Herbert Rinneberg

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.

Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla

A method for quantitative determination of the glutamate (Glu) concentration in human brain using PRESS-based single voxel MR spectroscopy (MRS) at 3 T has been developed and validated by repeatedly analyzing voxels comprising the anterior cingulate cortex (acc) and the left hippocampus (hc) in 40 healthy volunteer brains. At an optimum echo time of 80 ms, the C4 resonance of Glu appears well resolved and separated from major interferents, that is, glutamine and N-acetylaspartate. As a complementary method, a multiple quantum coherence filter sequence for Glu was employed. For quantification of Glu and the principal MRS-visible metabolites as well as for an estimate of the glutamine level, analysis of both types of in vivo spectra was carried out by a time domain-frequency domain method involving prior knowledge obtained from phantom spectra. Using PRESS, coefficients of variation (CV) for Glu concentration were of the order of 10%. When the concentrations were corrected by individual cerebrospinal fluid fractions obtained by segmentation using spm, CVs tended to increase and the correlation coefficients for the two MRS sessions tended to decrease, indicating that this type of correction adds uncertainty to the data. The concentrations of Glu in the two voxels studied were found to be significantly different (11.6 mmol/l in acc, 10.9 mmol/l in hc, P = 0.023) and decrease with age (P < 0.04). These concentrations agreed well with those determined using the quantum coherence filter method although the uncertainty of the latter limits reliable analysis.

Time-domain optical mammography: initial clinical results on detection and characterization of breast tumors.

Mammograms of 35 patients suspected of breast cancer were taken along craniocaudal and mediolateral projections with a dual-wavelength scanning laser pulse mammograph measuring time-resolved transmittance. Among 26 tumors known from routine clinical diagnostics, 17 tumors were detected retrospectively in optical mammograms. Effective tumor optical properties derived from a homogeneous model were used to deduce physiological information. All tumors exhibited increased total hemoglobin concentration and decreased or unchanged blood oxygen saturation compared with surrounding healthy tissue. Scatter plots based on a pixelwise analysis of individual mammograms were introduced and applied to represent corelations between characteristic quantities derived from measured distributions of times of flight of photons.

Human cardiac imaging at 3 T using phased array coils.

Using a two‐element phased array receiver coil, single breath‐hold, ECG gated cardiac images of signal‐to‐noise ratios up to 130 and contrast‐to‐noise ratios exceeding 35 between myocardium and blood were recorded at 3 T. At several locations within the myocardium, T*2 and B0 inhomogeneity were determined. Because of shorter T*2 times and larger B0 inhomogeneities attributable to enhanced susceptibility effects, real‐time cardiac imaging, the use of spiral scans, and echo planar imaging are expected to be considerably more difficult at 3 T. Magn Reson Med 44:978–982, 2000.

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.

Comparison of four magnetic resonance methods for mapping small temperature changes

Non-invasive detection of small temperature changes (< 1 degree C) is pivotal to the further advance of regional hyperthermia as a treatment modality for deep-seated tumours. Magnetic resonance (MR) thermography methods are considered to be a promising approach. Four methods exploiting temperature-dependent parameters were evaluated in phantom experiments. The investigated temperature indicators were spin-lattice relaxation time T1, diffusion coefficient D, shift of water proton resonance frequency (water PRF) and resonance frequency shift of the methoxy group of the praseodymium complex (Pr probe). The respective pulse sequences employed to detect temperature-dependent signal changes were the multiple readout single inversion recovery (T One by Multiple Read Out Pulses; TOMROP), the pulsed gradient spin echo (PGSE), the fast low-angle shot (FLASH) with phase difference reconstruction, and the classical chemical shift imaging (CSI). Applying these sequences, experiments were performed in two separate and consecutive steps. In the first step, calibration curves were recorded for all four methods. In the second step, applying these calibration data, maps of temperature changes were generated and verified. With the equal total acquisition time of approximately 4 min for all four methods, the uncertainties of temperature changes derived from the calibration curves were less than 1 degree C (Pr probe 0.11 degrees C, water PRF 0.22 degrees C, D 0.48 degrees C and T1 0.93 degrees C). The corresponding maps of temperature changes exhibited slightly higher errors but still in the range or less than 1 degree C (0.97 degrees C, 0.41 degrees C, 0.70 degrees C, 1.06 degrees C respectively). The calibration results indicate the Pr probe method to be most sensitive and accurate. However, this advantage could only be partially transferred to the thermographic maps because of the coarse 16 x 16 matrix of the classical CSI sequence. Therefore, at present the water PRF method appears to be most suitable for MR monitoring of small temperature changes during hyperthermia treatment.

