Initial Investigation into Microbleeds and White Matter Signal Changes following Radiotherapy for Low-Grade and Benign Brain Tumors Using Ultra-High-Field MRI Techniques.

BACKGROUND AND PURPOSE: External beam radiation therapy is a common treatment for many brain neoplasms. While external beam radiation therapy adheres to dose limits to protect the uninvolved brain, areas of high dose to normal tissue still occur. Patients treated with chemoradiotherapy can have adverse effects such as microbleeds and radiation necrosis, but few studies exist of patients treated without chemotherapy. MATERIALS AND METHODS: Ten patients were treated for low-grade or benign neoplasms with external beam radiation therapy only and scanned within 12-36 months following treatment with a 7T MR imaging scanner. A multiecho gradient-echo sequence was acquired and postprocessed into SWI, quantitative susceptibility mapping, and apparent transverse relaxation maps. Six patients returned for follow-up imaging approximately 18 months following their first research scan and were imaged with the same techniques. RESULTS: At the first visit, 7/10 patients had microbleeds evident on SWI, quantitative susceptibility mapping, and apparent transverse relaxation. All microbleeds were within a dose region of >45 Gy. Additionally, 4/10 patients had asymptomatic WM signal changes evident on standard imaging. Further analysis with our technique revealed that these lesions were venocentric, suggestive of a neuroinflammatory process. CONCLUSIONS: There exists a potential for microbleeds in patients treated with external beam radiation therapy without chemotherapy. This finding is of clinical relevance because it could be a precursor of future neurovascular disease and indicates that additional care should be taken when using therapies such as anticoagulants. Additionally, the appearance of venocentric WM lesions could be suggestive of a neuroinflammatory mechanism that has been suggested in diseases such as MS. Both findings merit further investigation in a larger population set.

Poster - Thur Eve - 13: Quantifying specific absorption rate of shielded RF coils through electromagnetic simulations for 7-T MRI.

Ultra-high field MRI has many advantages such as increasing spatial resolution and exploiting contrast never before seen in-vivo. This contrast has been shown to be beneficial for many applications such as monitoring early and late effect to radiation therapy and transient changes during disease to name a few. However, at higher field strengths the RF wave, needed to for transmitting and receiving signal, approaches that of the head. This leads to constructive and deconstructive interference and a non -uniform flip angle over the volume being imaged. A transmit or transceive RF surface coil arrays is currently a method of choice to overcome this problem; however, mutual inductance between elements poses a significant challenge for the designer. A method to decouple elements in such an array is by using circumferential shielding; however, the potential benefits and/or disadvantages have not been investigated. This abstract primarily focuses on understanding power deposition - measured through Specific Absorption Rate - in the sample using circumferentially shielded RF coils. Various geometries of circumferentially shielded coils are explored to determine the behaviour of shield width and its effect on required transmit power and power deposition to the sample. Our results indicate that there is an optimization on shield width depending on the imaging depth. Additionally, the circumferential shield focuses the field more than unshielded coils, meaning that slight SAR may even be lower for circumferential shielded RF coils in array.

Isolated chemotherapeutic perfusion of the pelvis for advanced rectal cancer.

OBJECTIVE: Isolated pelvic perfusion exposes tissue to high doses of drug without the toxicity of high-dose systemic therapy and may benefit patients with advanced malignancy. PATIENTS AND METHODS: There were 32 patients with locally advanced, previously irradiated cancer of the rectum and 5 patients with anal canal cancer. These patients underwent a total of 65 isolated pelvic perfusions using 5-Fu (1500 mg/m2) for 60 min; cisplatinum (100 mg/m2) and mitomycin (10-20 mg/m2) were added to some perfusions. Hospital stay averaged 3-5 days. RESULTS: Palliative perfusion in 15 patients with advanced rectal cancer resulted in symptomatic relief from 1 to 4 months in 11 of 14 with pelvic pain and limited benefit in 6 patients with mass, but no pain. Pre-operative perfusion in 16 rectal cancer patients achieved a complete response (no tumour in pelvis) in 1 patient and significant tumour regression in 8 patients rendering them potentially resectable. Five were resected with clear margins. Three patients with recurrent epidermoid cancer had significant tumour regression and were resected with clear margins. CONCLUSION: Isolated chemotherapeutic perfusion of the pelvis provides excellent palliation for patients with advanced or pelvic recurrence of rectal cancer or epidermoid cancer of anorectum and may potentiate resection in selected patients.

