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A multiparametric assessment of oxygen efflux from the brain.

A quantitative understanding of unidirectional versus net extraction of oxygen in the brain is required because an important factor in calculating oxidative metabolism by calibrated functional magnetic resonance imaging (fMRI) as well as oxygen inhalation methods of positron emission tomography (15O2-PET) and nuclear magnetic resonance (17O2-NMR)) is the degree of oxygen efflux from the brain back into the blood. Because mechanisms of oxygen transport from blood to brain are dependent on cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), and oxygen partial pressure (pO2) values in intravascular (Piv) and extravascular (Pev) compartments, we implemented multimodal measurements of these parameters into a compartmental model of oxygen transport and metabolism (i.e., hemoglobin-bound oxygen, oxygen dissolved in plasma and tissue spaces, oxygen metabolized in the mitochondria). In the alpha-chloralose anesthetized rat brain, we used magnetic resonance (7.0 T) and fluorescence quenching methods to measure CMRO2 (2.5+/-1.0 micromol/g min), CBF (0.7+/-0.2 mL/g min), Piv (74+/-10 mm Hg), and Pev (16+/-5 mm Hg) to estimate the degree of oxygen efflux from the brain. In the axially distributed compartmental model, oxygen molecules in blood had two possible fates: enter the tissue space or remain in the same compartment; while in tissue there were three possible fates: enter the blood or the mitochondrial space, or remain in the same compartment. The multiparametric results indicate that the probability of unmetabolized (i.e., dissolved) oxygen molecules reentering the blood from the tissue is negligible and thus its inclusion may unnecessarily complicate calculations of CMRO2 for 15O-PET, 17O-NMR, and calibrated fMRI methods.

Animals↗

Rationale for surgery as the first step in the multimodality treatment of small cell lung cancer (SCLC).

The role of surgery has to be reconsidered in combination with chemo/radiotherapy for patients with SCLC at early stages, determined by the pTNM-staging system. This combined multimodality treatment can be seen as a model-like example for the most effective progress gained during the last 20 years. Surgery followed by chemotherapy is used in ongoing cooperative studies. In other trials, chemotherapy is followed by surgery for responding patients. It seems reasonable to expect that after appropriate observation times the comparison of these ongoing trials would most probably lead to the conclusion that for stage I, II surgery should be the first step followed by chemo- and radiotherapy, whereas for stage III debulking chemotherapy should be given to distinguish responding patients, who may thereafter receive adjuvant surgery.

Carcinoma, Small Cell↗

Spirals and vortex lattices in quasi-self-imaging divide-by-three optical parametric oscillators.

A linear stability analysis is derived in self-imaging cavities for which the conditions for large Fresnel number are stated. In cases of both Fabry-Pérot and ring cavities a Hopf bifurcation is predicted at finite transverse wave number. The self-imaging Fabry-Pérot resonator operates as a longitudinal multimode cavity that invalidates the mean-field model. Above the bifurcation threshold, either vortex lattices, spirals, or targets occur, depending on the Fresnel number, the input intensity, and the mistunings. The time and spatial characteristics have different scales in the case of a self-imaging ring cavity, but the same sort of patterns are reported.

Journal Article↗

Determination of the optimum cluster parameters in a clustered free-space optical interconnect.

A model for a clustered free-space optical interconnect is developed and is used to determine the maximum array density that can be achieved, together with the optimal cluster parameters that maximize this density. This model includes misalignment tolerance and the impact of multimode vertical-cavity surface-emitting laser beams. We find that for short interconnect distances, the maximum channel density is limited by the speed of the relay lenses, but as the interconnect distance increases, geometric aberrations become the limiting factor. We also determine the interconnect distance below which a micro-channel relay is more suitable and the distance above which a single-lens solution is adequate.

Journal Article↗

The pervasive developmental disorder spectrum: a case illustration.

Children diagnosed with a pervasive developmental disorder experience difficulties along a spectrum of severity. Impairments in socialization, communication, and the ability to appropriately express and interpret affect in relationships are common features of the disorder. After summarizing salient thinking in the field, the author describes a case emphasizing the individual psychotherapy process in which the patient was involved. Although individual psychotherapy with such patients is currently viewed with skepticism, the one-on-one relationship may be a central feature of such treatment because it can serve as a model for other relationships. The author advocates a multimodal treatment plan appropriately geared to the needs of such patients.

