**4. Conclusions**

20 Will-be-set-by-IN-TECH

ln

 *I* (*τe*) *I*<sup>0</sup> (*τe*)

> ln 1 +

Oxy- and deoxy-hemoglobin concentrations for the upper layer and the lower layer can be easily obtained via Lambert-Beer law, from the estimated Δ*μa*. An example of application of this stratigraphic model is shown in Fig. 10, where data where collected during a Valsalva maneuver, that forces an increase of the systemic blood volume, resulting in an increase of both oxyhemoglobin and deoxyhemoglobin concentrations in the superficial layers of the

> -

Fig. 10. Estimated Δ*HbO*<sup>2</sup> and Δ*Hb* in the superficial layer (UP, continuous line) and in the brain (DOWN, dotted line) during the Valsalva maneuver without normalization. The two vertical dashed lines indicate the beginning and the end of the task period, respectively. During the Valsalva maneuver the sistemic blood volume dramatically increases, while the local blood volume in the brain is less affected by the maneuver effects. A proper depth

Recently a great interest in multimodality approaches has grown. Merging the advantages of different imaging and functional techniques, such as co-registration of NIRS with MRI [Merritt et al. (2002)], blood flow monitors, fMRI [Torricelli et al. (2007)] and PET, gives the possibility to build anatomo-functional images and movies to largely improve information visualization.

*I* (*τl*)

*<sup>I</sup>*<sup>0</sup> (*τl*) <sup>−</sup> *<sup>I</sup>* (*τe*)

*I*<sup>0</sup> (*τe*)

 

(57)

(58)

a subtraction can be performed as follow:

selectivity remarks this differences.

**3.2 Multimodality approach**



skin.

Δ*μUP*

Δ*μDOWN*

*<sup>a</sup>* <sup>=</sup> <sup>−</sup> <sup>1</sup>

*<sup>a</sup>* <sup>=</sup> <sup>−</sup> <sup>1</sup>

*LUP* (*τe*)

*LDOWN* (*τl*)

Near InfraRed Spectroscopy applied *in vivo* to cortical tissues has been widely investigated through the last two decades and big steps have been done.

From the technical point of view, the laser technology, and in particular the introduction of semiconductor laser diodes, has helped to fabricate compact and clinical instrumentations. Moreover, the improvements in light detectors has permitted to develop accurate devices, for example, in the time-resolved technology, the red-extended photocathodes well increased the quantum efficiency in the near red region.

Nevertheless, a lot more has to be done. Pulsed lasers sources are getting better and better, especially concerning time stability and output power. Photomultiplier tubes is an efficient and well established technology, but, in NIRS application, suffers the need of high voltage

Arridge, S. R. & Hebden, J. C. (1997). Optical imaging in medicine: Ii. modelling and

Functional Near Infrared Spectroscopy and Diffuse Optical Tomography in Neuroscience 73

Arridge, S. R. & Schweiger, M. (1995). Photon-measurement density functions. part 2:

Arridge, S. R., Schweiger, M., Hiraoka, M. & Delpy, D. T. (1993). A finite element approach for

Bandettini, P., Kwong, K., Davis, T., Tootell, R., Wong, E., Fox, P., Belliveau, J., Weisskoff, R. &

Boas, D. A., Dale, A. M. & Franceschini, M. A. (2004). Diffuse optical imaging of brain

*NeuroImage* 23(Supplement 1): S275 – S288. Mathematics in Brain Imaging. Boas, D., Culver, J., Stott, J. & Dunn, A. (2002). Three dimensional monte carlo code for photon

Butti, M., Contini, D., Molteni, E., Caffini, M., Spinelli, L., Baselli, G., Bianchi, A. M., Cerutti,

hemodynamic: A time-resolved fnirs study, *Medical Physics* 36(9): 4103–4114.

Caffini, M., Torricelli, A., Cubeddu, R., Custo, A., Dubb, J. & Boas, D. A. (2010). Validating

URL: *http://www.opticsinfobase.org/abstract.cfm?URI=BIOMED-2010-JMA87* Caffini, M., Zucchelli, L., Contini, D., Cubeddu, R., Spinelli, L., Boas, D. & Torricelli, A.

