjustment of intensity of light transmitted to the photodetectors rotating film filters were applied. They were prepared by printing black dots on Mylar film and composing nine zones with different trans− missions from 0 to 100%. This filter allowed for an easy adjustment of intensity of light reaching detectors in diffe− rent channels of the instrument.
2.2. Operation modes Construction of the instrument allows its use in several operation modes, as presented in Table 1. The system can be used for time−resolved measurements of optical properties, oxygenation changes or monitoring of an inflow and out− flow of the optical contrast agent. It should be noted, that changing the operating mode needs a short and easy proce− dure which takes less than 10 minutes for the most compli−
Table 1. Comparison of the various operation modes. Operation mode
Emission wavelengths
No. of channels
Fibre bundle type
Instrument setup time
687 nm, 760 nm
up to 8
single (8 pcs.)
< 5 min
Diffuse reflectance measurement
760 nm
up to 8
single (8 pcs.)
< 5 min
Fluorescence measurement
760 nm
up to 8
single (8 pcs.)
< 5 min
Combined reflectance− −fluorescence measurement
760 nm
4
bifurcated (4 pcs.)
< 10 min
Oxygenation measurement
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cated configuration (when the change of detection bundles is necessary). Acquisition of the DTOFs or DTAs can be done with a frequency of up to 20 Hz. It should be noted that the system is characterized by a short instrument setup time, which is the time necessary to achieve fully operational status for measurements after power on.
2.3. Data analysis Algorithms based on a mathematical model of the light trans− port in the turbid media [23,52] were used for analysis of the measured data. DTOFs and DTAs which were measured dur− ing the experiments were analysed by calculation of their sta− tistical moments [53]: total number of photons Ntot (zeroth mo− ment), mean time of flight/arrival of photons (first central− ized moment of DTOF/DTA) and variance of the DTOF/DTA. For the diffuse reflectance and fluorescence sig− nals differential nonlinearity of the analogue−digital converter (DNL) correction [54] and subtraction of background level was done. DNL measurement was realized with use of a re− sponse box in which red LED diode as a source of light was lo− cated. Background level was calculated as a mean value of number of photons in the beginning part of a DTOF/DTA curve in which only temporally uncorrelated photons were de− tected. In order to present the results of the changes in concen− tration of oxy− (DC HbO2 ) and deoxyhemoglobin (DC Hb ) in the intracerebral layer during the motor task, we used the data analysis algorithm based on analysis of changes of moments of DTOFs and sensitivity profiles derived using diffusion theory which was described elsewhere [48,55]. Signal processing was carried out in Matlab 13 environment (Mathworks Inc., USA).
2.4. Optode holders The presented instrument allows for acquisition of DTOFs, DTAs (or both) synchronously in up to eight (depending on operating mode) detection channels. For optical in−vivo experiments fixation of the source fibres and detecting bun− dles on the head of the subject remains a serious problem. Constructions of the optode holders developed were presen− ted in Fig. 5. For the measurements of diffuse reflectance or fluores− cence during the inflow of an optical contrast agent flexible
optode holders [see Fig. 5(a)] were prepared of copper sheet (which provides stability and flexibility) and rubber foam. This construction allows to adjust the construction to the shape of the head tissues and fixation of the optodes. In this construction two sources fibres and two detector bundles can be fixed on each hemisphere. The tips of the fibres and fibre bundles formed two squares with a source−detector separation of 3 cm. For the measurements of oxygenation changes an opto− de holder was constructed using a thermoplastic material (WFR/Aquaplast Corporation, Wyckoff, USA), rubber foam and Velcro strips. This optode holder allows to fix the source fibres and the detecting bundles on each hemisphere. Source fibre on each hemisphere has been located directly over the C3 and C4 positions of 10–20 EEG system and the locations of the tips of the detecting bundles form a cross with source position in the middle. For every source−detec− tor pair, the interoptode distance was 3 cm.
2.5. Measurement procedures The instrument was validated in experiments on liquid phantom and in−vivo studies on healthy subjects and on patients [41,45,48]. In this paper we show only examples of signals which can be obtained with the use of the instrument and provided results of two in−vivo experiments on the human head in healthy subjects. The in−vivo tests were car− ried out in supine subjects position.