Association of a gliotoxic activity with active multiple sclerosis in US patients.

We recently found that cerebrospinal fluid (CSF) from multiple sclerosis (MS) patients contains a gliotoxic activity which induces programmed cell death of astrocytes and oligodendrocytes and could be the main contributing factor to the massive glial cell death seen in MS active lesions. A previous clinical study aimed at evaluating the gliotoxicity of CSF from a cohort of MS patients from France indicated that MS patients with the active form of the disease do indeed present significant CSF gliotoxicity. To extend this observation, the effect of 141 CSFs from United States patients with different neurological diseases (including 71 MS) was tested on immortalized astrocytes. A cell death assay showed that a gliotoxic activity is significantly present in the CSF from MS patients with the active forms. Thus, this gliotoxic activity may represent a critical pathogenic factor in the neuropathology of active MS by playing a role both in demyelinisation and alteration of the blood-brain barrier.

The influence of brain tissue anisotropy on human EEG and MEG.

The influence of gray and white matter tissue anisotropy on the human electroencephalogram (EEG) and magnetoencephalogram (MEG) was examined with a high resolution finite element model of the head of an adult male subject. The conductivity tensor data for gray and white matter were estimated from magnetic resonance diffusion tensor imaging. Simulations were carried out with single dipoles or small extended sources in the cortical gray matter. The inclusion of anisotropic volume conduction in the brain was found to have a minor influence on the topology of EEG and MEG (and hence source localization). We found a major influence on the amplitude of EEG and MEG (and hence source strength estimation) due to the change in conductivity and the inclusion of anisotropy. We expect that inclusion of tissue anisotropy information will improve source estimation procedures.

Functional neuroanatomy of biological motion perception in humans.

We used whole brain functional MRI to investigate the neural network specifically engaged in the recognition of "biological motion" defined by point-lights attached to the major joints and head of a human walker. To examine the specificity of brain regions responsive to biological motion, brain activations obtained during a "walker vs. non-walker" discrimination task were compared with those elicited by two other tasks: (i) non-rigid motion (NRM), involving the discrimination of overall motion direction in the same "point-lights" display, and (ii) face-gender discrimination, involving the discrimination of gender in briefly presented photographs of men and women. Brain activity specific to "biological motion" recognition arose in the lateral cerebellum and in a region in the lateral occipital cortex presumably corresponding to the area KO previously shown to be particularly sensitive to kinetic contours. Additional areas significantly activated during the biological motion recognition task involved both, dorsal and ventral extrastriate cortical regions. In the ventral regions both face-gender discrimination and biological motion recognition elicited activation in the lingual and fusiform gyri and in the Brodmann areas 22 and 38 in superior temporal sulcus (STS). Along the dorsal pathway, both biological motion recognition and non-rigid direction discrimination gave rise to strong responses in several known motion sensitive areas. These included Brodmann areas 19/37, the inferior (Brodmann Area 39), and superior parietal lobule (Brodmann Area 7). Thus, we conjecture that, whereas face (and form) stimuli activate primarily the ventral system and motion stimuli primarily the dorsal system, recognition of biological motion stimuli may activate both systems as well as their confluence in STS. This hypothesis is consistent with our findings in stroke patients, with unilateral brain lesions involving at least one of these areas, who, although correctly reporting the direction of the point-light walker, fail on the biological motion task.

Conductivity tensor mapping of the human brain using diffusion tensor MRI.

