Functional mapping of the human visual cortex by magnetic resonance imaging.

Knowledge of regional cerebral hemodynamics has widespread application for both physiological research and clinical assessment because of the well-established interrelation between physiological function, energy metabolism, and localized blood supply. A magnetic resonance technique was developed for quantitative imaging of cerebral hemodynamics, allowing for measurement of regional cerebral blood volume during resting and activated cognitive states. This technique was used to generate the first functional magnetic resonance maps of human task activation, by using a visual stimulus paradigm. During photic stimulation, localized increases in blood volume (32 +/- 10 percent, n = 7 subjects) were detected in the primary visual cortex. Center-of-mass coordinates and linear extents of brain activation within the plane of the calcarine fissure are reported.

Borders of multiple visual areas in humans revealed by functional magnetic resonance imaging.

The borders of human visual areas V1, V2, VP, V3, and V4 were precisely and noninvasively determined. Functional magnetic resonance images were recorded during phase-encoded retinal stimulation. This volume data set was then sampled with a cortical surface reconstruction, making it possible to calculate the local visual field sign (mirror image versus non-mirror image representation). This method automatically and objectively outlines area borders because adjacent areas often have the opposite field sign. Cortical magnification factor curves for striate and extrastriate cortical areas were determined, which showed that human visual areas have a greater emphasis on the center-of-gaze than their counterparts in monkeys. Retinotopically organized visual areas in humans extend anteriorly to overlap several areas previously shown to be activated by written words.

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.

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.

Pharmacokinetic and toxicity evaluation of five-day continuous infusion versus intermittent bolus cis-diamminedichloroplatinum(II) in head and neck cancer patients.

We administered cis-diamminedichloroplatinum(II), 30 mg/m2/day for 5 days by continuous infusion to six patients with head and neck cancer, and compared the total and filterable plasma concentrations of platinum, and toxic effects, with those observed in five additional patients who received the same dose and schedule of cis-diamminedichloroplatinum(II) by intermittent bolus. In the continuous infusion group, the total 5-day exposure to filterable platinum, determined from the area under the concentration-time curve, was 1.5 to 2-fold higher (P less than 0.01) than that observed in the intermittent bolus group although the maximum filterable platinum concentration achieved was 8-fold lower (P less than 0.01). These differences were not reflected by total platinum levels. Subclinical nephrotoxicity, as judged by monitoring the urinary excretion of the renal enzymes N-acetyl-beta-D-glucosaminidase and alanine aminopeptidase, as well as ototoxicity, and the incidence and severity of nausea and vomiting were similar in both groups. In contrast, myelosuppression, and hypomagnesemia were more frequent in the continuous-infusion patients, suggesting that the total exposure to free platinum contributes more to these toxicities than peak levels achieved. Considering the clinically acceptable toxicity observed after administration by continuous infusion, we recommend larger therapeutic trials to define the efficacy of increased tumor exposure to filterable platinum.

Functional magnetic resonance imaging of symptom provocation in obsessive-compulsive disorder.

BACKGROUND: The new technique of functional magnetic resonance imaging was used to investigate the mediating neuroanatomy of obsessive-compulsive disorder symptoms. METHODS: Ten patients with obsessive-compulsive disorder and 5 normal subjects were studied via functional magnetic resonance imaging during control and provoked conditions. Data analysis entailed parametric and nonparametric statistical mapping. RESULTS: Statistical maps (nonparametric; P < 10(-3)) showed activation for 70% or more of patients with obsessive-compulsive disorder in medial orbitofrontal, lateral frontal, anterior temporal, anterior cingulate, and insular cortex, as well as caudate, lenticulate, and amygdala. No normal subjects exhibited activation in any brain region. CONCLUSIONS: Results of functional magnetic resonance imaging were consistent with past studies of obsessive-compulsive disorder that used other functional neuroimaging modalities. However, paralimbic and limbic activations were more prominent in the present study.

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.

Gliotoxicity, reverse transcriptase activity and retroviral RNA in monocyte/macrophage culture supernatants from patients with multiple sclerosis.