2.5.1. Phantom experiments A liquid phantom allowing for simultaneous data acquisition from 8 source−detector pairs was developed. A tank (size of 15×15×10 cm) was constructed from black polymethyl metha− crylate plates of 6 mm thick. The tank was filled with a solu− tion of 20% Intralipid (Fresenius Kabi, Germany), water and black ink (Black Indian Ink, Winsor& Newton, UK). The re− sulting optical properties matched to the optical properties of typical living tissue (μs’ » 12 cm–1 and μa » 0.15 cm–1) [56]. Values of absorption and scattering coefficients were deter− mined using the method based on statistical moments de− scribed earlier [53]. All eight detecting optodes were located on a circle of a diameter of 6 cm with the source fibre located in its centre (source detector separation was 3 cm). For fixing the optodes nine holes were drilled in the front wall of the phantom. The optodes were located not closer than 3 cm apart from the walls and surface of the phantom, which minimized influence of photons reflected from the walls of the phantom. Moreover during the experiment phantom and all optodes were covered with black material sheet to avoid influence of ambient light.
2.5.2. Brain oxygenation measurements
Fig. 5. Optode holders. Opto−Electron. Rev., 22, no. 1, 2014
In presentation of the oxygenation changes measurements functional motor stimulation was applied [57]. The protocol proposed in nEUROPt consortium was used which consists of periods of hand gripping and rest periods. To activate the mo− tor cortex, the subject was asked to squeeze with the right hand D. Milej
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Time−resolved multi−channel optical system for assessment of brain oxygenation and perfusion by monitoring... a small soft ball made of foam rubber with a repetition fre− quency of about 2 Hz. To ensure the stimulation frequency, a 2 Hz acoustic signal (click) was emitted by a metronome. The experiment consisted of 20 repetitions of periods of 30 s of right hand squeeze followed by 30 s of rest. For this type of measurements five healthy adult volun− teers were recruited (two females and three males, mean age 32 years). All subjects were right−handed and had normal or corrected−to−normal vision. The volunteers were lying on an adjustable bed in supine position. Optodes were fixed on the head using EEG cap and plastic foam [Fig. 5(b)]. For every source fibre and detecting bundle, the hair was removed from the space between the skin and the fibre/fibre bundle tip. The source fibres and detecting bundles were fixed in a stand that was positioned over the subject’s head to avoid bending and movement of the fibres. Optode holders were centered on the patient's head according to C3 and C4 posi− tions of 10−20 EEG system [Fig. 5(b)]. The recorded DTOFs were analysed by calculation of their statistical mo− ments for both wavelengths. For every subject, the signals of the moments were averaged synchronously with the cyc− les of the right−hand movement.
2.5.3. Monitoring of inflow and washout of an optical contrast agent Indocyanine Green was used for the diffuse reflectance and fluorescence measurements during the inflow and washout of an optical contrast agent. A dose of 5 mg of ICG diluted
in 3 ml of aqua pro injectione was rapidly injected (injection time of about 1 s) into the forearm vein and flushed by con− secutive quick injection of 10 ml of normal saline. For the monitoring of inflow and washout of ICG five healthy adult volunteers were recruited (one female and four males, mean age 31 years). Subjects were examined in supine position. Optodes were fixed on the head using optode holders presented in a Fig. 5(a). Optode holders were centred on the patient's head on C3 and C4 positions of 10–20 EEG system. The recorded DTOFs and DTAs were analysed by calculation of their statistical moments. For pre− sentation, all signals were smoothed with a 3 s long moving average.
3. Results 3.1. Phantom experiments Stability of the system was tested on a liquid phantom using protocols similar to those proposed by the European Net− work MEDPHOT [58]. Measurements were carried out for all wavelengths used in the instrument. For each wavelength DTOFs corresponding to eight source−detector pairs were measured during 60 min period which started just after switching on all the subunits of the instrument. Time courses of the moments of DTOFs recorded during these ex− periments were presented in Fig. 6. For the total number of detected photons Ntot, the mean time of flight and the variance V of the DTOF, only small fluctuations can be ob−
Fig. 6. Evaluation of the instrument stability. The time courses of statistical moments of DTOFs observed during 1 h after switching on the in− strument for different operating wavelengths. Black line represent mean values, grey thin lines stand for minimum and maximum values from all channels.
