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Mapping of brain activation in response to pharmacological agents using fMRI in the rat.

Functional MRI (fMRI) was used to investigate the effects of psychotropic compound activity in the rat brain in vivo. The effects of dizocilpine (MK-801) an N-methyl-D-aspartate receptor antagonist and m-chlorophenylpiperazine (mCPP), a 5-HT(2b/2c)-receptor agonist on rat brain activity were investigated over a time interval of about 1 h and the results were compared to published glucose utilisation and cerebral blood flow data. Signal magnitude increases were observed predominantly in limbic regions following MK-801 administration (0.5 mg/kg i.v) whereas signal decreases were restricted to neocortical areas; a characteristic, time dependent pattern of regional changes evolved from the thalamic nuclei to cortical regions. In contrast, mCPP (25 mg/kg i.p) produced gradual signal intensity increases in limbic and motor regions with signal decreases restricted to the visual, parietal and motor cortices. The results from both compounds show remarkable similarity with autoradiographic measurements of cerebral blood flow and glucose uptake. These experiments suggest that the spatio-temporal capabilities of fMRI may be applied to the in vivo investigation of psychoactive compound activity with potential for clinical applications.

Animals↗

Evaluation of using absolute versus relative base level when analyzing brain activation images using the scale-space primal sketch.

A dominant approach to brain mapping is to define functional regions in the brain by analyzing images of brain activation obtained from positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). This paper presents an evaluation of using one such tool, called the scale-space primal sketch, for brain activation analysis. A comparison is made concerning two possible definitions of a significance measure of blob structures in scale-space, where local contrast is measured either relative to a local or global reference level. Experiments on real brain data show that (i) the global approach with absolute base level has a higher degree of correspondence to a traditional statistical method than a local approach with relative base level, and that (ii) the global approach with absolute base level gives a higher significance to small blobs that are superimposed on larger scale structures, whereas the significance of isolated blobs largely remains unaffected. Relative to previously reported works, the following two technical improvements are also presented. (i) A post-processing tool is introduced for merging blobs that are multiple responses to image structures. This simplifies automated analysis from the scale-space primal sketch. (ii) A new approach is introduced for scale-space normalization of the significance measure, by collecting reference statistics of residual noise images obtained from the general linear model.

Algorithms↗

Tomographic mapping of brain intracellular pH and extracellular water space in stroke patients.

Functional images of regional intracellular pH (pHi) and of fractional volume of extracellular water (FVECW) were obtained in 10 patients with recent hemispheric infarction (between 10 and 19 days after onset of symptoms) using positron emission tomography (PET). The volume of extracellular water relative to that of total water was evaluated in each pixel of the PET scan 7-8 h after injection of 76Br. The pHi image was calculated from the data obtained after injection of [11C]5,5-dimethyl-2,4-oxazolidinedione and from the FVECW image. Regional CBF, oxygen extraction, and oxygen metabolism were also measured in the same patients. In normal hemisphere, mean +/- SD values for FVECW and pHi were 0.12 +/- 0.01 and 6.86 +/- 0.11, respectively. FVECW was increased in the infarcted area in most patients. pHi was increased in the infarct in seven patients and unchanged in three. The increase in pHi was not correlated with changes in FVECW, CBF, or CMRO2, but there was a significant correlation with the decrease in oxygen extraction fraction in the same region. Thus, the decreased H+ content in the infarcted area was correlated with the occurrence of perfusion in excess of metabolic demand. An alkaline shift in pHi enhances the glycolysis rate and could explain why the glucose metabolism is less affected than the oxygen metabolism in recent cerebral infarction. The pHi measured in the infarct could represent mainly the pHi of phagocytic cells that use aerobic glycolysis to synthesize hydrogen peroxide.

Adult↗

Enzymatic characterization and functional domain mapping of brain myosin-V.

The actin binding and ATPase properties, as well as the functional domain structure of chick brain myosin-V, a two-headed, unconventional myosin, is reported here. Compared to conventional myosin from skeletal muscle, brain myosin-V exhibits low K-EDTA- and Ca-ATPase activities (1.8 and 0.8 ATP/s per head). The physiologically relevant Mg-ATPase is also low (approximately 0.3 ATP/s), unless activated by the presence of both F-actin and Ca2+ (Vmax of 27 ATP/s). Ca2+ stimulates the actin-activated Mg-ATPase over a narrow concentration range between 1 and 3 microM. In the presence of saturating Ca2+ and 75 mM KCl, surprisingly low concentrations of F-actin activate the Mg-ATPase in a hyperbolic manner (KATPase of 1.3 microM). Brain myosin-V also binds with relatively high affinity (compared to other known myosins) to F-actin in the presence of ATP, as assayed by cosedimentation. Digestion of brain myosin-V with calpain yielded a 65-kDa head domain fragment that cosediments with actin in an ATP-sensitive manner and a 80-kDa tail fragment that does not interact with F-actin. The 80-kDa fragment results from cleavage one residue beyond the proline-, glutamate-, serine-, threonine-rich region. Our data indicate that the Mg-ATPase cycle of brain myosin-V is tightly regulated by Ca2+, probably via direct binding to the calmodulin light chains in the neck domain, which like brush border myosin-I, results in partial (approximately 30%) dissociation of the calmodulin associated with brain myosin-V. The effect of Ca2+ binding, which appears to relieve suppression by the neck domain, can be mimicked by calpain cleavage near the head/neck junction.

