Changes in the expression of neurotransmitter receptors in Parkin and DJ-1 knockout mice--A quantitative multireceptor study.

Parkinson's disease (PD) is a well-characterized neurological disorder with regard to its neuropathological and symptomatic appearance. At the genetic level, mutations of particular genes, e.g. Parkin and DJ-1, were found in human hereditary PD with early onset. Neurotransmitter receptors constitute decisive elements in neural signal transduction. Furthermore, since they are often altered in neurological and psychiatric diseases, receptors have been successful targets for pharmacological agents. However, the consequences of PD-associated gene mutations on the expression of transmitter receptors are largely unknown. Therefore, we studied the expression of 16 different receptor binding sites of the neurotransmitters glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine by means of quantitative receptor autoradiography in Parkin and DJ-1 knockout mice. These knockout mice exhibit electrophysiological and behavioral deficits, but do not show the typical dopaminergic cell loss. We demonstrated differential changes of binding site densities in eleven brain regions. Most prominently, we found an up-regulation of GABA(B) and kainate receptor densities in numerous cortical areas of Parkin and DJ-1 knockout mice, as well as increased NMDA but decreased AMPA receptor densities in different brain regions of the Parkin knockout mice. The alterations of three different glutamate receptor types may indicate the potential relevance of the glutamatergic system in the pathogenesis of PD. Furthermore, the cholinergic M1, M2 and nicotinic receptors as well as the adrenergic α2 and the adenosine A(2A) receptors showed differentially increased densities in Parkin and DJ-1 knockout mice. Taken together, knockout of the PD-associated genes Parkin or DJ-1 results in differential changes of neurotransmitter receptor densities, highlighting a possible role of altered non-dopaminergic, and in particular of glutamatergic neurotransmission in PD pathogenesis.

Serotonin 5-HT(1A) receptor binding sites in the brain of the pigeon (Columba livia).

Present knowledge about the serotonergic system in birdbrains is very limited, although the pigeon was used as an animal model in various studies focused on the behavioral effects of serotonergic transmission. In the mammalian brain the 5-HT(1A) receptor is the most widespread serotonin receptor type, and is involved in various functions. Less is known about the distribution of 5-HT(1A) receptors in the avian species. Therefore, we analyzed serotonin 5-HT(1A) receptor binding sites in the pigeon brain using quantitative in vitro receptor autoradiography with the selective radioligand [³H]-8-hydroxy-2-(di-n-propylamino)tetralin ([³H]-8-OH-DPAT). The receptor is differentially distributed throughout the pigeon brain. High levels of 5-HT(1A) receptors are found in the nucleus pretectalis (PT). Moderate densities were detected in the tectum, as well as in the telencephalic nidopallium and hyperpallium. Very low levels were found in the hippocampal formation, the amygdaloid complex, the basal ganglia, and several thalamic nuclei. Furthermore, local variations in 5-HT(1A) receptor densities support the concept of further subdivisions of the entopallium. The regional distribution patterns of 5-HT(1A) receptors mostly display a similar distribution as found in homologue brain structures of mammals.

The circling ci2 rat mutant revisited: receptor architecture of the motor cortex.

Circling behaviour of the ci2 rat mutant has been associated with an abnormal laterality concerning nigrostriatal and vestibular dopamine content and densities of several neurotransmitter receptors. Since not only subcortical, but also cortical activity subserve behavioural asymmetry, we applied quantitative in vitro receptor autoradiography to determine the densities of twenty neurotransmitter receptors in three areas of the motor cortex (Fr1, Fr2, Fr3) of the left and right hemispheres in adult male circling mutant rats (ci2/ci2), non-circling littermates (ci2/+) and aged-matched rats from the background strain (LEW/Ztm, wild type). Rats had previously been monitored for motor behaviour and swimming abilities. Wild type and ci2/+ rats did not differ from the behavioural point of view, whereas ci2/ci2 animals were characterized by pronounced lateralized circling behaviour and were not able to perform the swimming test correctly. Left Fr2 of wild type rats contained significantly lower NMDA receptor densities than its right counterpart. No interhemispheric differences were found in the motor cortex of ci2/+ or ci2/ci2 animals. All three areas of wild type rats contain higher GABA(A) and adenosine A(1) receptor densities than those of ci2/+ and ci2/ci2 animals, respectively. Serotonin 5-HT(2) receptor densities were significantly lower in the motor cortex of ci2/ci2 animals than in that of their heterozygous littermates. Thus, since the ci2 rat mutant presents a wide range of behavioural and neurochemical lateralization anomalies, in addition to representing a model of Usher syndrome type 1, it may prove useful to understand the mechanisms underlying abnormal rotational behaviour and its relevance as a model of disturbances in cerebral asymmetry and their consequences.

Pentylenetetrazole-induced seizures affect binding site densities for GABA, glutamate and adenosine receptors in the rat brain.

