Adam Liebert

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

We report on multidistance time-resolved diffuse reflectance spectroscopy of the head of a healthy adult after intravenous administration of a bolus of indocyanine green. Intracerebral and extracerebral changes in absorption are deduced from moments (integral, mean time of flight, and variance) of the distributions of times of flight of photons (DTOFs), recorded simultaneously at four different source-detector separations. We calculate the sensitivity factors converting depth-dependent changes in absorption into changes of moments of DTOFs by Monte Carlo simulations by using a layered model of the head. We validate our method by analyzing moments of DTOFs simulated for the assumed changes in absorption in different layers of the head model.

Bed-side assessment of cerebral perfusion in stroke patients based on optical monitoring of a dye bolus by time-resolved diffuse reflectance

We present a minimally invasive optical method, that is, multi-channel time-domain diffuse near-infrared reflectometry of the head to assess cerebral blood perfusion that is applicable at the bed-side and repetitively at short intervals. Following intravenous injection of an ICG bolus, its transit through intra- and extracerebral tissue is monitored based on changes in moments of distributions of times of flight of photons, recorded with a 4-channel instrument simultaneously on both hemispheres. In healthy volunteers, we found that variance of distributions of times of flight of photons is well suited to assess latency and initial slope of the increase in absorption of intracerebral tissue due to the bolus. We successfully applied our method in two patients demonstrating a reversible cerebral perfusion deficit in an ischemic stroke patient who was treated by thrombolysis and in another patient with a permanent impaired unilateral perfusion due to ipsilateral internal carotid artery occlusion. In either case, we observed a difference in bolus transit time between the hemispheres. In the stroke patient, this difference resolved when re-evaluated 1 day after thrombolysis. The study demonstrates the necessity of a technique with sub-nanosecond time resolution to allow for depth discrimination if clinical perfusion monitoring of cerebrovascular diseases is addressed by optical methods.

Evaluation of optical properties of highly scattering media by moments of distributions of times of flight of photons

A novel method for the determination of the optical properties of tissue from time-domain measurements is presented. The data analysis is based on the evaluation of the first moment and the second centralized moment, i.e., the mean time of flight and the variance of the measured distribution of times of flight (DTOF) of photons injected by short (picosecond) laser pulses. Analytical expressions are derived for calculation of absorption and of reduced scattering coefficients from these moments by application of diffusion theory for infinite and semi-infinite homogeneous media. The proposed method was tested on experimental data obtained with phantoms, and results for absorption and reduced scattering coefficients obtained by the proposed method are compared with those obtained by fitting of the same data with analytical solutions of the diffusion equation. Furthermore, the accuracy of the moment analysis was investigated for a range of integration limits of the DTOF. The moment analysis may serve as a comparatively fast method for evaluating optical properties with sufficient accuracy and can be used, e.g., for on-line monitoring of optical properties of biological tissue.

Non-invasive detection of fluorescence from exogenous chromophores in the adult human brain

This is the first report on results proving that fluorescence of exogenous dyes inside the human brain can be excited and detected non-invasively at the surface of the adult head. Boli of indocyanine green (ICG) were intravenously applied to healthy volunteers, and the passage of the contrast agent in the brain was monitored by detecting the corresponding fluorescence signal following pulsed laser excitation at 780 nm. Our hypothesis that the observed fluorescence signal contains a considerable cortical fraction was corroborated by performing measurements with picosecond temporal resolution and analyzing distributions of times of arrival of photons, hence taking advantage of the well-known depth selectivity of that method. Our experimental findings are explained by Monte Carlo simulations modeling the head as a layered medium and taking into account realistic bolus kinetics within the extra- and intracerebral compartment. Although a particular non-specific dye (ICG) was used, the results clearly demonstrate that fluorescence-mediated imaging of the adult human brain is generally feasible. In particular, we will discuss how these results serve as proof of concept for non-invasive fluorescence brain imaging and may thus open the door towards optical molecular imaging of the human brain.