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served during the instrument warm−up period. The signal fluctuations which occur in Ntot and do not exceed 1% within the 1h long period of measurement. Fluctuations ob− served in variance signals are larger, but they do not exceed 5% of the mean value. The uncertainty of the measurement caused by limited number of photons detected was evaluated by calculation of the coefficient of variation (CV) for each of the statistical moments of the DTOFs for all the source−detector pairs. The coefficient of variation is defined as the ratio of the standard deviation of the moments and its mean value [48]. The coef− ficients of variations of the moments for three wavelengths were presented in Fig. 7. It can be observed that even for a small number of detected photons (20,000), the uncer− tainty of the measurement of the moments was on the level of a few percent. The coefficient of variation decreases with an increase of number of photons collected. It should be noted that the CV for the variance of the DTOF was a few percent higher than for other moments.
3.2. In vivo experiments Several tests were performed to show feasibility of the con− structed instrument in in−vivo measurements on the human head. Two main applications of the system were tested: measurements of the cerebral oxygenation change during the motor stimulation and monitoring of an optical contrast agent inflow and washout by measurements of diffuse ref− lectance and fluorescence.
As an example, results of the motor stimulation experi− ment for one selected subject are presented in Fig. 8. The averaged changes in Ntot, Dt, and V obtained for a single emitter−detector pair placed above the hemisphere which was active during the stimulation are presented. The vertical dotted lines mark the beginning and end of the right−hand movement period. A typical change with the opposite trends of the signals change which were measured at the two wave− lengths located on the opposite sides of the isobestic point in all statistical moments can be observed. These opposite changes in the motor cortex activation are caused by chan− ges of the absorption coefficients (for 687 nm and 832 nm wavelengths) which result from increase in oxyhemoglobin concentration and decrease in deoxyhemoglobin con− centration [59–67]. Using the data analysis algorithms based on moments described in detail in Refs. 48 and 68 the signals corre− sponding to the changes in concentration of oxy− DC HbO2 and deoxyhemoglobin DC Hb in the intracerebral tissue com− partments during the right−hand movement task were obtained. Results are presented in Fig. 9. In subplots a and b the signals obtained from optodes located on the left hemi− sphere and right hemisphere were presented, respectively. For the left (contralateral) hemisphere, increase in DC HbO2 and decrease in DC Hb is clearly visible. For right (ipsilatre− ral) hemisphere only a small amplitude response in the motor cortex can be observed.
Fig. 7. Coefficients of variation (CV) of the statistical moments of the DTOFs vs. number of photons collected. The averaged data for all 8 de− tecting channel are presented. Black dots represent mean values, starlets stand for minimum and maximum values of CV from all 8 channels of the instrument. Gray lines represent CV values calculated from the moments of DTOFs using theory presented by Liebert et al. [53]. Opto−Electron. Rev., 22, no. 1, 2014
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Time−resolved multi−channel optical system for assessment of brain oxygenation and perfusion by monitoring...
Fig. 8. Time courses of statistical moments of the DTOFs obtained during motor stimulation experiment averaged over all cycles of right hand grip are presented. Signals averaged from all source−de− tector pairs located on contralateral hemisphere in respect to the hand grip: DNtot – changes in total number of photons, Dt – changes in mean time of flight of photons and DV – changes in variance of the DTOF. Changes in moments were calculated for two wave− lengths 687 nm (red line) and 832 nm (blue line). Vertical black dot− ted lines mark the beginning and end of the right hand grip task.