Actins↗

Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET.

The regional distributions of monoamine oxidase (MAO) types A and B have been identified in human brain in vivo with intravenously injected 11C-labeled suicide enzyme inactivators, clorgyline and L-deprenyl, and positron emission tomography. The rapid brain uptake and retention of radioactivity for both 11C tracers indicated irreversible trapping. The anatomical distribution of 11C paralleled the distribution of MAO A and MAO B in human brain in autopsy material. The corpus striatum, thalamus, and brainstem contained high MAO activity. The magnitudes of uptake of both [11C]clorgyline and L-[11C]deprenyl were markedly reduced in one subject treated with the antidepressant MAO inhibitor phenelzine. A comparison of the brain uptake and retention of the 11C-labeled inactive (D-) and active (L-) enantiomers of deprenyl showed rapid clearance of the inactive enantiomer and retention of the active enantiomer within MAO B-rich brain structures, in agreement with the known stereoselectivity of MAO B for L-deprenyl. Prior treatment with unlabeled L-deprenyl prevented retention of L-[11C]deprenyl. Thus, suicide enzyme inactivators labeled with positron emitters can be used to quantitate the distribution and kinetic characteristics of MAO in human brain structures.

Adult↗

Mapping of brain tumor metabolites with proton MR spectroscopic imaging: clinical relevance.

Brain tumor metabolism was studied with hydrogen-1 magnetic resonance spectroscopy and positron emission tomography with fluorine-18 fluorodeoxyglucose in 50 patients. N-acetylaspartate (NAA) was generally decreased in tumors and radiation necrosis but was somewhat preserved at neoplasm margins. Choline was increased in most solid tumors. Solid high-grade gliomas had higher normalized choline values than did solid low-grade gliomas (P < .02), but the normalized choline value was not a discriminator of tumor grade, since necrotic high-grade lesions had reduced choline values. Serial studies in one case showed an increase in choline as the glioma underwent malignant degeneration. Choline values were lower in chronic radiation necrosis than in solid anaplastic tumors (P < .001). In two cases studied before and after treatment, clinical improvement and a reduction in choline followed therapy. Lactate is more likely to be found in high-grade gliomas, but its presence is not a reliable indicator of malignancy.

Adolescent↗

[Neuropsychological findings of functional cortical mapping in patients with brain tumors].

In 3 patients with brain tumors involving language areas, we investigated functional cortical regions and epileptogenic foci using subdural electrode stimulation before operation. These stimulation studies were useful in preserving postoperatively their language function. The following neuropsychological findings were obtained; (1) Stimulation of Broca area (Brodmann 44 and 45) did not produce anarthria (phonetic disintegration), but semantic and phonemic parahasias and word finding difficulties. (2) Stimulation of lower motor cortex elicited anarthria. (3) Buccofacial apraxia was not produced only by stimulation of frontal operculum. (4) When anarthria was elicited by stimulation, difficulty in retrieving both Kana and Kanji letter-forms and paragraphia in Kana letters were sometimes observed. (5) Stimulation at Exner's writing centre did not produce writing deficits, but elicited word finding difficulties and paraphasias.

Adult↗

[Preoperative applications of cortical mapping with functional magnetic resonance].

The authors describe a clinical experience in cortical brain mapping by Functional Magnetic Resonance Imaging (FMRI) with a 1.0 T MR scanner with BOLD technique and echo-planar imaging (EPI). A brief review is made of the theoretical basis of the BOLD technique and of the different functional tasks used. The main clinical applications of FMRI cortical mapping regarding the sensorimotor cortex of the hand and of language are mentioned. The experiment involves 29 patients, 16 with gliomas (G), 7 with mesial temporal sclerosis (MT S) and 6 with arteriovenous malformations (AVM) The most frequent clinical applications were the determination of the topographic relationship of the cerebral lesions with these eloquent cortices as well as the presurgical lateralization of language in medically intractable epileptic patients. The results are discussed in order to assess the FMRI cortical mapping role as a noninvasive method for presurgical planning, regarding the evaluation of the potential neurosurgical risks and the identification of viable cortex regions displaced or reorganized as a consequence of disease. Additionally, FMRI cortical mapping can also assess the atypical speech representations and the language lateralization of the patients.

Adolescent↗

A 3D digital map of rat brain.