Time-resolved optical imager for assessment of cerebral oxygenation

A time-resolved optical instrument allowing for noninvasive assessment of cerebral oxygenation is presented. The instrument is equipped with picosecond diode lasers, fast photodetectors, and time-correlated single photon counting electronics. This technology enables depth-resolved estimation of changes in absorption and, in consequence, assessment of changes in hemoglobin concentrations in the brain cortex. Changes in oxyhemoglobin (HbO(2)) and deoxyhemoglobin (Hb) can be evaluated selectively in extra- and intracerebral tissue compartments using the moments of distributions of times of flight of photons measured at two wavelengths in the near-infrared region. The combination of the data acquired from multiple sources and detectors located on the surface of the head with the depth-resolved analysis, based on the moments, enables imaging of cortex oxygenation. Results of the tests on physical phantoms as well as in vivo validation of the instrument during the motor stimulation experiment are presented.

Fiber dispersion in time domain measurements compromising the accuracy of determination of optical properties of strongly scattering media

Limitations in the accuracy of measurements of optical properties (absorption and scattering coefficients) of strongly scattering media that are due to temporal dispersion inside the detection fibers of a time-of-flight setup were investigated for a tissue-like phantom. It is shown that the absorption and reduced scattering coefficients may be overestimated by up to 90% (depending on length and numerical aperture of the fibers) if the instrumental response measurements for the setup are performed by direct illumination of the tip of the detection fibers with collimated short laser pulses. However, the accuracy can be improved significantly if a thin layer of scattering media is used in front of the detection fibers during the response measurements. The relevance of the investigated dispersion effects is discussed with respect to frequency-domain measurements as well.

Determination of reference values for optical properties of liquid phantoms based on Intralipid and India ink

A multi-center study has been set up to accurately characterize the optical properties of diffusive liquid phantoms based on Intralipid and India ink at near-infrared (NIR) wavelengths. Nine research laboratories from six countries adopting different measurement techniques, instrumental set-ups, and data analysis methods determined at their best the optical properties and relative uncertainties of diffusive dilutions prepared with common samples of the two compounds. By exploiting a suitable statistical model, comprehensive reference values at three NIR wavelengths for the intrinsic absorption coefficient of India ink and the intrinsic reduced scattering coefficient of Intralipid-20% were determined with an uncertainty of about 2% or better, depending on the wavelength considered, and 1%, respectively. Even if in this study we focused on particular batches of India ink and Intralipid, the reference values determined here represent a solid and useful starting point for preparing diffusive liquid phantoms with accurately defined optical properties. Furthermore, due to the ready availability, low cost, long-term stability and batch-to-batch reproducibility of these compounds, they provide a unique fundamental tool for the calibration and performance assessment of diffuse optical spectroscopy instrumentation intended to be used in laboratory or clinical environment. Finally, the collaborative work presented here demonstrates that the accuracy level attained in this work for optical properties of diffusive phantoms is reliable.

Time-Resolved Near-Infrared Spectroscopy and Imaging of the Adult Human Brain

Near-infrared spectroscopy (NIRS) of the human brain is aiming at the non-invasive determination of concentration changes of oxy- and deoxyhemoglobin in the cortex. However, it usually relies on the assumption of spatially homogeneous absorption changes. To overcome this limitation we performed instrumental and methodological developments of time-resolved NIRS with the aim to achieve depth resolution. We present our recently developed time-domain near-infrared brain imager based on picosecond diode lasers and time-correlated single photon counting (TCSPC) which can be used at the bedside. To achieve depth localization of absorption changes we analysed statistical moments (integral, mean time of flight and variance) of measured time-of-flight distributions of diffusely reflected photons. In particular, variance has a selective sensitivity to deep absorptions changes and provides a suitable representation of cerebral signals. The separation of cerebral and extracerebral changes of hemoglobin concentrations is demonstrated for a motor stimulation experiment.

High-count-rate multichannel TCSPC for optical tomography

An improved Time-Correlated Single Photon Counting (TCSPC) technique features high count rate, low differential nonlinearity and multi-detector capability. The system has four completely parallel TCSPC channels and achieves an effective overall count rate of 20 MHz. By an active routing technique, up to eight detectors can be connected to each of the TCSPC channels. We used the system to record optical mammograms after pulsed laser illumination at different wavelengths and projection angles.

Towards noninvasive molecular fluorescence imaging of the human brain

Fluorescence molecular brain imaging is a new modality allowing the detection of specific contrast agents down to very low concentration ranges (picomolar) in disease models. Here we demonstrate a first noninvasive application of fluorescence imaging in the human brain, where concentrations down to about 100 nM of a nonspecific dye were detected. We argue that due to its high sensitivity, optical molecular imaging of the brain is feasible, which – together with its bedside applicability – makes it a promising technique for use in patients.