Time-domain scanning optical mammography : II. Optical properties and tissue parameters of 87 carcinomas

Within a clinical trial on scanning time-domain optical mammography reported on in a companion publication (part I), craniocaudal and mediolateral projection optical mammograms were recorded from 154 patients, suspected of having breast cancer. Here we report on in vivo optical properties of the subset of 87 histologically validated carcinomas which were visible in optical mammograms recorded at two or three near-infrared wavelengths. Tumour absorption and reduced scattering coefficients were derived from distributions of times of flight of photons recorded at the tumour site employing the model of diffraction of photon density waves by a spherical inhomogeneity, located in an otherwise homogeneous tissue slab. Effective tumour radii, taken from pathology, and tumour location along the compression direction, deduced from off-axis optical scans of the tumour region, were included in the analysis as prior knowledge, if available. On average, tumour absorption coefficients exceeded those of surrounding healthy breast tissue by a factor of about 2.5 (670 nm), whereas tumour reduced scattering coefficients were larger by about 20% (670 nm). From absorption coefficients at 670 nm and 785 nm total haemoglobin concentration and blood oxygen saturation were deduced for tumours and surrounding healthy breast tissue. Apart from a few outliers total haemoglobin concentration was observed to be systematically larger in tumours compared to healthy breast tissue. In contrast, blood oxygen saturation was found to be a poor discriminator for tumours and healthy breast tissue; both median values of blood oxygen saturation are the same within their statistical uncertainties. However, the ratio of total haemoglobin concentration over blood oxygen saturation further improves discrimination between tumours and healthy breast tissue. For 29 tumours detected in optical mammograms recorded at three wavelengths (670 nm, 785 nm, 843 nm or 884 nm), scatter power was derived from transport scattering coefficients. Scatter power of tumours tends to be larger than that of surrounding healthy breast tissue, yet the 95% confidence intervals of both medians overlap.

Concentration and oxygen saturation of haemoglobin of 50 breast tumours determined by time-domain optical mammography

Using a dual-wavelength (670 nm, 785 nm) time-domain scanning instrument we have recorded optical mammograms of 93 patients suspected of having breast cancer which was subsequently assessed histologically. Among 65 histologically confirmed carcinomas, 54 were detectable in at least one of two optical mammograms recorded of each tumour-bearing breast in craniocaudal and mediolateral projection. Optical mammograms were based on photon counts in selected time windows of measured distributions of times of flight of photons. Optical properties of 50 carcinomas investigated at both wavelengths were derived by modelling the breast as partially homogeneous infinite slab with an embedded spherical inhomogeneity representing the tumour and by calculating the diffraction of photon density waves. In selected cases, additional information about the location of the tumour along the compression direction was used that was obtained from scans at selected offsets between source and detector optical fibres. A correlation plot of haemoglobin concentration and blood oxygen saturation of tumours and healthy tissue shows good separation between both kinds of tissue. The majority of carcinomas exhibited increased total haemoglobin concentration compared to healthy tissue.

Somatosensory evoked fast optical intensity changes detected non-invasively in the adult human head

This work is the first to report optical intensity changes (DeltaI/I approximately 0.05%) with a latency between 60 and 160ms after electrical median nerve stimulation at 5Hz detected non-invasively through the intact adult human skull in volunteers. The signal is localised and reproducible when measuring at the same position on successive examinations. Compared to previous reports of fast optical changes in the human adult by a single group (Psychophysiology, 32 (1995) 505) the here reported changes are much smaller. They are in line with results from a photon transport calculation on a head model employing data from exposed cortical tissue. The origin of the signal found here is still unclear, however, they might be the non-invasive equivalent to the scattering changes found in exposed cortical tissue studies (J. Neurophysiol., 78 (1997) 1707).

Macromolecular Contrast Agents for Optical Imaging of Tumors: Comparison of Indotricarbocyanine-labeled Human Serum Albumin and Transferrin¶

Abstract Macromolecules accumulate in solid tumors and can thus be used as carriers for the delivery of attached contrast agents to tumors. We report the synthesis and use of serum protein–dye conjugates consisting of transferrin (Tf) or human serum albumin (HSA) and an indotricarbocyanine (ITCC) derivative as contrast agents for the optical imaging of tumors. The compounds were characterized with respect to their photophysical properties and tested in vitro for their ability to bind to tumor cells and in vivo for their potential to delineate experimental tumors. In contrast to HAS-ITTC, Tf-ITCC showed receptor-mediated uptake by HT29 human colon cancer cells in vitro. After intravenous injection into HT29 tumor-bearing nude mice both compounds induced increased fluorescence contrast of tumors in vivo. After 24 h the contrast between tumor and normal tissue was significantly higher for Tf-ITCC than for HAS-ITCC. Dye-induced fluorescence was found to be predominantly located in perinecrotic areas of the tumor. Furthermore, Tf-ITCC produced fluorescence of viable tumor cells, whereas HAS-ITCC fluorescence was recorded along connective tissue. We conclude that ITCC-labeled Tf and HSA can serve as macromolecular contrast agents for the optical imaging of tumors, with Tf-ITCC showing higher efficiency.