Knowledge of the electrical conductivity properties of excitable tissues is essential for relating the electromagnetic fields generated by the tissue to the underlying electrophysiological currents. Efforts to characterize these endogenous currents from measurements of the associated electromagnetic fields would significantly benefit from the ability to measure the electrical conductivity properties of the tissue noninvasively. Here, using an effective medium approach, we show how the electrical conductivity tensor of tissue can be quantitatively inferred from the water self-diffusion tensor as measured by diffusion tensor magnetic resonance imaging. The effective medium model indicates a strong linear relationship between the conductivity and diffusion tensor eigenvalues (respectively, final sigma and d) in agreement with theoretical bounds and experimental measurements presented here (final sigma/d approximately 0.844 +/- 0.0545 S small middle dots/mm(3), r(2) = 0.945). The extension to other biological transport phenomena is also discussed.

Influence of EEG electrodes on the BOLD fMRI signal.

Measurement of the EEG during fMRI scanning can give rise to image distortions due to magnetic susceptibility, eddy currents or chemical shift artifacts caused by certain types of EEG electrodes, cream, leads, or amplifiers. Two different creams were tested using MRS and T2* measurements, and we found that the one with higher water content was superior. This study introduces an index that quantifies the influence of EEG equipment on the BOLD fMRI signal. This index can also be used more generally to measure the changes in the fMRI signal due to the presence of any type of device inside (or outside) of the field of view (e.g., with fMRI and diffuse optical tomography, infrared imaging, transcranial magnetic stimulation, ultrasound imaging, etc.). Quantitative noise measurements are hampered by the normal variability of functional activation within the same subject and by the different slice profiles obtained when inserting a subject multiple times inside a MR imaging system. Our measurements account for these problems by using a matched filtering of cortical surface maps of functional activations. The results demonstrate that the BOLD signal is not influenced by the presence of EEG electrodes when using a properly constructed MRI compatible recording cap.

The general matching law describes choice on concurrent variable-interval schedules of wheel-running reinforcement.

Six male Wistar rats were exposed to concurrent variable-interval schedules of wheel-running reinforcement. The reinforcer associated with each alternative was the opportunity to run for 15 s, and the duration of the changeover delay was 1 s. Results suggested that time allocation was more sensitive to relative reinforcement rate than was response allocation. For time allocation, the mean slopes and intercepts were 0.82 and 0.008, respectively. In contrast, for response allocation, mean slopes and intercepts were 0.60 and 0.03, respectively. Correction for low response rates and high rates of changing over, however, increased slopes for response allocation to about equal those for time allocation. The results of the present study suggest that the two-operant form of the matching law can be extended to wheel-running reinforcement. 'I'he effects of a low overall response rate, a short Changeover delay, and long postreinforcement pausing on the assessment of matching in the present study are discussed.

Spatiotemporal brain imaging of visual-evoked activity using interleaved EEG and fMRI recordings.

Combined analysis of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) has the potential to provide higher spatiotemporal resolution than either method alone. In some situations, in which the activity of interest cannot be reliably reproduced (e.g., epilepsy, learning, sleep states), accurate combined analysis requires simultaneous acquisition of EEG and fMRI. Simultaneous measurements ensure that the EEG and fMRI recordings reflect the exact same brain activity state. We took advantage of the spatial filtering properties of the bipolar montage to allow recording of very short (125--250 ms) visual-evoked potentials (VEPs) during fMRI. These EEG and fMRI measurements are of sufficient quality to allow source localization of the cortical generators. In addition, our source localization approach provides a combined EEG/fMRI analysis that does not require any manual selection of fMRI activations or placement of source dipoles. The source of the VEP was found to be located in the occipital cortex. Separate analysis of EEG and fMRI data demonstrated good spatial overlap of the observed activated sites. As expected, the combined EEG/fMRI analysis provided better spatiotemporal resolution than either approach alone. The resulting spatiotemporal movie allows for the millisecond-to-millisecond display of changes in cortical activity caused by visual stimulation. These data reveal two peaks in activity corresponding to the N75 and the P100 components. This type of simultaneous acquisition and analysis allows for the accurate characterization of the location and timing of neurophysiological activity in the human brain.

The solubility of calcium oxalate in tissue culture media.