The constructed instrument can be used for monitoring of an optical contrast agent inflow. As an example the results of ICG inflow measurement are presented. Changes in Ntot, Dt, and V averaged from all source−detector pairs for one selected subject were shown in Fig. 10. In the results of the time−resolved reflectance measurements we can observe the decrease in each of the measured statistical moments of DTOFs. In the fluorescence measurements increase in Ntot and decrease of the signals representing first and second order moments of DTAs can be observed. This pattern of changes matches well with the previous reports [42–46].
4. Discussion and conclusions In the last several years research groups developed time− −resolved systems allowing tissue imaging and dedicated specifically for brain studies. In the proposed setups differ−
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Fig. 9. Time courses of changes in concentration of oxy− (red line) and deoxy− (blue line) hemoglobin observed in the (a) left and (b) right hemisphere. Panels refer to the positions of the optodes on the surface of the head. Vertical black dotted lines mark the beginning and end of the right hand grip task.
ent detection scenarios based on PMTs, APDs or ICCD cameras were utilized. Most of them are dedicated to the measurement of oxygenation changes or changes in the optical properties of tissue. Few of them allow for monitor− ing inflow of an optical contrast agent, but only by measur− ing the diffuse reflectance signals. Comparison of the systems proposed for the time−resol− ved measurements on the brain is presented in Table 2. It can be noted that our setup is the only one which allows for the simultaneous measurement of diffuse reflectance and fluorescence during inflow of the contras agent. The instru− ment constructed in Physikalisch−Technische Bundesanstalt was used in these two modes of operation (diffuse reflec− tance or fluorescence detection) in two separate studies only [40,44]. In addition, the only one multichannel fluorescence detection system which was used by Jelzow et al. [44] did not allow to compare fluorescence signals obtained from both hemispheres of the brain. Simultaneously measure− ments of diffuse reflectance and fluorescence was perfor− med by Liebert et al. [42], but conducted only for one pair of source and detector, and never repeat until now. In this aspect the setup proposed in the present study represents an
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Fig. 10. Results of the time−resolved measurements during the inflow and washout of ICG in the head of healthy subject. Normalized changes of moments of the DTOFs measured in diffuse reflectance mode (a, b) and DTAs measured in fluorescence light acquisition (c, d): DN – changes in total number of photons (red line), Dt – changes in mean time of flight/arrival of photons (green line) and DV – changes in variance (blue line). Changes in moments were calculated for left hemisphere (a, c) and right hemisphere (b, d). Panels refer to different posi− tions of the source−detector pairs on the head.
extension of the previous solutions and we will show in next investigation usefulness of such simultaneous measure− ments of diffuse reflectance and fluorescence carried out on both hemispheres in patients with impaired brain perfusion. Furthermore, the setup proposed can be applied in both kinds of experiments – tissue perfusion assessment and oxy− genation studies. This device was successfully applied in studies related to monitoring of focal changes in brain cor− tex oxygenation during motor stimulation. The instrument allows also for evaluation of optical contrast agent inflow and washout which can be used in estimation of brain perfu− sion parameters [33,79–81]. In series of experiments on phantoms and in healthy volunteers we showed feasibility of time resolved measurements in diffuse reflectance mode and fluorescence light detection. Metrological properties of the setup were also tested. Analysis of the stability of the system presented above shows drifts of the measured signals of statistical moments of DTOFs and DTAs not larger than 3% within one hour Opto−Electron. Rev., 22, no. 1, 2014