Contini, D. (2007). *Time-resolved functional Near Infrared Spectroscopy for Neuroscience*, PhD

Contini, D., Martelli, F. & Zaccanti, G. (1997). Photon migration through a turbid slab

Contini, D., Spinelli, L., Torricelli, A., Pifferi, A. & Cubeddu, R. (2007). Novel method for

URL: *http://www.opticsexpress.org/abstract.cfm?URI=oe-10-3-159*

*Biomedical Optics*, Optical Society of America, p. JMA87.

URL: *http://ao.osa.org/abstract.cfm?URI=ao-36-19-4587*

*of Tissue*, Optical Society of America, p. 6629.

Rosen, B. (1997). Characterization of cerebral blood oxygenation and flow changes

cortically constrained diffuse optical tomography of human brain function, *Appl. Opt.*

activation: approaches to optimizing image sensitivity, resolution, and accuracy,

migration through complex heterogeneous media including the adult human head,

S., Cubeddu, R. & Torricelli, A. (2009). Effect of prolonged stimulation on cerebral

an Anatomical Brain Atlas for Analyzing NIRS Measurements of Brain Activation,

(2011). Anatomical brain atlas for nirs measurements of brain activation, *Proc. SPIE*

described by a model based on diffusion approximation. i. theory, *Appl. Opt.*

depth-resolved brain functional imaging by time-domain nirs, *Diffuse Optical Imaging*

reconstruction, *Physics in Medicine and Biology* 42(5): 841–853.

URL: *http://ao.osa.org/abstract.cfm?URI=ao-34-34-8026*

URL: *http://ao.osa.org/abstract.cfm?URI=ao-44-10-1957*

URL: *http://link.aip.org/link/?MPH/36/4103/1*

Finite-element-method calculations, *Appl. Opt.* 34(34): 8026–8037.

modeling photon transport in tissue, *Medical Physics* 20(2): 299–309.

during prolonged brain activation, *Human Brain Mapping* 5(2): 93–109. Becker, W. (2005). *Advanced Time-Correlated Single Photon Counting Techniques*, Springer. Boas, D. A. (1996). *Diffuse Photon Probes of Structural and Dynamical Properties of Turbid Media: Theory and Biomedical Applications*, PhD thesis, University of Pennsylvania. Boas, D. A. & Dale, A. M. (2005). Simulation study of magnetic resonance imaging-guided

URL: *http://stacks.iop.org/0031-9155/42/841*

URL: *http://link.aip.org/link/?MPH/20/299/1*

44(10): 1957–1968.

8088(1): 808809.

36(19): 4587–4599.

thesis, Politecnico di Milano.

*Opt. Express* 10(3): 159–170.

supplies and the necessity to work in a dark environment, to avoid background light. Single Photon Avalanche Diodes (SPAD) are the available technology that best fits the needs of Near InfraRed Spectroscopy. Actual work is to integrate SPADs into NIRS setups by means of increased light sensitive area and better quantum efficiency in the near red spectrum. For more information about SPAD detectors see [Cova et al. (2010)].

An interesting future perspective, is the so-called null-distance measurement setup, that is the possibility to collect light from the very same point of injection. Only time resolved techniques allow this possibility and a few successful efforts have been made in this direction [Pifferi et al. (2008)].

From the medical point of view, hundreds of physiological studies and psychological tasks have been carried out and a massive literature is available on the subject. For these reason, a larger clinical use of non-invasive optical imaging in the next years is expected. In particular, we expect time resolved NIRS to be the best candidate for this purpose. The four-year nEUROPt Project [*nEUROPt Project* (2008-2012)], financed by the European Union under The Seventh Framework Programme for research and technological development (FP7) for the period 2008-2011, and coordinated by the Authors, aims at the development and clinical validation of advanced non-invasive optical methodologies for in-vivo diagnosis, monitoring, and prognosis of major neurological diseases (stroke, epilepsy, ischemia), based on diffuse optical imaging by pulsed near infrared light. The consortium plans major developments in technology and data analysis that will enhance TD-NIRS with respect to spatial resolution, sensitivity, robustness of quantification as well as performance of related instruments in clinical diagnosis and monitoring. A strong clinical basis is being produced and the diagnostic value of TD-NIRS applications to brain study will be assessed, by putting using standard methodologies (such EEG) and new optical methods side by side, in a co-registration setup. The potential commercialization of TD-NIRS systems will be then evaluated by European system manufacturers.

