Functional optical imaging of the brain
Time-resolved near-infrared spectroscopy and imaging of the adult brain
Aims
Non-invasive determination of changes in blood volume, oxygen saturation and perfusion in the adult human cortex. Development of a compact, portable instrument suited for bedside monitoring. Development of robust algorithms for data analysis.
Potential neurological applications
- Recording of the cerebral haemodynamic response to functional stimulation, in particular in combination with DC-magnetoencephalography (DC-MEG) and functional magnetic resonance imaging (fMRI)
Aim: Elucidation of neurovascular coupling in physiological and pathological conditions - Recording of boli of the contrast agent indocyanine green (ICG) in the brain
Aim: Assessment of cerebral perfusion, in particular in stroke patients
Method
Short (~ 100 ps) laser pulses are delivered to the head via an optical fibre. Photons exiting the tissue after multiple scattering at a distance of, e.g., 3 cm from the source ("diffuse reflectance") are collected by an optical fibre bundle and fed to a fast detector. By time-correlated single photon counting the time of flight of each detected photon is measured and the distribution of times of flight is accumulated.
The spread of times of flight of photons depends on the optical properties (scattering and absorption coefficient) of the traversed tissue. By analysing the shape of the distribution of times of flight, depth-resolved assessment of optical properties is possible: Photons arriving after short times of flight ("early photons") on average penetrate less deeply into the tissue than photons with long times of flight ("late photons"). Simultaneous measurement at several wavelengths allows to investigate changes in the concentrations of oxy- and deoxyhaemoglobin.
Instrumentation
The technical realization of this method relies on picosecond diode lasers emitting at various wavelengths and multi-channel time-correlated single photon counting.
- Time-domain NIR brain imager (prototype) [Wabnitz et al. 2005]:
4 simultaneous detection channels, 9 source positions (by optical fibre switch), modular design, largely automated - Upgrade for optional detection of fluorescence
- Upgrade for simultaneous recording of indocyanine green boli in diffuse reflectance on both hemispheres:
1 laser (785 nm) for 2 source positions and 2 detection channels resulting in 4 source-detector pairs per hemisphere - Technical approval (certificate Z-08-111-MP) for use in clinical studies
Data analysis
- Method for depth-resolved measurements of absorption changes based on a multi-layered model and time-dependent mean partial pathlengths [Steinbrink 2000, Steinbrink et al. 2001]
- Simulation of light propagation in a multi-layered model by a Monte-Carlo technique
- Test of the method on multi-layered phantoms and application to various in-vivo experiments on healthy volunteers
- Method for determination of oxygen saturation of blood in deep tissue layers based on a homogeneous diffusion model with particular emphasis on late photons; test on simulated data and in vivo on healthy volunteers.
- Analysis based on moments of measured distributions of times of flight [Liebert et al. 2004, Liebert et al. 2005, Liebert et al. 2012]
- Determination of depth-resolved absorption changes from multi-distance measurements
- Depth discrimination: Variance selectively sensitive to deep absorption changes (cortex) (s. Fig. 3)
- Development of an efficient Monte-Carlo code for the simulation of generation and propagation of fluorescence in a layered tissue model [Liebert et al. 2008]
Results
Assessment of cerebral perfusion in stroke [Liebert et al. 2005] (s. Fig. 4)
- Successful clinical study in a German-Polish cooperation in neuroscience on tracking of perfusion dynamics in stroke patients with optical imaging [Steinkellner et al. 2010, 2012]
Fluorescence detection of ICG boli
- Successful recording of ICG fluorescence from the human cortex [Liebert et al. 2006, Steinbrink et al. 2008]
- Method for separation of bolus time courses in skin and brain [Jelzow et al. 2012]
Time-domain functional near-infrared spectroscopy (fNIRS) of the brain [Wabnitz et al. 2010]
- Mapping of responses to motor stimulation in healthy subjects [Wabnitz et al. 2005] (s. Fig. 5)
- Concurrent measurements with DC-MEG of responses to motor stimulation in healthy subjects [Sander et al. 2007, Mackert et al. 2008, Sander et al. 2010] and stroke patients [Leistner et al. 2011]
- Concurrent measurement of responses to functional stimulation with fMRI
- Investigation of systemic artefacts with cognitive stimulation (fNIRS, fMRI, peripheral physiological signals) [Kirilina et al. 2012]
EU-Projekt "nEUROPt"
- Non-contact brain imaging at small source-detector separation [Mazurenka et al. 2012]
- Development and application of common protocols for performance assessment of time-domain optical brain imagers [Wabnitz et al. 2011]
Ongoing work
- Participation in the European project nEUROPt (“Non-invasive imaging of brain function and disease by pulsed near infrared light”)
- Instrumental and methodical developments for time-domain optical brain imaging
- Performance comparison of instruments
- Clinical applications
- Clinical study on perfusion assessment by ICG bolus tracking in stroke patients
- Combined measurements with DC-MEG of responses to motor stimulation in stroke patients (neurovascular coupling)
Collaboration
Funding
- Berlin NeuroImaging Center (BMBF 01 GO 0208) (2002-2008)
German-Polish Cooperation in Neuroscience: “Hypo- and Hyperfusion during subacute Stroke. Tracking Perfusion Dynamics in stroke Patients with Optical Imaging” (BMBF 01GZ0711) (2007-2010)- DFG Exzellenzakademie Medizintechnik (KI-1337/1-1) (2008)
- European collaborative project (FP7) nEUROPt “Non-invasive imaging of brain function and disease by pulsed near infrared light” (HEALTH-F5-2008-20176) (2008-2012)
Publications
Steinbrink J,
Nahinfrarotspektroskopie am Kopf des Erwachsenen mit Pikosekunden-Zeitauflösung,
Dissertation, Freie Universität Berlin 2000.