after beginning of the measurements. Analysis of changes of coefficient of variation as a function of the total number of measured photons shows that uncertainty of the measure− ment of the moments was only slightly higher than the val− ues obtained with the theoretical analysis. This result sug− gests that the systematic noise components represent only small fraction of the noise in the measured DTOFs and DTAs. Unfortunately, the uncertainty related to the number of photons detected is an intrinsic property of the TCSPC technology [54]. Analysis of the data recorded during focal stimulation of the motor cortex shows that significant changes in the signals of statistical moments of the DTOFs obtained at 687 nm and 832 nm can be observed. Moreover, utilization of moments of DTOFs, allowed to evaluate the changes in oxy− and deoxyhemoglobin with depth discrimination. Changes in he− moglobin concentration observed for two hemispheres of the brain showed that the instrument can be successfully used in monitoring of brain oxygenation changes during motor stim−
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Time−resolved multi−channel optical system for assessment of brain oxygenation and perfusion by monitoring... Table 2. Comparison of the time−resolved optical systems dedicated for brain studies. Sources/ detectors
Emission wavelengths
Politechnico di Milano, Italy
1/SPAD
672 or 750nm
Physikalisch−Technische Bundesanstalt, Berlin, Germany
1/SPAD
690 nm
diffuse reflectance at short Mazurenka et al. source−detector separation [70] Sawosz et al. [71]
scanning the source position, ICCD used to image directly the tissue, only phantom experiments
Group
Measurements type
Author
Comments
diffuse reflectance at short Pifferi et al. [69] single source−detector pair source−detector separation scanning system
Institute of Biocybernetics and Biomedical Engineering, Poland
1/ICCD
780 nm
diffuse reflectance at short source−detector separation
Massachusetts General Hospital Athinoula A. Martinos Center, USA
32/ICCD
tunable between 750−850 nm
diffuse reflectance
Selb et al. [72]
detection bundles positioned in front of the time−gated ICCD
University of Strasbourg, Institut de Physique Biologique, Strasbourg, France
1/ICCD
655, 785, 830, 870 nm
diffuse reflectance
Poulet et al. [73]
distributed illumination, ICCD used to image directly the medium, phantom experiments only
Institute of Biocybernetics and Biomedical Engineering, Poland
9/ICCD
780 nm
diffuse reflectance
Sawosz et al. [74]
ICCD used to image directly the tissue
University College London, UK
32/32
800 nm
optical tomography
Hebden et al. [75]
applied only in neonates
Lawson Health Research Institute, London, Canada
1/4
802 nm
diffuse reflectance
Diop et al. [76]
piglet measurements
Université Louis Pasteur of Strasbourg, France
2/8
690, 785, 830 nm
oxygenation
Montcel et al. [77]
Politechnico di Milano, Italy
18/16
690, 820 nm
oxygenation
Contini et al. [78]
Institute of Biocybernetics and Biomedical Engineering, Poland
18/8
687, 832 nm
oxygenation
Kacprzak et al. [48]
Physikalisch−Technische Bundesanstalt, Germany
9/4
687, 803, 826 nm
oxygenation
Wabnitz et al. [65]
diffuse reflectance
Steinkellner et al. [40]
fluorescence
Jelzow et al. [44]
diffuse reflectance and fluorescence
Liebert et al. [42]
4/4 Physikalisch−Technische Bundesanstalt, Germany
1/2
785 nm
1/1 Institute of Biocybernetics and Biomedical Engineering, Poland
2/8 4/8
687, 832 nm
oxygenation
760 nm
diffuse reflectance fluorescence
ulations and thus it is expected that the setup can be applied in functional brain study fNIRS experiments. It was also shown that changes in statistical moments of DTOFs and DTAs can be obtained during in−vivo experi− ments during injections of optical contrast agent, e.g. ICG [82]. Quality of the signals measured suggest that the instru− ment can be used in estimation of brain perfusion using techniques proposed in several previous studies [37,39,40, 44,83,84].
64
present study
ICG inflow and washout
ICG inflow and washout
Modular construction of the instrument allows for quick interchange of modes of its operation and adjustment of sen− sitivities in selected optical channels of the setup. The time needed to switch between both modes of operation is short (below 5 min) and this feature of the setup is of importance for use in clinical experiments. Moreover, the presented instrument is compact and can be easily transported and used in clinical environment.
Opto−Electron. Rev., 22, no. 1, 2014
© 2014 SEP, Warsaw
Acknowledgements Studies financed by EC Seventh Framework Programme un− der grant agreement n°201076 – project nEUROPt “Non−inva− sive imaging of brain function and disease by pulsed near in− frared light” and Polish National Centre of Science under grant agreement 2011/03/N/ST7/02598. This work has been also supported with a scholarship from the European Social Fund, Human Capital Operational Programme for the execution of the project “Support for bio tech med scientists in technology transfer”; (UDA−POKL.08.02.01− 14−041/09).
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