#### **5. Acknowledgements**

We wish to acknowledge partial support from the EC's Seventh Framework Programme (FP7/ 2007 - 2013) under grant 201076.

#### **6. References**

Arridge, S. R. (1995). Photon-measurement density functions. part i: Analytical forms, *Appl. Opt.* 34(31): 7395–7409.

URL: *http://ao.osa.org/abstract.cfm?URI=ao-34-31-7395*


22 Will-be-set-by-IN-TECH

supplies and the necessity to work in a dark environment, to avoid background light. Single Photon Avalanche Diodes (SPAD) are the available technology that best fits the needs of Near InfraRed Spectroscopy. Actual work is to integrate SPADs into NIRS setups by means of increased light sensitive area and better quantum efficiency in the near red spectrum. For

An interesting future perspective, is the so-called null-distance measurement setup, that is the possibility to collect light from the very same point of injection. Only time resolved techniques allow this possibility and a few successful efforts have been made in this direction [Pifferi et al.

From the medical point of view, hundreds of physiological studies and psychological tasks have been carried out and a massive literature is available on the subject. For these reason, a larger clinical use of non-invasive optical imaging in the next years is expected. In particular, we expect time resolved NIRS to be the best candidate for this purpose. The four-year nEUROPt Project [*nEUROPt Project* (2008-2012)], financed by the European Union under The Seventh Framework Programme for research and technological development (FP7) for the period 2008-2011, and coordinated by the Authors, aims at the development and clinical validation of advanced non-invasive optical methodologies for in-vivo diagnosis, monitoring, and prognosis of major neurological diseases (stroke, epilepsy, ischemia), based on diffuse optical imaging by pulsed near infrared light. The consortium plans major developments in technology and data analysis that will enhance TD-NIRS with respect to spatial resolution, sensitivity, robustness of quantification as well as performance of related instruments in clinical diagnosis and monitoring. A strong clinical basis is being produced and the diagnostic value of TD-NIRS applications to brain study will be assessed, by putting using standard methodologies (such EEG) and new optical methods side by side, in a co-registration setup. The potential commercialization of TD-NIRS systems will be then evaluated by European

We wish to acknowledge partial support from the EC's Seventh Framework Programme (FP7/

Arridge, S. R. (1995). Photon-measurement density functions. part i: Analytical forms, *Appl.*

Arridge, S. R. (1999). Optical tomography in medical imaging, *Inverse Problems* 15(2): R41–R93.

Arridge, S. R., Dehghani, H., Schweiger, M. & Okada, E. (2000). The finite element model

for the propagation of light in scattering media: A direct method for domains with

URL: *http://ao.osa.org/abstract.cfm?URI=ao-34-31-7395*

nonscattering regions, *Medical Physics* 27(1): 252–264.

URL: *http://stacks.iop.org/0266-5611/15/R41*

URL: *http://link.aip.org/link/?MPH/27/252/1*

more information about SPAD detectors see [Cova et al. (2010)].

(2008)].

system manufacturers.

**5. Acknowledgements**

**6. References**

2007 - 2013) under grant 201076.

*Opt.* 34(31): 7395–7409.


URL: *http://ao.osa.org/abstract.cfm?URI=ao-44-10-1957*


URL: *http://www.opticsexpress.org/abstract.cfm?URI=oe-10-3-159*


URL: *http://ao.osa.org/abstract.cfm?URI=ao-36-19-4587*

Contini, D., Spinelli, L., Torricelli, A., Pifferi, A. & Cubeddu, R. (2007). Novel method for depth-resolved brain functional imaging by time-domain nirs, *Diffuse Optical Imaging of Tissue*, Optical Society of America, p. 6629.