The equilibrium parameters for calcium oxalate solubility in tissue culture media were investigated because of the current interest in oxalate toxicity. The calcium selective ion electrode methodology was evaluated and calcium concentrations from potentiometric calculations were verified by d-c argon plasma emission spectroscopy. The experimental K(sp)'s at 25 degrees C for Dulbecco's modified Eagle media and McCoys 5A media are equivalent to the literature K(sp) of 2.3 x 10(-9) for low ionic strength. The equilibrium concentration products, [Ca2+] [C2O2-(4)], are ten times higher than the K(sp)'s due to the high ionic strengths of tissue culture media. At 37 degrees C, addition of soluble oxalate at the 10(-3) to 10(-4) M level causes >50% precipitation of the oxalate resulting in equilibrium oxalate concentrations of less than 6 x 10(-5) M. This relatively inexpensive selective ion technique allows the determination of oxalate concentrations in equilibrium-saturated media which are substantially less than those calculated by the amount of soluble oxalate added to the media.

Pharmacokinetics of intraperitoneal oxaliplatin: experimental studies.

BACKGROUND AND OBJECTIVES: Oxaliplatin is an antineoplastic platinum-based compound which has shown significant activity against advanced colon cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue absorption of intraperitoneal versus intravenous oxaliplatin. METHODS: In the first phase of this study, fifteen Sprague Dawley rats were given a single dose of oxaliplatin then randomized into three groups according to dose and route of delivery (5 mg/kg intravenously, 5 mg/kg intraperitoneally, or 25 mg/kg intraperitoneally). In the second phase, 10 Sprague Dawley rats were given a continuous intraperitoneal perfusion of oxaliplatin (15 mg/kg) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic vs. hyperthermic). In both phases, peritoneal fluid and blood were sampled using a standardized protocol. At the end of each procedure the animals were sacrificed. Selected tissue samples were taken in the second phase only. For all samples, platinum levels were measured by direct current (d-c) plasma emission spectroscopy. RESULTS: When oxaliplatin was delivered at 5 mg/kg the area under the curve (AUC) of the peritoneal fluid was 15-fold higher with intraperitoneal administration as compared to intravenous administration (P < 0.0001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 16 (+/- 5):1 for intraperitoneal delivery as opposed to 1:5 (+/- 2) for intravenous delivery (P = 0.0059). The AUC ratio for intraperitoneal oxaliplatin at 25 mg/kg was 17 (+/- 8):1. With the exception of the kidneys and the mesenteric nodes, tissue samples in the hyperthermic group exhibited increased oxaliplatin concentrations. These differences were not significant. For both groups colon tissues had the highest oxaliplatin concentrations. CONCLUSIONS: These experiments demonstrated that the exposure of peritoneal surfaces to oxaliplatin was significantly increased with intraperitoneal administration. Although the differences were not statistically significant, hyperthermia did show a trend toward the enhancement of tissue absorption of oxaliplatin. The high concentration of drug observed in colonic tissues suggests the need for clinical studies to evaluate intraperitoneal oxaliplatin for microscopic residual tumor after surgical resection of colon malignancies.

High microvascular blood volume is associated with high glucose uptake and tumor angiogenesis in human gliomas.

The purpose of this investigation was to elucidate the association between microvascular blood volume and glucose uptake and to link these measures with tumor angiogenesis. We demonstrate a regionally specific correlation between tumor relative microvascular blood volume (CBV), determined in vivo with functional magnetic resonance imaging techniques, and tumor glucose uptake determined with fluorodeoxyglucose positron emission tomography. Regions of maximum glucose uptake were well matched with maximum CBV across all patients (n = 21; r = 0.572; P = 0.023). High-grade gliomas showed significantly elevated CBV and glucose uptake compared with low-grade gliomas, (P = 0.009 and 0.008, respectively). Correlations between CBV and glucose uptake were then determined on a voxel-by-voxel basis within each patient's glioma. Correlation indices varied widely, but in 16 of 21 cases of human glioma, CBV and glucose uptake were correlated (r > 0.150). These measures were well correlated in all cases when comparing healthy brain tissue in these same patients. Tumor vascularity, as determined immunohistochemically and morphometrically on clinical samples, revealed statistically significant relationships with functional imaging characteristics in vivo. Regional heterogeneities in glucose uptake were well matched with functional magnetic resonance imaging CBV maps. Our findings support the concept that there is an association of microvascular density and tumor energy metabolism in most human gliomas. In addition, the findings are likely to have important clinical applications in the initial evaluation, treatment, and longitudinal monitoring of patients with malignant gliomas.

