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Biomedical subjects

S Warach

Publications and source records attributed to S Warach.

18 recordsLinked to original sources

New magnetic resonance techniques for acute ischemic stroke.

Neuroimaging was revolutionized by the development of computed tomography (CT) and standard T1- and T2-weighted magnetic resonance imaging (MRI). Magnetic resonance imaging and CT can adequately distinguish hemorrhage from infarction and depict ischemic stroke 12 to 24 hours after onset. However, during the critical initial hours after the onset of ischemic stroke, these imaging technologies do not adequately demonstrate the location and extent of infarction. Diffusion-weighted MRI and perfusion imaging, as well as advances in magnetic resonance spectroscopy, will enhance our ability to evaluate ischemic stroke shortly after onset. Some of the uses of MRI techniques are as follows: (1) Diffusion-weighted imaging can depict the location and extent of the ischemic lesion as soon as a stroke patient is available for examination. (2) Perfusion imaging evaluates blood flow within the brain's microvasculature and can reveal regions of perfusion deficits corresponding to major vascular territories. (3) Magnetic resonance spectroscopy evaluates metabolic abnormalities associated with focal brain ischemia by specific biochemical measurements. These MRI techniques will rapidly provide important information to clinicians about ischemia, guiding diagnosis and helping in the development of acute stroke interventions to improve outcome.

Brain Ischemia

Shared neural substrates controlling hand movements in human motor cortex.

Voluntary hand movements in humans involve the primary motor cortex (M1). A functional magnetic resonance imaging method that measures relative cerebral blood flow was used to identify a distributed, overlapping pattern of hand movement representation within the posterior precentral gyrus, which contains M1. The observed pattern resembles those reported in nonhuman primates and differs from a somatotopically organized plan typically used to portray human motor cortex organization. Finger and wrist movements activated a wide expanse of the posterior precentral gyrus, and representations for different finger movements overlapped each other and the wrist representation. Multiple sites of activation occurred in the precentral gyrus for all movements. The overlapping representations may mediate motor and cognitive functions requiring coordinated neural processing for finger and wrist actions rather than discrete control implied by somatotopic maps.

Brain Mapping

Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging.

Our purpose was to use whole brain echo planar magnetic resonance imaging (MRI) to identify and characterize diffusion abnormalities in acute cerebral ischemia. We studied 40 patients as early as 3 hours after onset of signs and symptoms of cerebral ischemia. Diffusion-weighted imaging (DWI) of the entire brain could be completed in 3 seconds or, using seven different diffusion sensitivities (maximum b = 1,271 sec/mm2), in 48 seconds. Measurements and synthetic maps were made of apparent diffusion coefficients (ADC), a physiological parameter that characterizes the self-diffusion of water in tissue. Early ischemic lesions were identified with DWI as hyperintense regions of decreased ADC in all patients who subsequently developed infarction, before changes were evident on conventional MRI in cases studied earlier than 6 hours after onset of ischemic symptoms. Lesions as small as 4 mm in diameter were identified. The extent of lesions within white matter was best defined by controlling for the anisotropic effect of axonal orientation. The mean ADC (+/- SD) for control regions in the 36 patients was 9.15 (+/- 2.91) x 10(-4) mm2/sec. Mean ADC of ischemic regions was 56% of control values at 6 hours or less and stayed significantly reduced for 3 to 4 days after onset of ischemia. The relative ADC increased progressively over time to be pseudonormalized at 5 to 10 days and elevated in the chronic state, making the distinction of acute lesions adjacent to chronic infarcts readily apparent. DWI with echo planar imaging measures a unique physiological parameter that is sensitive to ischemic changes before conventional MRI. Its potential role in the quantitative study of human stroke pathophysiology and therapeutics is the subject of further investigation.

Adult

Brain lesions in patients with multiple sclerosis: detection with echo-planar imaging.

PURPOSE: To evaluate the detection of brain lesions with echo-planar imaging relative to conventional spin-echo (SE) imaging. MATERIALS AND METHODS: In 17 patients (three men, 14 women; mean age, 31 years) with multiple sclerosis, the following were compared: single-shot proton-density- and T2-weighted and thin-section T2-weighted echo-planar, proton-density- and T2-weighted multishot echo-planar, and conventional SE sequences. Quantitative and qualitative criteria as well as lesion detectability were evaluated. The proton-density-weighted SE sequence was used as the standard of reference. RESULTS: Multishot sequences were superior to single-shot sequences in image quality and lesion detectability. With the multishot proton-density-weighted sequence, 53 of 54 large lesions and 23 of 30 small lesions were detected; with the single-shot proton-density-weighted sequence, 38 of 54 large lesions and five of 30 small lesions were detected. CONCLUSION: With multishot echo-planar sequences, detectability of large lesions is similar to that with conventional SE imaging. Susceptibility artifact is diminished in comparison to single-shot echo-planar sequences.