Patterson, M. S., Chance, B. & Wilson, B. C. (1989). Time resolved reflectance and

Functional Near Infrared Spectroscopy and Diffuse Optical Tomography in Neuroscience 75

Pifferi, A., Taroni, P., Valentini, G. & Andersson-Engels, S. (1998). Real-time method for

Pifferi, A., Torricelli, A., Spinelli, L., Contini, D., Cubeddu, R., Martelli, F., Zaccanti, G., Tosi,

URL: *http://www.opticsinfobase.org/abstract.cfm?URI=BIOMED-2008-BWC6* Press, W. H., Teukolsky, S. A., Vetterling, W. T. & Flannery, B. P. (1992). *Numerical Recipes in C*

Rutherford, E. (1911). The scattering of alpha and beta particles by matter and the structure of

Saager, R. B. & Berger, A. J. (2005). Direct characterization and removal of interfering absorption trends in two-layer turbid media, *J. Opt. Soc. Am. A* 22(9): 1874–1882.

Sanchez, R. & McCormick, N. J. (1982). A review of neutron transport approximations, *Nuclear*

Sassaroli, A. & Fantini, S. (2004). Comment on the modified beer-lambert law for scattering

Selb, J., Stott, J. J., Franceschini, M. A., Sorensen, A. G. & Boas, D. A. (2005). Improved

Steinbrink, J., Wabnitz, H., Obrig, H., Villringer, A. & Rinneberg, H. (2001). Determining

Strangman, G., Boas, D. A. & Sutton, J. P. (2002). Non-invasive neuroimaging using

Torricelli, A., Contini, D., Pifferi, A., Spinelli, L., Cubeddu, R., Nocetti, L., Manginelli, A.-A.

Tsuchiya, Y. (2001). Photon path distribution and optical responses of turbid media: theoretical

Wabnitz, H., Liebert, A., Contini, D., Spinelli, L. & Torricelli, A. (2008). Depth selectivity

near-infrared light, *Society of Biological Psychiatry* 52: 679–693.

sensitivity to cerebral hemodynamics during brain activation with a time-gated optical system: analytical model and experimental validation, *Journal of Biomedical*

changes in nir absorption using a layered model of the human head, *Physics in*

& Baraldi, P. (2007). Simultaneous acquisition of time-domain fnirs and fmri during

analysis based on the microscopic beer-lambert law, *Physics in Medicine and Biology*

in time-domain optical brain imaging based on time windows and moments of

*- The Art of Scientific Computing*, Cambridge University Press.

the atom, *Philosophical Magazine Series 6* 21(125): 669–688.

URL: *http://josaa.osa.org/abstract.cfm?URI=josaa-22-9-1874*

media, *Physics in Medicine and Biology* 49(14): N255–N257.

URL: *http://ao.osa.org/abstract.cfm?URI=ao-28-12-2331*

URL: *http://ao.osa.org/abstract.cfm?URI=ao-37-13-2774*

*Opt.* 28(12): 2331–2336.

America, p. BWC6.

*Optics* 10(1): 011013.

46(8): 2067–2084.

model, *Appl. Opt.* 37(13): 2774–2780.

*Science and Engineering* 80(4): 481–535.

URL: *http://stacks.iop.org/0031-9155/49/N255*

URL: *http://link.aip.org/link/?JBO/10/011013/1*

motor activity, *Proc. SPIE* 6631(1): 66310A. URL: *http://dx.doi.org/doi/10.1117/12.727699*

URL: *http://stacks.iop.org/0031-9155/46/2067*

*Medicine and Biology* 46(3): 879–896. URL: *http://stacks.iop.org/0031-9155/46/879*

transmittance for the non-invasive measurement of tissue optical properties, *Appl.*

fitting time-resolved reflectance and transmittance measurements with a monte carlo

A., Mora, A. D., Zappa, F. & Cova, S. (2008). Time-resolved functional near-infrared spectroscopy at null source-detector separation, *Biomedical Optics*, Optical Society of


URL: *http://rstb.royalsocietypublishing.org/content/352/1354/743.abstract*

	- *der Physik* 330(3): 377–445.