In investigating a possible link between a novel retroviral agent (provisionally called MSRV), recently characterised in multiple sclerosis (MS), and the neuropathology of MS, it was found that there was a significant correlation between gliotoxicity and reverse transcriptase activity in monocyte/macrophage culture supernatants (MMCS) unique to MS patients. MMCS from healthy controls and patients with other neurological diseases did not display either gliotoxicity or reverse transcriptase activity. The observed gliotoxic effect was an initial, intermediate filament network disorganization and subsequent cell death which was specific to astrocytes and oligodendrocytes. The reverse transcriptase activity and MSRV-specific RNA were observed during the first 2 weeks of culture in MMCS from patients with active MS. The further elucidation of the molecular form(s) of this gliotoxic factor and its original source may be crucial in elucidating important etiopathogenic mechanisms in MS.

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.

Rationale for integrating early postoperative intraperitoneal chemotherapy into the surgical treatment of gastrointestinal cancer.

A new concept in the natural history of gastrointestinal (GI) cancer suggests that recurrence of this malignancy can be separated into two types. Hematogenous and lymphatic metastases occur before surgical removal of the primary cancer. The spread of cancer to the resection site and to peritoneal surfaces occurs at the time of surgical removal of the primary tumor. Surgical trauma leads to a dispersal of malignant tumor emboli, which then implant within the raw tissue surfaces of the resection site and abraded peritoneal surfaces. Instillation of chemotherapy directly into the peritoneal cavity, as part of GI surgery, provides cytotoxic levels of drug that may change the natural history of GI cancer. The most common sites of disease recurrence have been, in the past, at the resection site and on peritoneal surfaces. With the optimal use of intraperitoneal chemotherapy, these sites of surgical treatment failure should no longer occur. Early phase I and II and pharmacologic studies suggest that an effective dose and schedule have been achieved, that toxicity is at reasonable levels, and that responses with small volumes of intra-abdominal cancer are exceptionally high. Chemotherapy that has an impact on the surgical event by decreasing cancer spread to the resection site and to peritoneal surfaces may significantly improve survival and quality of life in patients with GI cancer.

Magnetic resonance imaging mapping of brain function. Human visual cortex.

Magnetic resonance imaging (MRI) studies of human brain activity are described. Task-induced changes in brain cognitive state were measured using high-speed MRI techniques sensitive to changes in cerebral blood volume (CBV), blood flow (CBF), and blood oxygenation. These techniques were used to generate the first functional MRI maps of human task activation, by using a visual stimulus paradigm. The methodology of MRI brain mapping and results from the investigation of the functional organization and frequency response of human primary visual cortex (V1) are presented.

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.

Category-specific brain activation in fMRI during picture naming.

Neuropsychological, computational, and psycholinguistic data suggest the existence of semantic maps, i.e. localized representations of semantic information in the brain. Using functional magnetic resonance imaging, this hypothesis was directly tested with a picture naming task involving items from four different semantic categories. Small left lateralized fronto-temporal cortical sites of category-specific activation were found when brain activation signals were averaged. Data suggest the existence of multiple maps coding high-level representations of objects, such that meaningful distinctions, at least in part, govern the physical distribution of cortical semantic storage.

Functional magnetic resonance imaging shows localized brain activation during serial transcranial stimulation in man.

Area and depth penetration of transcranial stimulation methods such as transcranial electrical stimulation (TES) are poorly defined. We investigated the feasibility of a simultaneous TES and fMRI measurement. The aim was to compare the signal intensity changes measured using BOLD fMRI during sequential finger movement with the signal response during artificial transcranial stimulation. Tes induced contralateral finger contractions and in T2* weighted images a transient signal increase was observed in the area underlying the electrodes. Compared with the signal obtained during sequential finger movements, the area activated by TES was more localized, signal amplitude, was smaller and there was no post-stimulus undershoot. These data indicate that TES induces a local blood flow increase associated with a drop in the concentration of deoxyhaemoglobin.

Modulation of auditory and visual cortex by selective attention is modality-dependent.

Using functional magnetic resonance imaging (fMRI), we investigated whether the response of auditory and visual cortex was modulated by attending selectively to either heard or seen numbers presented simultaneously. Alternating attention between modalities modulated fMRI signal within the corresponding sensory cortex. This study provides evidence that attention acts locally during early auditory cognitive sensory processing, and that modulation of auditory and visual sensory cortex by attention is modality-dependent.