Adolescent↗

[New aspects of complex chronic tinnitus. I: Assessment of a multi-modality behavioral medicine treatment concept].

"Complex tinnitus" is a diagnostic term denoting a disturbance pattern where the patient hears highly annoying and painful noises or sounds that do not originate from a recognisable external source and can be described only by the patient himself. It seems that the suffering mainly depends upon the extent to which the tinnitus is experienced as a phenomenon that is beyond control. Part I reports on an examination of the treatment success achieved with 28 consecutive patients who had been treated according to an integrative multimodal behavioural medicine concept. This resulted--despite continual loudness--in a decrease in the degree of unpleasantness of the tinnitus, by 17% (p less than 0.01) with corresponding normalisation of decisive symptom factors in Hopkins Symptom-Check-List (SCL-90-R) and Freiburg Personality-Inventary (FPI-R). On the whole, 19 out of the total of 28 patients showed essential to marked improvement of the disturbance pattern. Part II presents a multidimensional tinnitus model and the essential psychotherapeutic focal points of a multimodal psychotherapy concept in complex chronic tinnitus, as well as the parallel phenomena in the chronic pain syndrome.

Adult↗

[New aspects of complex chronic tinnitus. II: The lost silence: effects and psychotherapeutic possibilities in complex chronic tinnitus].

"Complex tinnitus" is a diagnostic term denoting a disturbance pattern where the patient hears highly annoying and painful noises or sounds that do not originate from a recognisable external source and can be described only by the patient himself. It seems that the suffering mainly depends upon the extent to which the tinnitus is experienced as a phenomenon that is beyond control. Part I reports on an examination of the treatment success achieved with 28 consecutive patients who had been treated according to an integrative multimodal behavioural medicine concept. This resulted--despite continual loudness--in a decrease in the degree of unpleasantness of the tinnitus, by 17% (p less than 0.01) with corresponding normalisation of decisive symptom factors in Hopkins-Symptom-Check-List (SCL-90-R) and Freiburg Personality-Inventary (FPI-R). On the whole, 19 out of the total of 28 patients showed essential to marked improvement of the disturbance pattern. Part II presents a multidimensional tinnitus model and the essential psychotherapeutic focal points of a multimodal psychotherapy concept in complex chronic tinnitus, as well as the parallel phenomena in the chronic pain syndrome.

Behavior Therapy↗

The three-loop model: a neural network for the generation of saccadic reaction times.

This paper presents a computer simulation of the three-loop model for the temporal aspects of the generation of visually guided saccadic eye movements. The intention is to reproduce complex experimental reaction time distributions by a simple neural network. The operating elements are artificial but realistic neurones. Four modules are constructed, each consisting of 16 neural elements. Within each module, the elements are connected in an all-to-all manner. The modules are working parallel and serial according to the anatomically and physiologically identified visuomotor pathways including the superior colliculus, the frontal eye fields, and the parietal cortex. Two transient-sustained input lines drive the network: one represents the visual activity produced by the onset of the saccade target, the other represents a central activity controlling the preparation of saccades, e.g. the end of active fixation. The model works completely deterministically; its stochastic output is a consequence of the stochastic properties of the input only. Simulations show how multimodal distributions of saccadic reaction times are produced as a natural consequence of the model structure. The gap effect on saccadic reaction times is correctly produced by the model: depending only on the gap duration (all model parameters unchanged) express, fast-regular, and slow-regular saccades are obtained in different numbers. In agreement with the experiments, bi- or trimodal distributions are produced only for medium gap durations (around 200 ms), while for shorter or longer gaps the express mode disappears and the distributions turn bi- or even unimodal. The effect of varying the strength of the transient-sustained components and the ongoing activity driving the hierarchically highest module are considered to account for the interindividual variability of the latency distributions obtained from different subjects, effects of different instructions to the same subject, and the observation of express makers (subjects who produce exclusively express saccades). How the model can be extended to describe the spatial aspects of the saccade system will be discussed as well as the effects of training and/or rapid adaptation to experimental conditions.