URL: *http://dx.doi.org/10.1002/andp.19083300302*

*nEUROPt Project* (2008-2012).

URL: *www.neuropt.eu*

O'Connor, D. V. & Phillips, D. (1984). *Time correlated single photon counting*, Academic Press.

Patterson, M. S., Chance, B. & Wilson, B. C. (1989). Time resolved reflectance and transmittance for the non-invasive measurement of tissue optical properties, *Appl. Opt.* 28(12): 2331–2336.

URL: *http://ao.osa.org/abstract.cfm?URI=ao-28-12-2331*

24 Will-be-set-by-IN-TECH

Cova, S., Ghioni, M., Zappa, F., Gulinatti, A., Rech, I. & Tosi, A. (2010). Single photon counting

D'Arceuil, H. E., Hotakainen, M. P., Liu, C., Themelis, G., de Crespigny, A. J. & Franceschini,

Fang, Q. & Boas, D. A. (2009). Monte carlo simulation of photon migration in 3d turbid media accelerated by graphics processing units, *Optics Express* 17(22): 20178–20190.

Fantini, S., Franceschini, M.-A., Maier, J. S., Walker, S. A., Barbieri, B. B. & Gratton, E. (1995).

Feynman, R. P., Leighton, R. B. & Sands, M. (1964). *The Feynman Lectures on Physics including Feynman's Tips on Physics: The Definitive and Extended Edition*, Addison-Wesley. Heekeren, H. R., Obrig, H., Wenzel, R., Eberle, K., Ruben, J., Villringer, K., Kurth, R. &

Liebert, A., Wabnitz, H., Steinbrink, J., Obrig, H., Möller, M., Macdonald, R., Villringer, A.

Martelli, F., Bianco, S. D., Ismaelli, A. & Zaccanti, G. (2010). *Photon Migration Through Diffusive*

Martelli, F., Bianco, S. D. & Zaccanti, G. (2005). Perturbation model for light propagation through diffusive layered media, *Physics in Medicine and Biology* 50(9): 2159–2166.

Merritt, S., Bevilacqua, F., Durkin, A. J., Cuccia, D. J., Lanning, R. & Tromberg, B. J. (2002).

Mie, G. (1908). Beiträge zur optik trüber medien, speziell kolloidaler metallösungen, *Annalen*

O'Connor, D. V. & Phillips, D. (1984). *Time correlated single photon counting*, Academic Press.

*Biomedical Topical Meeting*, Optical Society of America, p. SuE1. URL: *http://www.opticsinfobase.org/abstract.cfm?URI=BIO-2002-SuE1*

Near-infrared spectroscopy and mri co-registration of tumor tissue physiology,

distribution of times of flight of photons, *Appl. Opt.* 43(15): 3037–3047.

URL: *http://www.opticsexpress.org/abstract.cfm?URI=oe-17-22-20178*

*Society of London. Series B: Biological Sciences* 352(1354): 743–750. URL: *http://rstb.royalsocietypublishing.org/content/352/1354/743.abstract* Ishimaru, A. (1978). *Wave Propagation and Scattering in Random Media*, Academic Press.

*Photonics Society, PHOTINICS 2010*, pp. 177–178.

neonatal rabbits, *Journal of Biomedical Optics* 10(1).

and oximetry, *Optical Engineering* 34(1): 32–42. URL: *http://link.aip.org/link/?JOE/34/32/1*

Jackson, J. D. (1999). *Classical Electrodynamics*, 3rd edn, Wiley.

URL: *http://ao.osa.org/abstract.cfm?URI=ao-43-15-3037*

*Media: Theory, Solutions and Software*, SPIE Press.

URL: *http://stacks.iop.org/0031-9155/50/2159*

URL: *http://dx.doi.org/10.1002/andp.19083300302*

*der Physik* 330(3): 377–445.

URL: *www.neuropt.eu*

*nEUROPt Project* (2008-2012).

Donati, S. (1998). *Fotorivelatori*, 2a edizione edn, AEI.