Dynamic statistical parametric mapping: combining fMRI and MEG for high-resolution imaging of cortical activity.

Functional magnetic resonance imaging (fMRI) can provide maps of brain activation with millimeter spatial resolution but is limited in its temporal resolution to the order of seconds. Here, we describe a technique that combines structural and functional MRI with magnetoencephalography (MEG) to obtain spatiotemporal maps of human brain activity with millisecond temporal resolution. This new technique was used to obtain dynamic statistical parametric maps of cortical activity during semantic processing of visually presented words. An initial wave of activity was found to spread rapidly from occipital visual cortex to temporal, parietal, and frontal areas within 185 ms, with a high degree of temporal overlap between different areas. Repetition effects were observed in many of the same areas following this initial wave of activation, providing evidence for the involvement of feedback mechanisms in repetition priming.

EEG-Linked functional magnetic resonance imaging in epilepsy and cognitive neurophysiology.

The ability to trigger functional magnetic resonance imaging (fMRI) acquisitions related to the occurrence of EEG-based physiologic transients has changed the field of fMRI into a more dynamically based technique. By knowing the temporal relationship between focal increases in neuronal firing rates and the provoked focal increase in blood flow, investigators are able to maximize the fMR-linked images that show where the activity originates. Our mastery of recording EEG inside the bore of a MR scanner has also allowed us to develop cognitive paradigms that record not only the fMR BOLD images, but also the evoked potentials (EPs). The EPs can subsequently be subjected to localization paradigms that can be compared to the localization seen on the BOLD images. These two techniques will most probably be complimentary. BOLD responses are dependent on a focal increase in metabolic demand while the EPs may or may not be related to energy demand increases. Additionally, recording EPs require that the source or sources of that potential come from an area that is able to generate far-field potentials. These potentials are related to the laminar organization of the neuronal population generating that potential. As best we know the BOLD response does not depend on any inherent laminar neuronal organization. Therefore, by merging these two recording methods, it is likely that we will gain a more detailed understanding of not only the areas involved in certain physiologic events, e.g. focal epilepsy or cognitive processing, but also on the sequencing of the activation of the various participating regions.

Spatiotemporal activity of a cortical network for processing visual motion revealed by MEG and fMRI.

A sudden change in the direction of motion is a particularly salient and relevant feature of visual information. Extensive research has identified cortical areas responsive to visual motion and characterized their sensitivity to different features of motion, such as directional specificity. However, relatively little is known about responses to sudden changes in direction. Electrophysiological data from animals and functional imaging data from humans suggest a number of brain areas responsive to motion, presumably working as a network. Temporal patterns of activity allow the same network to process information in different ways. The present study in humans sought to determine which motion-sensitive areas are involved in processing changes in the direction of motion and to characterize the temporal patterns of processing within this network of brain regions. To accomplish this, we used both magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). The fMRI data were used as supplementary information in the localization of MEG sources. The change in the direction of visual motion was found to activate a number of areas, each displaying a different temporal behavior. The fMRI revealed motion-related activity in areas MT+ (the human homologue of monkey middle temporal area and possibly also other motion sensitive areas next to MT), a region near the posterior end of the superior temporal sulcus (pSTS), V3A, and V1/V2. The MEG data suggested additional frontal sources. An equivalent dipole model for the generators of MEG signals indicated activity in MT+, starting at 130 ms and peaking at 170 ms after the reversal of the direction of motion, and then again at approximately 260 ms. Frontal activity began 0-20 ms later than in MT+, and peaked approximately 180 ms. Both pSTS and FEF+ showed long-duration activity continuing over the latency range of 200-400 ms. MEG responses in the region of V3A and V1/V2 were relatively small, and peaked at longer latencies than the initial peak in MT+. These data revealed characteristic patterns of activity in this cortical network for processing sudden changes in the direction of visual motion.

Visual evoked potential (VEP) measured by simultaneous 64-channel EEG and 3T fMRI.