Steinbrink J, Wabnitz H, Obrig H, Villringer A, Rinneberg H (2001),
Determining changes in NIR absorption using a layered model of the human head,
Phys. Med. Biol. 46: 879-896,doi:10.1088/0031-9155/46/3/320.
Liebert A, Wabnitz H, Grosenick D, Macdonald R (2003a),
Fiber dispersion in time domain measurements compromising the accuracy of determination of optical properties of strongly scattering media,
J. Biomed. Opt. 8: 512-6,
doi:10.1117/1.1578088.
Liebert A, Wabnitz H, Grosenick D, Möller M, Macdonald R (2003b),
Evaluation of optical properties of highly scattering media by moments of distributions of times of flight of photons,
Appl. Opt. 42: 5785-92,doi:10.1364/AO.42.005785.
Liebert A, Wabnitz H, Steinbrink J, Obrig H, Möller M, Macdonald R, Villringer A, Rinneberg H (2004),
Time-resolved multidistance near-infrared spectroscopy of the adult head: intracerebral and extracerebral absorption changes from moments of distribution of times of flight of photons,
Appl. Opt. 43: 3037-47,
doi:10.1364/AO.43.003037.
Liebert A, Wabnitz H, Möller M, Macdonald R, Rinneberg H, Steinbrink J, Villringer A, Obrig H (2005),
Bed-side assessment of cerebral perfusion in stroke patients based on optical monitoring of a dye bolus by time-resolved diffuse reflectance,
Neuroimage 24: 425-435,doi:10.1016/j.neuroimage.2004.08.046.
Wabnitz H, Moeller M, Liebert A, Walter A, Erdmann R, Raitza O, Drenckhahn C, Dreier JP, Obrig H, Steinbrink J, Macdonald R (2005),
A time-domain NIR brain imager applied in functional stimulation experiments,
in “Photon Migration and Diffuse-Light Imaging II”,
Proc. SPIE 5859, 58590H,doi:10.1117/12.632837.
Liebert A, Wabnitz H, Obrig H, Erdmann R, Möller M, Macdonald R, Rinneberg H, Villringer A, Steinbrink J (2006),
Non-invasive detection of fluorescence from exogenous chromophores in the adult human brain,
Neuroimage 31: 600-608,doi:10.1016/j.neuroimage.2005.12.046.
Sander TH, Liebert A, Mackert BM, Wabnitz H, Leistner S, Curio G, Burghoff M, Macdonald R, Trahms L (2007),
DC-magnetoencephalography and time-resolved near-infrared spectroscopy combined to study neuronal and vascular brain responses,
Physiol Meas. 28: 651-64,doi:10.1088/0967-3334/28/6/004.
Sander TH, Liebert A, Burghoff M, Wabnitz H, Macdonald R, Trahms L (2007),
Cross-correlation analysis of the correspondence between magnetoencephalographic and near-infrared cortical signals,
Meth. Information in Medicine 46: 164-8.
Mackert BM, Leistner S, Sander T, Liebert A, Wabnitz H, Burghoff M, Trahms L, Macdonald R, Curio G (2008),
Dynamics of cortical neurovascular coupling analyzed by simultaneous DC magnetoencephalography and time-resolved near-infrared spectroscopy,
Neuroimage 39: 979-86,doi:10.1016/j.neuroimage.2007.09.037.
Steinbrink J, Liebert A, Wabnitz H, Macdonald R, Obrig H, Wunder A, Bourayou R, Betz T, Klohs J, Lindauer U, Dirnagl U, Villringer A (2008),
Towards Noninvasive Molecular Fluorescence Imaging of the Human Brain,
Neurodegenerative Dis. 5: 296–303,
doi:10.1159/000135614.