Computer Simulation↗

Diagnostic concepts, multimodal and multiaxial approaches in psychotherapy and psychosomatics.

Basic questions concerning diagnostic models in psychoanalytic psychotherapy and psychosomatics are discussed in this paper. Against the background of the different areas in psychodynamic-oriented diagnoses, the advantages and disadvantages of descriptive multiaxial diagnostical models like DSM-III-R and ICD-10 are examined. These conceptual reflections have been built on the findings from participation in Germany of a great number of psychotherapeutic/psychosomatic institutions in the field trials for the assessment of the Diagnostic Criteria for Research of ICD-10, chapter V. Some of the most important issues this study has raised are discussed.

Conversion Disorder↗

Performance enhancement for audio-visual speaker identification using dynamic facial muscle model.

Science of human identification using physiological characteristics or biometry has been of great concern in security systems. However, robust multimodal identification systems based on audio-visual information has not been thoroughly investigated yet. Therefore, the aim of this work to propose a model-based feature extraction method which employs physiological characteristics of facial muscles producing lip movements. This approach adopts the intrinsic properties of muscles such as viscosity, elasticity, and mass which are extracted from the dynamic lip model. These parameters are exclusively dependent on the neuro-muscular properties of speaker; consequently, imitation of valid speakers could be reduced to a large extent. These parameters are applied to a hidden Markov model (HMM) audio-visual identification system. In this work, a combination of audio and video features has been employed by adopting a multistream pseudo-synchronized HMM training method. Noise robust audio features such as Mel-frequency cepstral coefficients (MFCC), spectral subtraction (SS), and relative spectra perceptual linear prediction (J-RASTA-PLP) have been used to evaluate the performance of the multimodal system once efficient audio feature extraction methods have been utilized. The superior performance of the proposed system is demonstrated on a large multispeaker database of continuously spoken digits, along with a sentence that is phonetically rich. To evaluate the robustness of algorithms, some experiments were performed on genetically identical twins. Furthermore, changes in speaker voice were simulated with drug inhalation tests. In 3 dB signal to noise ratio (SNR), the dynamic muscle model improved the identification rate of the audio-visual system from 91 to 98%. Results on identical twins revealed that there was an apparent improvement on the performance for the dynamic muscle model-based system, in which the identification rate of the audio-visual system was enhanced from 87 to 96%.

Adult↗

Cortical source estimate of combined high resolution EEG and fMRI data related to voluntary movements.

OBJECTIVES: In this paper, we employed advanced methods for the modeling of human cortical activity related to voluntary right one-digit movements from combined high-resolution electroencepholography (EEG) and functional magnetic resonance imaging (fMRI). METHODS: Multimodal integration between EEG and fMRI data was performed by using realistic head models, a large number of scalp electrodes (128) and the estimation of current density strengths by linear inverse estimation. RESULTS: Increasing of spatial details of the estimated cortical density distributions has been detected by using the proposed integration method with respect to the estimation using EEG data alone. CONCLUSION: The proposed method of multimodal EEG-fMRI data is useful to increase spatial resolution of movement-related potentials and can also be applied to other kinds of event-related potentials.

Brain Mapping↗

Augmentation of reality using an operating microscope for otolaryngology and neurosurgical guidance.

The operating microscope is an integral part of many neurosurgery and otolaryngology procedures; the surgeon often uses the microscopic view for a large portion of the operation. Information from preoperative radiological images is often viewed only on X-ray films. The surgeon then has the difficult task of relating this information to the appearance of the surgical view. Image guidance techniques attempt to relate these two sets of information by registering the patient in the operating room to preoperative images using locating devices. Conventionally, image data are presented on a computer monitor, which requires the surgeon to look away from the operative scene. We describe a guidance system, for procedures in which the operating microscope is used, which super-imposes image-derived data upon the operative scene. We create a model of relevant structures (e.g., tumor volume, blood vessels, and nerves) from multimodality preoperative images. By calibrating microscope optics, registering the patient to image coordinates, and tracking the microscope and patient intraoperatively, we can generate stereo projections of the three-dimensional model and project them into the microscope eyepieces, allowing critical structures to be overlaid on the operative scene in the correct position. Measurements with a head phantom gave a root mean square (RMS) error of 1.08 mm, and the estimated error for a human volunteer is between 2 and 3 mm. Initial evaluation in the operating room was very promising.