Isolated pelvic perfusion for unresectable cancer using a balloon occlusion technique.

Previously irradiated recurrent pelvic malignancy is refractory to most treatment modalities. Ten patients with local recurrences (six with rectal cancer; three, anal cancer; and one, anorectal melanoma) were treated with a total of 17 courses of isolated pelvic perfusion chemotherapy (12 with multiple agents) using standard hemodialysis technology. Aortic and inferior vena caval occlusion was maintained via transfemoral balloon catheters, with a single intraoperative balloon disruption. Mean pelvic-systemic drug exposure ratios were 9.8:1 for fluorouracil, 4.8:1 for cisplatin, and 4.4:1 for mitomycin C. Results were three partial responses (two patients subsequently underwent resection) and three minor responses, all in patients with a visible tumor. Pelvic pain was relieved in six of eight symptomatic patients (mean duration, 4 months). Using limited access, this procedure produces high pelvic-systemic concentration gradients, prolonged palliation for recurrent pelvic cancers, and increased resectability in selected patients.

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.

Detection of a gliotoxic activity in the cerebrospinal fluid from multiple sclerosis patients.

We recently showed that peripheral blood cell supernatants from multiple sclerosis (MS) patients, containing reverse transcriptase activity and retroviral RNA from the newly human identified multiple sclerosis retrovirus (MSRV), also secrete a cytotoxin which induces death of primary mouse cortical glial cells. We have hypothesized that macrophages could release this cytotoxin in the cerebrospinal fluid. The cerebrospinal fluid cytotoxicity from 166 patients with various neurological diseases (including MS patients) was tested on glial cells in vitro. Our bioassay shows that a glial cytotoxic activity is significantly present in cerebrospinal fluid from patients with relapsing-remitting MS at relapse. Since this cytotoxic activity seems to correlate with active cases of MS, it may represent a critical pathogenic factor in the neuropathology of MS.

Location of language in the cortex: a comparison between functional MR imaging and electrocortical stimulation.

PURPOSE: To determine the accuracy of functional MR imaging in locating language areas for planning surgical resection. METHODS: Intraoperative photographs were digitized and overlaid on functional MR language maps. The sensitivity and specificity of functional MR imaging for identifying language areas were determined for five different language tasks by comparing functional MR areas of language activation with results of electrocortical stimulation. A match was considered to occur if an activated area contacted overlapped, or surrounded a language tag. The borders of the activation areas were extended by 1 and 2 cm to determine whether the number of matches changed. Language and nonlanguage tag matches were tabulated separately. RESULTS: Sensitivity/specificity for all patients and all language tasks ranged from 81%/53% for areas that touched to 92%/0% for areas separated by 2 cm. Individual language tasks were not as sensitive as a battery of language tasks combined. Location of language areas varied among subjects for a given task and among tasks for a given subject. CONCLUSION: Functional MR imaging should be considered a useful presurgical planning tool for mapping cortical language areas, because it is sensitive, it provides increased time for planning before surgery, and it is noninvasive.

A gliotoxic factor and multiple sclerosis.

The pathogenesis of multiple sclerosis (MS) is unknown. Searching for possible toxic factors, it was found that 3-day exposure to heat-treated cerebrospinal fluid (CSF) from MS patients caused apoptotic death of astrocytes and oligodendrocytes, but not fibroblasts, myoblasts, Schwann cells, endothelial cells and neurons, in vitro. CSFs from other inflammatory or non-inflammatory neurological diseases showed no toxicity. Exposure of these glial cells to partially purified MS CSF produced DNA fragmentation, apoptotic bodies, chromatin condensation, cell shrinkage, and changes in the levels of known cytokines. A cytotoxic factor, called gliotoxin, was characterized chromatographically as a stable 17-kDa glycoprotein. Since this protein is highly cytotoxic for astrocytes and oligodendrocytes, it may represent an initial pathogenic factor, leading to the neuropathological features of MS, such as blood-brain barrier involvement and demyelination.