We present the first simultaneous measurements of evoked potentials (EPs) and fMRI hemodynamic responses to visual stimulation. Visual evoked potentials (VEPs) were recorded both inside and outside the static 3T magnetic field, and during fMRI examination. We designed, constructed, and tested a non-magnetic 64-channel EEG recording cap. By using a large number of EEG channels it is possible to design a spatial filter capable of removing the artifact noise present when recording EEG/EPs within a strong magnetic field. We show that the designed spatial filter is capable of recovering the ballistocardiogram-contaminated original EEG signal. Isopotential plots of the electrode array recordings at the peak of the VEP response (approximately 100ms) correspond well with simultaneous fMRI observed activated areas of primary and secondary visual cortices.

A pharmacokinetic model and the clinical pharmacology of cis-platinum, 5-fluorouracil and mitomycin-C in isolated pelvic perfusion.

PURPOSE: An isolated pelvic perfusion technique using multiple agents was used both in patients with unresectable recurrent pelvic neoplasms and as a preoperative therapy for advanced pelvic malignancy. METHODS: The technique consisted of vascular occlusion via transfemoral balloon catheters, circulation and drug infusion using standard hemodialysis technology, and a 45-min isolation period. Blood and urine samples were analyzed for the levels of cis-platinum (17 patients, 21 courses of therapy, 50-100 mg/m2, infusion 0-10 min), 5-fluorouracil (12 patients, 14 courses, 1500 mg/m2, infusion 1/3 dose 0-1 min, 2/3 dose 1-20 min) and mitomycin-C (11 patients, 14 courses, 10-20 mg/m2, infusion 10-20 min). An empirical, four-compartment pharmacokinetic model was developed to establish drug distribution curves for the pelvic and systemic circulations and to yield valid estimates of the pharmacokinetic parameters. RESULTS: Pelvic isolation of drug was demonstrated by the pelvic-systemic drug exposure ratios of 6.0:1 for cis-platinum, 8.4:1 for 5-fluorouracil and 9.0:1 for mitomycin-C. Isolation at the L3-4 interspace resulted in minor urine drug elimination during isolation (cis-platinum 7.2% of drug, 5-fluorouracil 2.4% and mitomycin-C 2.5%). Because drug infusion was limited to the first 20 min of isolation, drug levels at the end of the isolation period were reduced to the extent that no extracorporeal drug removal mechanism was needed. CONCLUSION: These pharmacokinetic results indicate that this isolation technique has the potential to provide increased therapeutic indices and is a suitable system for evaluating fast-acting highly toxic experimental drugs to human pelvic cancers which are poorly responsive to conventional clinical protocols.

Language dominance determined by whole brain functional MRI in patients with brain lesions.

BACKGROUND: Functional MRI (fMRI) is of potential value in determining hemisphere dominance for language in epileptic patients. OBJECTIVE: To develop and validate an fMRI-based method of determining language dominance for patients with a wide range of potentially operable brain lesions in addition to epilepsy. METHODS: Initially, a within-subjects design was used with 19 healthy volunteers (11 strongly right-handed, 8 left-handed) to determine the relative lateralizing usefulness of three different language tasks in fMRI. An automated, hemispheric analysis of laterality was used to analyze whole brain fMRI data sets. To evaluate the clinical usefulness of this method, we compared fMRI-determined laterality with laterality determined by Wada testing or electrocortical stimulation mapping, or both, in 23 consecutive patients undergoing presurgical evaluation of language dominance. RESULTS: Only the verb generation task was reliably lateralizing. fMRI, using the verb generation task and an automated hemispheric analysis method, was concordant with invasive measures in 22 of 23 patients (12 Wada, 11 cortical stimulation). For the single patient who was discordant, in whom a tumor involved one-third of the left hemisphere, fMRI became concordant when the tumor and its reflection in the right hemisphere were excluded from laterality analysis. No significant negative correlation was obtained between lesion size and strength of laterality for the patients with lesions involving the dominant hemisphere. CONCLUSION: This fMRI method shows potential for evaluating language dominance in patients with a variety of brain lesions.