Computer Simulation↗

Efficient computation and cue integration with noisy population codes.

The brain represents sensory and motor variables through the activity of large populations of neurons. It is not understood how the nervous system computes with these population codes, given that individual neurons are noisy and thus unreliable. We focus here on two general types of computation, function approximation and cue integration, as these are powerful enough to handle a range of tasks, including sensorimotor transformations, feature extraction in sensory systems and multisensory integration. We demonstrate that a particular class of neural networks, basis function networks with multidimensional attractors, can perform both types of computation optimally with noisy neurons. Moreover, neurons in the intermediate layers of our model show response properties similar to those observed in several multimodal cortical areas. Thus, basis function networks with multidimensional attractors may be used by the brain to compute efficiently with population codes.

Action Potentials↗

Squamous cell carcinoma growth in irradiated tissue: a murine model for quantitative assessment of treatment.

Locoregional recurrent and distant metastases from squamous cell carcinomas, despite multimodality therapy, remain troublesome clinical realities. Discrepancies in success rates of various surgery and radiation treatment regimens dealing with these problems are confusing to the clinician attempting to recommend the most beneficial treatments. There is a need for an experimental model to assess therapeutic effectiveness quantitatively from which guidelines for developing clinical trials may be suggested. In this study, we provide such a model. We injected DBA-2 mice with defined numbers of KLN-205 squamous carcinoma cells to obtain baseline growth characteristics; 216 animals had no previous irradiation. The remaining 131 received 30 Gy irradiation to the right leg 50 days before injection of the tumor cells. Tumor incidence, growth and number, and location of tumor metastasis were determined in both previously irradiated and nonirradiated groups. The data demonstrate a growth-retardant effect on tumor groups by the previous irradiation (tumor bed effect). The data also show that the incidence of hematogenously spread metastases was more frequent in mice in which tumors developed in previously irradiated tissue than in mice with tumors in nonirradiated tissue.

Animals↗

Future perspectives for intraoperative MRI.

MRI-guided neurosurgery not only represents a technical challenge but a transformation from conventional hand-eye coordination to interactive navigational operations. In the future, multimodality-based images will be merged into a single model, in which anatomy and pathologic changes are at once distinguished and integrated into the same intuitive framework. The long-term goals of improving surgical procedures and attendant outcomes, reducing costs, and achieving broad use can be achieved with a three-pronged approach: 1. Improving the presentation of preoperative and real-time intraoperative image information 2. Integrating imaging and treatment-related technology into therapy delivery systems 3. Testing the clinical utility of image guidance in surgery The recent focus in technology development is on improving our ability to understand and apply medical images and imaging systems. Areas of active research include image processing, model-based image analysis, model deformation, real-time registration, real-time 3D (so-called "four-dimensional") imaging, and the integration and presentation of image and sensing information in the operating room. Key elements of the technical matrix also include visualization and display platforms and related software for information and display, model-based image understanding, the use of computing clusters to speed computation (ie, algorithms with partitioned computation to optimize performance), and advanced devices and systems for 3D device tracking (navigation). Current clinical applications are successfully incorporating real-time and/or continuously up-dated image-based information for direct intra-operative visualization. In addition to using traditional imaging systems during surgery, we foresee optimized use of molecular marker technology, direct measures of tissue characterization (ie, optical measurements and/or imaging), and integration of the next generation of surgical and therapy devices (including image-guided robotic systems). Although we expect the primary clinical thrusts of MRI-guided therapy to remain in neurosurgery, with the possible addition of other areas like orthopedic, head, neck, and spine surgery, we also anticipate increased use of image-guided focal thermal ablative methods (eg, laser, RF, cryoablation, high-intensity focused ultrasound). By validating the effectiveness of MRI-guided therapy in specific clinical procedures while refining the technology that serves as its underpinning at the same time, we expect many neurosurgeons will eventually embrace MRI as their intraoperative imaging choice. Clearly, intraoperative MRI offers several palpable advantages. Most important among these are improved medical outcomes, shorter hospitalization, and better and faster procedures with fewer complications. Certain economic and practical barriers also impede the large-scale use of intraoperative MRI. Although there has been a concerted technical effort to increase the benefit/cost ratio by gathering more accurate information, designing more localized and less invasive treatment devices, and developing better methods to orient and position therapy end-effectors, further research is needed. Indeed, the drive to improve and upgrade technology is ongoing. Specifically, in the context of the real-time representation of the patient's anatomy, we have improved the quality and utility of the information presented to the surgeon, which, in turn, contributes to more successful surgical outcomes. We can also expect improvements in intraoperative imaging systems as well as increased use of nonimaging sensors and robotics to facilitate more widespread use of intraoperative MRI.