Adult

Diffusion and perfusion imaging techniques.

Diffusion imaging techniques including the Stejskal-Tanner and the stimulated emission of amplitude echoes (STEAM) pulse sequences are discussed. The calculation of apparent diffusion coefficient (ADC) maps is reviewed. The perfusion imaging techniques of blood oxygen level dependent (BOLD) and first pass bolus perfusion techniques as well as the newer technique of echo-planar imaging with signal targeting and altering radiofrequency (EPISTAR) are also discussed. Finally, the theory of intravoxel incoherent motion (IVIM) and its relationship to both diffusion and perfusion phenomena is examined.

Brain Diseases

Stroke and ischemia.

With the introduction of diffusion imaging the diagnosis and acute stroke can be made within minutes of clinical onset. In combination with perfusion imaging, tissue viability can be assessed. The etiology of ischemia can in most cases be investigated by MR angiography. The current applications of these techniques are reviewed, and pitfalls as well as problems in the diagnosis of acute stroke are discussed. With the availability of these techniques, patients can almost instantaneously be approved for pharmacotherapy and monitored and thus clinical outcome potentially can be improved tremendously.

Acute Disease

Qualitative mapping of cerebral blood flow and functional localization with echo-planar MR imaging and signal targeting with alternating radio frequency.

PURPOSE: To create qualitative maps of cerebral blood flow (CBF) with the EPISTAR (echo-planar imaging and signal targeting with alternating radio frequency) technique. MATERIALS AND METHODS: The EPISTAR technique was performed in a pig model of hypercapnia and then tested in 26 volunteers by using various paradigms for cortical activation. Echo-planar images were acquired with and without use of a radio-frequency inversion pulse applied to inflowing arterial spins. A qualitative map of CBF was then created by subtracting the image obtained without the radio-frequency pulse from that obtained with the radio-frequency pulse. RESULTS: Progressively more distal portions of the tagged vessels were seen as the inflow time was lengthened until cortical enhancement was seen for inflow times of approximately 1 second or longer. Signal intensity increases from rest to sensorimotor activation ranged from 13% to 193%. CBF changes in the motor strip, primary visual cortex, and the motor area for eye movements were well localized to the cortical gray matter ribbon. CONCLUSION: The EPISTAR technique is a rapid, noninvasive means for creating qualitative maps of CBF.

Animals

Hyperperfusion of ictal seizure focus demonstrated by MR perfusion imaging.

MR using a susceptibility-weighted sequence and dynamic contrast enhancement with gadolinium demonstrated relative hyperperfusion of the right temporoparietal cortex in a patient in focal status epilepticus. A single-photon emission CT (SPECT) scan also demonstrated hyperperfusion of the right temporoparietal cortex. Perfusion MR, SPECT, and electroencephalogram normalized when the seizures ended.

Adult

Monitoring the patient's EEG during echo planar MRI.

The recording of an EEG while the patient is undergoing magnetic resonance imaging (MRI) data acquisition, as far as we are aware, has not been previously accomplished. By careful selection and arrangement of analog multiplexed cable-telemetry equipment to eliminate both ferrous and RF sources, a stable, readable EEG can be obtained without interfering with the diagnostic quality of the MRI. This arrangement does not cause localized heating or burning at the electrode sites. This technical capability permits more accurate neurophysiological control during the acquisition of echo planar functional MRI studies as well as providing indications of anatomical localization of electrical sources.

Echo-Planar Imaging

Decreases in frontal and parietal lobe regional cerebral blood flow related to habituation.