A three dimensional (3D) computerized map of rat brain anatomy created with digital imaging techniques is described. Six male Sprague-Dawley rats, weighing 270-320 g, were used in the generation of this atlas. Their heads were frozen, and closely spaced cryosectional images were digitally captured. Each serial data set was organized into a digital volume, reoriented into a flat skull position, and brought into register with each other. A volume representative of the group following registration was chosen based on its anatomic correspondence with the other specimens as measured by image correlation coefficients and landmark matching. Mean positions of lambda, bregma, and the interaural plane of the group within the common coordinate system were used to transform the representative volume into a 3D map of rat neuroanatomy. images reconstructed from this 3D map are available to the public via Internet with an anonymous file transfer protocol (FTP) and World Wide Web. A complete description of the digital map is provided in a comprehensive set of sagittal planes (up to 0.031 mm spacing) containing stereotaxic reference grids. Sets of coronal and horizontal planes, resampled at the same increment, also are included. Specific anatomic features are identified in a second collection of images. Stylized anatomic boundaries and structural labels were incorporated into selected orthogonal planes. Electronic sharing and interactive use are benefits afforded by a digital format, but the foremost advantage of this 3D map is its whole brain integrated representation of rat in situ neuroanatomy.

Animals↗

Dorsal premotor cortex and conditional movement selection: A PET functional mapping study.

Positron emission tomography (PET) brain mapping was used to investigate whether or not human dorsal premotor cortex is involved in selecting motor acts based on arbitrary visual stimuli. Normal subjects performed four movement selection tasks. A manipulandum with three graspable stations was used. An imperative visual cue (LEDs illuminated in random order) indicated which station to grasp next with no instructional delay period. In a power task, a large aperture power grip was used for all trials, irrespective of the LED color. In a precision task, a pincer grasp of thumb and index finger was used. In a conditional task, the type of grasp (power or precision) was randomly determined by LED color. Comparison of the conditional selection task versus the average of the power and precision tasks revealed increased blood flow in left dorsal premotor cortex and superior parietal lobule. The average rate of producing the different grasp types and transport to the manipulandum stations was equivalent across this comparison, minimizing the contribution of movement attributes such as planning the individual movements (as distinct from planning associated with use of instructional stimuli), kinematics, or direction of target or limb movement. A comparison of all three movement tasks versus a rest task identified movement related activity involving a large area of central, precentral and postcentral cortex. In the region of the precentral sulcus movement related activity was located immediately caudal to the area activated during selection. The results establish a role for human dorsal premotor cortex and superior parietal cortex in selecting stimulus guided movements and suggest functional segregation within dorsal premotor cortex.

Adult↗

Quantitative mapping analyzer for determining the distribution of neurochemicals in the human brain.

We developed a human brain mapping analyzer to determine the quantitative distribution of specific molecules, such as neurotransmitters or neuromodulators, based on a fluorescence microphotometry system that we had previously developed. The immunohistochemical fluorescence emitted from each microarea of a brain slice is collected into a photomultiplier tube through the pinhole and objective lens of a microscope. The brain slice is moved in the x- or y-direction by a motorized scanning stage under the objective lens, and the fluorescence intensities are measured quantitatively. The scanning speed is approximately 100 microareas/s, the maximum stage motion is 150 x 150 mm, and an unlimited amount of data can be gathered continuously by transfer to external memory devices. In this paper, this analyzer is characterized in detail, and the methods used for the preparation and analysis of human brain slices are described. As an example, the cholinergic distribution in hemispheric coronal slices of the adult human brain is analyzed. Each slice, immunohistochemically stained for choline acetyltransferase, was divided into approximately 3 million microareas (one area is 50 microm in diameter), and the distribution of the cholinergic neurons is shown.

Aged↗

Saccade-related spread of activity across superior colliculus may arise from asymmetry of internal connections.

The superior colliculus (SC) receives a retinotopic projection of the contralateral visual field in which the representation of the central field is expanded with respect to the peripheral field. The visual projection forms a nonlinear, approximately logarithmic, map on the SC. Models of the SC commonly assume that the function defining the strength of neuronal connections within this map (the kernel) depends only on the distance between two neurons, and is thus isotropic and homogeneous. However, if the connection strength is based on the distance between two stimuli in sensory space, the kernel will be asymmetric because of the nonlinear projection onto the brain map. We show, using a model of the SC, that one consequence of these asymmetric intrinsic connections is that activity initiated at one point spreads across the map. We compare this simulated spread with the spread observed experimentally around the time of saccadic eye movements with respect to direction of spread, differing effects of local and global inhibition, and the consequences of localized inactivation on the SC map. Early studies suggested that the SC spread was caused by feedback of eye displacement during a saccade, but subsequent studies were inconsistent with this feedback hypothesis. In our new model, the spread is autonomous, resulting from intrinsic connections within the SC, and thus does not depend on eye movement feedback. Other sensory maps in the brain (e.g., visual cortex) are also nonlinear and our analysis suggests that the consequences of asymmetric connections in those areas should be considered.

Algorithms↗