URL: *www.scopus.com*

detectors in action: Retrospect and prospect, *2010 23rd Annual Meeting of the IEEE*

M. A. (2005). Near-infrared frequency-domain optical spectroscopy and magnetic resonance imaging: a combined approach to studying cerebral maturation in

Frequency-domain multichannel optical detector for noninvasive tissue spectroscopy

Villringer, A. (1997). Cerebral haemoglobin oxygenation during sustained visual stimulation – a near–infrared spectroscopy study, *Philosophical Transactions of the Royal*

& Rinneberg, H. (2004). Time-resolved multidistance near-infrared spectroscopy of the adult head: Intracerebral and extracerebral absorption changes from moments of


URL: *http://www.opticsinfobase.org/abstract.cfm?URI=BIOMED-2008-BWC6*


URL: *http://link.aip.org/link/?JBO/10/011013/1*

Steinbrink, J., Wabnitz, H., Obrig, H., Villringer, A. & Rinneberg, H. (2001). Determining changes in nir absorption using a layered model of the human head, *Physics in Medicine and Biology* 46(3): 879–896.

URL: *http://stacks.iop.org/0031-9155/46/879*


URL: *http://stacks.iop.org/0031-9155/46/2067*

Wabnitz, H., Liebert, A., Contini, D., Spinelli, L. & Torricelli, A. (2008). Depth selectivity in time-domain optical brain imaging based on time windows and moments of

**5** 

*USA* 

**Intraoperative Human Functional Brain** 

Sameer A. Sheth, Vijay Yanamadala and Emad N. Eskandar

*Department of Neurosurgery, Massachusetts General Hospital,* 

*Harvard Medical School, Boston,* 

**Mapping Using Optical Intrinsic Signal Imaging** 

Functional brain mapping strives to describe the brain's organization as a mosaic of distinct regions, each of which subserves a particular function. Advances in our understanding of functional brain organization over the past decades have been propelled by the availability of increasingly sophisticated methods for assessing various aspects of neuronal activity *in vivo*. These methods can be broadly categorized as "direct" or "indirect" measures of neuronal activity (Figure 1). Direct techniques measure changes in electromagnetic fields resulting from neuronal action potentials and synaptic activity. Indirect techniques measure changes in other tissue properties that are related to neural activity. This distinction does not imply the superiority of direct over indirect techniques. Certain disadvantages of direct measures were the very motivation for the development of indirect measures. Indeed, the most widely used functional brain imaging modality currently is functional magnetic resonance imaging (fMRI), an indirect technique. A subset of indirect techniques are based on changes in blood flow subsequent to and produced by neural activity. These perfusiondependent functional brain imaging techniques include fMRI, positron emission tomography (PET), and others. Although they are among the most commonly used methods for investigating brain function, they rely on vascular responses that are not completely understood. In this chapter, we will focus on indirect measures of brain activity, emphasizing the technique of optical intrinsic signal imaging (OISI). We discuss the physical basis of perfusion imaging and OISI, animal and human studies of OISI to date, and its

In framing OISI, we first discuss the broad category of perfusion-based imaging techniques to which it belongs. Perfusion-based brain imaging techniques measure physiological events linked to neuronal activity, such as changes in metabolism or blood flow, and include positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and OISI. These techniques do not measure neuronal activity *per se*; rather, they measure surrogate metabolic and vascular markers of activity. In essence, hemodynamic responses provide a map of neuronal activity spatially and temporally broadened by passage through a vascular filter. Despite their indirect nature, however, perfusion-based brain imaging

potential as a powerful intraoperative functional brain mapping tool.

**2. Perfusion-based functional brain imaging** 

**1. Introduction** 

time-of-flight distributions, *Biomedical Optics*, Optical Society of America, p. BMD9. URL: *http://www.opticsinfobase.org/abstract.cfm?URI=BIOMED-2008-BMD9*

Wolf, M., Ferrari, M. & Quaresima, V. (2007). Progress of near-infrared spectroscopy and topography for brain and muscle clinical applications, *Journal of Biomedical Optics* 12(6): 062104.

URL: *http://link.aip.org/link/?JBO/12/062104/1*

Zege, E. P., Ivanov, A. I. & Katsev, I. L. (1991). *Image Transfer through a Scattering Medium*, Springer-Verlag.