We previously reported decreased mean CBF between consecutive resting conditions, ascribed to habituation. Here we address the regional specificity of habituation over three consecutive flow studies. Regional CBF (rCBF) was measured in 55 adults (12 right-handed men, 12 right-handed women, 14 left-handed men, 17 left-handed women), with the 133Xe inhalation technique, during three conditions: resting, verbal tasks (analogies), and spatial tasks (line orientation). Changes in rCBF attributable to the cognitive tasks were eliminated by correcting these values to a resting equivalent. There was a progressive decrease in mean rCBF over time, reflecting habituation. This effect differed by region, with specificity at frontal (prefrontal, inferior frontal, midfrontal, superior frontal) and inferior parietal regions. In the inferior parietal region, habituation was more marked in the left than the right hemisphere. Right-handers showed greater habituation than did left-handers. There was no sex difference in global habituation, but males showed greater left whereas females showed greater right hemispheric habituation. The results suggest that habituation to the experimental setting has measurable effects on rCBF, which are differently lateralized for men and women. These effects are superimposed on task activation and are most pronounced in regions that have been implicated in attentional processes. Thus, regional decrement in brain activity related to habituation seems to complement attentional effects, suggesting a neural network for habituation reciprocating that for attention.

Adult

Acute cerebral ischemia: evaluation with dynamic contrast-enhanced MR imaging and MR angiography.

Dynamic contrast-enhanced T2-weighted magnetic resonance (MR) imaging and MR angiography (MRA) were used to evaluate cerebral blood volume and the intracranial arterial system in 34 patients within 48 hours after the onset of cerebral ischemia. In 24 of the patients, an abnormality identified on T2-weighted images corresponded to the acute clinical deficit. Intracranial MRA demonstrated occlusions or severe stenoses of major vessels supplying the area of infarction in 16 of these patients, and decreased blood volume correlated well with MRA abnormalities. Infarcts less than 2 cm in diameter were not reliably shown with MRA or blood volume studies. Correlation between lesions seen with MRA and decreased blood volume in acute infarcts was good, and both techniques demonstrated lesions early in the clinical course. By providing information about hemodynamics not available with conventional T1- or T2-weighted images, MRA and dynamic MR imaging could prove helpful in describing the pathophysiologic characteristics of stroke and in guiding early therapeutic intervention.

Adult

Fast magnetic resonance diffusion-weighted imaging of acute human stroke.

Rapid MRI of the molecular diffusion of water demonstrated cerebral infarcts in 32 patients. We studied these patients at various times following the onset of ischemic symptoms and found that diffusion-weighted imaging revealed the infarcts sooner than conventional T2-weighted spin-echo imaging did; four hyperacute infarcts were shown only by diffusion-weighted imaging. Acute infarcts had lower apparent diffusion coefficients (ADCs) than noninfarcted regions did. This relative difference in ADC reached a nadir in the first 24 hours and rose progressively thereafter. Chronic infarcts showed a relative increase in diffusion and were readily distinguishable from acute infarcts. The technique takes less than 2 minutes to apply using a standard 1.5-tesla scanner in the clinical setting. Diffusion-weighted imaging has the potential to play a role in improving the early anatomic diagnosis of stroke and therefore in the development and implementation of early stroke interventions.

Adult

Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity.

Excessive activation of NMDA receptors is thought to mediate the calcium-dependent neurotoxicity associated with hypoxic-ischemic brain injury, trauma, epilepsy, and several neurodegenerative diseases. For this reason, various NMDA antagonists have been investigated for their therapeutic potential in these diseases, but heretofore none have proven to be both effective and safe. In the present study, memantine, an adamantane derivative similar to the antiviral drug amantadine, is shown to block the channels activated by NMDA receptor stimulation. From whole-cell and single-channel recording experiments, the mechanism of action of memantine is deduced to be open-channel block, similar to MK-801; however, unlike MK-801, memantine is well tolerated clinically. Compared to MK-801, memantine's safety may be related to its faster kinetics of action with rapid blocking and unblocking rates at low micromolar concentrations. Furthermore, at these levels memantine is an uncompetitive antagonist and should theoretically allow near-normal physiological NMDA activity throughout the brain even in the face of pathologically high focal concentrations of glutamate. These pharmacological properties confer upon memantine a therapeutic advantage against NMDA receptor-mediated neurotoxicity with few side effects compared with other organic NMDA open-channel blockers. Moreover, memantine is increasingly effective against escalating levels of glutamate, such as those observed during a stroke. Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model. These results suggest that memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMDA receptor-mediated neurotoxicity.

Animals

The reproducibility of the 133Xe inhalation technique in resting studies: task order and sex related effects in healthy young adults.