Humans↗

In vitro response of human glioblastoma and canine glioma cells to hyperthermia, radiation, and chemotherapy.

Little is known about the sensitivity of human glioblastoma cells to hyperthermia alone and in combination with other therapies. We carried out in vitro cell survival studies on the human glioblastoma cell line U-87MG and our model canine glioma canine brain tumor (CBT) cells after multimodality treatment. Ionizing radiation was administered to flasks of cells in logarithmic growth at 500 rads (5 Gy) with consecutive treatment by hyperthermia, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), or cisplatin. Cells were treated with single doses of BCNU at 5 microM with sequentially added radiation or hyperthermia and at 1 to 2 micrograms/ml of cisplatin with hyperthermia. Hyperthermia was administered in a precision controlled water bath at 44 degrees C for 30 minutes in combination with chemotherapy or radiation. In general, the sensitivity of U-87MG and CBT cells was similar for all test regimens. For example, colony formation efficiency decreased by 64% in CBT cells and by 64.4% in U-87MG cells after hyperthermia alone at 44 degrees C for 60 minutes. All combinations of BCNU, hyperthermia, and radiation administered in vitro produced enhanced cell killing, but the effects of multiple modalities were generally additive in both cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 selectively potentiates radiation response of human tumors in nude mice, with a marked improvement in therapeutic index.

PURPOSE: The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) markedly potentiates the efficacy of many cytotoxic agents against several human cancer xenografts, irrespective of tumor EGFR expression levels. We subsequently investigated the extent to which ZD1839 might improve radiation therapy (RT) in similar animal models of human cancer within the limits of tolerance at a relevant organ site. EXPERIMENTAL DESIGN: We carried out studies of ZD1839 in in vivo models of human non-small cell lung (A549 and SK-LC-16) and breast (MDA-MB468) cancers and human mesothelioma (JMN). The tumors were implanted s.c. over the rib cage or on the most proximate breast and RT given ventral dorsally to the chest only, with mediastinal protection. After the tumor reached a palpable size (0.4-0.6 mm), treatment was initiated with the maximum-tolerated dose (MTD) of ZD1839 (150 mg/kg once daily x 5 for 2 successive weeks), RT (a total of 40 Gy given fractionally at 4 Gy once daily x 5 for 2 successive weeks), or both ZD1839 and RT. RESULTS: This level of RT induced no untoward effects in the mice and was effective (18-72%) in bringing about regression of the tumors with a few complete regressions. ZD1839 alone, given p.o. on the same schedule at its MTD (150 mg/kg), was modestly inhibitory (35-40%) to tumor growth. RT and ZD1839 could be given together at the same doses on the same schedule, resulting in marked regression (50-99%) and a large number of complete regressions of each of the tumors studied. In these studies, the MTD of ZD1839 could be combined with the MTD of RT with no change in schedule or increase toxicity over ZD1839 or RT alone. CONCLUSIONS: ZD1839 significantly enhanced the antitumor action of RT against the test tumors without significant adverse effects, increasing the therapeutic selectively of ionizing radiation in these model systems. These results predict substantial benefits for this multimodality regimen of therapy in patients.

Animals↗