Liebert A, Wabnitz H, Zolek N, Macdonald R (2008),
Monte Carlo algorithm for efficient simulation of time-resolved fluorescence in layered turbid media,
Opt. Express 16:13188-202,doi:10.1364/OE.16.013188.
Sander TH, Leistner S, Wabnitz H, Mackert B-M, Macdonald R, Trahms L (2010),
Cross-correlation of motor activity signals from dc- magnetoencephalography, near-infrared spectroscopy, and electromyography,
Comput Intell Neurosci 2010 (2010), Article ID 785279, 8 Seiten,
doi:10.1155/2010/785279.
Wabnitz H, Moeller M, Liebert A, Obrig H, Steinbrink J, Macdonald R (2010),
Time-resolved near-infrared spectroscopy and imaging of the adult human brain,
Adv. Exp. Med. Biol. 662: 143-8,
doi:10.1007/978-1-4419-1241-1_20.
Steinkellner O, Gruber C, Wabnitz H, Jelzow A, Steinbrink J, Fiebach JB, Macdonald R, Obrig H (2010),
Optical bedside monitoring of cerebral perfusion: technological and methodological advances applied in a study on acute ischemic stroke,
J. Biomed. Opt. 15: 061708,doi:10.1117/1.3505009.
Wabnitz H, Pifferi A, Torricelli A, Taubert D R, Mazurenka M, Jelzow A, Farina A, Bargigia I, Contini D, Caffini M, Zucchelli L, Spinelli L, Sawosz P, Liebert A, Macdonald R, Cubeddu R (2011),
Assessment of basic instrumental performance of time-domain optical brain imagers,
Proc. SPIE 7896, 789602,
doi:10.1117/12.874654.
Steinkellner O, Wabnitz H, Schmid S, Steingräber R, Schmidt H, Krüger J, Macdonald R (2011),
Robot-assisted motor activation monitored by time-domain optical brain imaging,
Proc. SPIE 8088, 808807,
doi:10.1117/12.889505.
Jelzow A, Tachtsidis I, Kirilina E, Niessing M, Brühl R, Wabnitz H, Heine A, Ittermann B, Macdonald R (2011),
Simultaneous measurement of time-domain fNIRS and physiological signals during a cognitive task ,
Proc. SPIE 8088, 808803,
doi:10.1117/12.889484.
Leistner S, Sander-Thoemmes T, Wabnitz H, Moeller M, Wachs M, Curio G, Macdonald R, Trahms L, Mackert BM (2011),
Non-invasive simultaneous recording of neuronal and vascular signals in subacute ischemic stroke,
Biomed. Tech. (Berl). 56: 85-90,
doi:10.1515/BMT.2011.002.
Kirilina E, Jelzow A, Heine A, Niessing M, Wabnitz H, Brühl R, Ittermann B, Jacobs AM, Tachtsidis I. (2012),
The physiological origin of task-evoked systemic artefacts in functional near infrared spectroscopy,
Neuroimage 61: 70–81,
doi:10.1016/j.neuroimage.2012.02.074.
Mazurenka M, Jelzow A, Wabnitz H, Contini D, Spinelli L, Pifferi A, Cubeddu R, Mora AD, Tosi A, Zappa F, Macdonald R. (2012),
Non-contact time-resolved diffuse reflectance imaging at null source-detector separation,
Opt. Express. 20: 283-90,
doi:10.1364/OE.20.000283.
Jelzow A, Wabnitz H, Obrig H, Macdonald R, Steinbrink J (2012),
Separation of indocyanine green boluses in the human brain and scalp based on time-resolved in-vivo fluorescence measurements,
J. Biomed. Opt. 17: 057003,
doi:10.1117/1.JBO.17.5.057003.
Liebert A, Wabnitz H, Elster C (2012),
Determination of absorption changes from moments of distributions of times of flight of photons: optimization of measurement conditions for a two-layered tissue model,
J. Biomed. Opt. 17: 057005,
doi:10.1117/1.JBO.17.5.057005.
Steinkellner O, Wabnitz H, Jelzow A, Macdonald R, Gruber C, Steinbrink J, Obrig H (2012),
Cerebral perfusion in acute stroke monitored by time-domain near-infrared reflectometry,
Biocybernetics and Biomedical Engineering 32: 3-16.
Grosenick D, Wabnitz H, Ebert B (2012),
Review: Recent advances in contrast-enhanced near infrared diffuse optical imaging of diseases using indocyanine green,
J. Near Infrared Spectrosc. 20: 203–221,
doi:10.1255/jnirs.964.
Patent application
Liebert A, Wabnitz H, Steinbrink J, Obrig H, Macdonald R. (26.03.2004)
Verfahren und Gerät zur Detektion eines in den Körper eines Lebewesens injizierten Farbstoff-Bolus.
DE 10 2004 015 682 B4, WO 2005/094670 A1