Repeated applications of the 133Xe inhalation technique for measuring regional CBF (rCBF) were made during consecutive resting conditions in a sample of young healthy subjects. Subjects were grouped by order and by sex [nine had resting studies as the initial two measurements in a series of four measurement (six men, three women) and six had these measurements later (two men, four women)]. Three flow parameters were examined: f1 (fast flow) and IS (initial slope) for gray matter CBF, and CBF-15 for mean CBF (gray and white matter over 15-min integration), as well as w1, the percentage of tissue with fast clearing characteristics. With all groups combined, there were no significant differences between the two resting measurements, and high test-retest correlations were obtained for the flow parameters and w1. Analyses by order and sex grouping revealed, for the flow parameters, significant interactions of test-retest difference with order. Repeated initial studies showed reduced CBF from the first to second measurement, whereas resting studies performed later in the series showed no reduction. Interactions for test-retest difference with sex indicated that reduced CBF in serial measures was more pronounced for women. No hemispheric or regional specificity to account for these effects was found. Correction for PaCO2 differences did not alter these results. The results resemble data regarding habituation effects measured for other psychophysiologic measures, and suggest that reduction in CBF for consecutive measurements made on the same day may reflect habituation. This underscores the importance of controlling for effects of habituation on serial measurements of CBF and metabolism.

Administration, Intranasal

A cognitive-motor network demonstrated by positron emission tomography.

The rate of local cerebral glucose metabolism was measured in subjects receiving a verbal (n = 4) and a spatial (n = 4) task. The verbal task produced greater metabolism in Wernicke's area relative to the right hemispheric homotopic region, whereas the spatial task produced greater metabolic activity in the right hemispheric homotopic region. Broca's area and its right hemisphere counterpart showed symmetrical activity during the verbal task, but there was a significant asymmetry to the right during the spatial task. Lateralized task effects were also obtained in the frontal eye fields, supporting a hypothesized neural network linking cognitive activity with motor orientation.

Adult

The anterior border zones of primary somatic sensory (S1) neocortex and their relation to cerebral convolutions, shown by micromapping of peripheral projections to the region of the fourth forepaw digit representation in raccoons.

In raccoons the somatic sensory neocortex is greatly expanded, with separate gyral crowns devoted to and intervening sulci separating, sensory representations of separate body parts, most strikingly those of the volar surfaces of individual forepaw digits. Most of the cortex in this region is buried in widely ramifying sulcal walls, wherein sensory projections have not been studied. We have determined mechanosensory projections to the fourth digit representation region including all neighboring sulcal walls, using tungsten microelectrodes for 3-dimensional micromapping. We found no significant alteration in the location and pattern of projections when the following different anesthetics were used: dial-urethane, chloralose, or methoxyflurane with nitrous oxide. The precisely organized somatotopic representation of the distal volar surface of the fourth digit, on the causal aspect of its gyral crown, continues down the anterior bank of the triradiate sulcus. This meets, at the fundus, projections from the proximal volar surface of the digit which occupy the posterior sulcus wall; they in turn meet projections from the volar palm at the gyral crown. In the anterior part of the crown containing the representation of the distal volar digit, across the crown. In the anterior part of the crown containing the representation of the distal volar digit, across the crown of the gyral bridge intervening between the medial and lateral segments of the central sulcus, throughout the posterior walls of the central sulci, and in the walls of the interbrachial sulcus, we found a distinctive border-zone of projections from heterogeneous receptive fields. Within a roughly somatotopic basic pattern of organization we found intermingled projections from single and multiple claws and dorsal hairy surfaces of digits and proximal hand, along with additional projections from volar surfaces. These projections can be construed as forming something of a distorted mirror-image of the representation of the volar hand. Beyond this was a second zone of distinctive projections from afferents of the forelimb muscles, in the anterior walls of the central sulci. These projections are interrupted where the sulci are interrupted. The zone of muscle afferent projections corresponds to those seen between sensory and motor regions in other species; its strict association with sulcal folding here and in other species suggests a general relationship of these projections to central sulci. The zone of heterogeneous projections resembles similar zones seen at other levels of this system in raccoons, in the cortex of other species, and it may relate to some of the multiple representation reported in other species. It also may be related to the formation of sulci in this region and may be a specialized zone for cortico-cortical connections.

Animals

Puromycin-induced argyrophilia as an alternative to Golgi methods: reliable impregnations of hypothalamic cell groups following lateral ventricular injections in rats.

Parenchymal injections of puromycin were known to induce Golgi-like silver impregnations upon treatment with the cupric-silver method. We have found lateral ventricular injections (5 microliter, 0.1 M) also effective. Such injections consistently led to detailed Golgi-like profiles of cells in a number of hypothalamic regions including one, the paraventricular nucleus, which traditionally is quite recalcitrant to Golgi methods. It is concluded that this technique is a reliable alternative to Golgi methods for the study of many hypothalamic regions.

Animals