Pentylenetetrazole (PTZ) is a convulsant used to model epileptic seizures in rats. In the PTZ-model, altered heat shock protein 27 (HSP-27) expression highlights seizure-affected astrocytes, which play an important role in glutamate and GABA metabolism. This raises the question whether impaired neurotransmitter metabolism leads to an imbalance in neurotransmitter receptor expression. Consequently, we investigated the effects of seizures on the densities of seven different neurotransmitter receptors in rats which were repeatedly treated with PTZ (40 mg/kg) over a period of 14 days. Quantitative in vitro receptor autoradiography was used to measure the regional binding site densities of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors, the adenosine receptor type 1 (A(1)), which is part of the system controlling glutamate release, and the gamma-aminobutyric acid (GABA) receptors GABA(A) and GABA(B) as well as the GABA(A)-associated benzodiazepine (BZ) binding sites in each rat. Our results demonstrate altered receptor densities in brain regions of PTZ-treated animals, including the HSP-27 expressing foci (i.e. amygdala, piriform and entorhinal cortex, dentate gyrus). A general decrease of kainate receptor densities was observed together with an increase of NMDA binding sites in the hippocampus, the somatosensory, piriform and the entorhinal cortices. Furthermore, A(1) binding sites were decreased in the amygdala and hippocampal CA1 region (CA1), while BZ binding sites were increased in the dentate gyrus and CA1. Our data demonstrate the impact of PTZ induced seizures on the densities of kainate, NMDA, A(1) and BZ binding sites in epileptic brain. These changes are not restricted to regions showing glial impairment. Thus, an altered balance between different excitatory (NMDA) and modulatory receptors (A(1), BZ binding sites, kainate) shows a much wider regional distribution than that of glial HSP-27 expression, indicating that receptor changes are not following the glial stress responses, but may precede the HSP-27 expression.

Quantitative imaging of zinc, copper and lead in three distinct regions of the human brain by laser ablation inductively coupled plasma mass spectrometry.

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was used to determine the distribution of the trace elements zinc, copper and lead in insular, central and hippocampal areas of thin tissue sections (thickness 20microm) through an entire human brain hemisphere. For the investigation of the tissue samples, a commercial laser ablation system was coupled to a double-focusing sector field ICP-MS. The regions of interest of healthy brain tissue (thickness 20microm) were scanned (raster area approximately 200mm(2)) with a focused laser beam (wavelength 266nm, diameter of laser crater 200microm and laser power density 3x10(9)Wcm(-2)). The ion intensities of (64)Zn(+), (63)Cu(+) and (208)Pb(+) were measured by LA-ICP-MS within the ablated area. For quantification purposes, matrix-matched laboratory standards were prepared by means of dosing of each analyte to the pieces of brain tissue. The mass spectrometric analysis yielded inhomogeneous and largely reciprocal distributions of Zn and Cu in the selected areas of investigated brain samples. The highest concentrations of Zn and Cu with the most distinct distribution pattern were found in the hippocampus (up to 15microg g(-1)). In contrast to zinc and copper, for lead, a more homogeneous distribution throughout all regions examined was found at a low concentration (in the ngg(-1) range) level within the analytical range of LA-ICP-MS.

Impaired maze performance in aged rats is accompanied by increased density of NMDA, 5-HT1A, and alpha-adrenoceptor binding in hippocampus.

Using quantitative receptor autoradiography, we assessed binding site densities and distribution patterns of glutamate, GABA(A), acetylcholine (ACh), and monoamine receptors in the hippocampus of 32-month-old Fischer 344/Brown Norway rats. Prior to autoradiography, the rats were divided into two groups according to their retention performance in a water maze reference memory task, which was assessed 1 week after 8 days of daily maze training. The animals of the inferior group showed less long-term retention of the hidden-platform task but did not differ from superior rats in their navigation performance during place training and cued trials. The decreased retention performance in the group of inferior learners was primarily accompanied by increased alpha(1)-adrenoceptors in all hippocampal subregions under inspection (CA1-CA4 and dentate gyrus), while elevated alpha(2)-adrenoceptor binding was observed in the CA1 region and DG. Furthermore, inferior learners had higher NMDA binding in the CA2 and CA4 and increased 5-HT(1A) binding sites in the CA2, CA3, and CA4 region. No significant differences between inferior and superior learners were evident with regard to AMPA, kainate, GABA(A), muscarinergic M(1), dopamine D(1), and 5-HT(2) binding densities in any hippocampal region analyzed. These results show that increased NMDA, 5-HT(1A), and alpha-adrenoceptor binding in the hippocampus is associated with a decline in spatial memory. The increased receptor binding observed in the group of old rats with inferior maze performance might be the result of neural adaptation triggered by age-related changes in synaptic connectivity and/or synaptic activity.

Quantitative architectural analysis: a new approach to cortical mapping.

Recent progress in anatomical and functional MRI has revived the demand for a reliable, topographic map of the human cerebral cortex. Till date, interpretations of specific activations found in functional imaging studies and their topographical analysis in a spatial reference system are, often, still based on classical architectonic maps. The most commonly used reference atlas is that of Brodmann and his successors, despite its severe inherent drawbacks. One obvious weakness in traditional, architectural mapping is the subjective nature of localising borders between cortical areas, by means of a purely visual, microscopical examination of histological specimens. To overcome this limitation, more objective, quantitative mapping procedures have been established in the past years. The quantification of the neocortical, laminar pattern by defining intensity line profiles across the cortical layers, has a long tradition. During the last years, this method has been extended to enable a reliable, reproducible mapping of the cortex based on image analysis and multivariate statistics. Methodological approaches to such algorithm-based, cortical mapping were published for various architectural modalities. In our contribution, principles of algorithm-based mapping are described for cyto- and receptorarchitecture. In a cytoarchitectural parcellation of the human auditory cortex, using a sliding window procedure, the classical areal pattern of the human superior temporal gyrus was modified by a replacing of Brodmann's areas 41, 42, 22 and parts of area 21, with a novel, more detailed map. An extension and optimisation of the sliding window procedure to the specific requirements of receptorarchitectonic mapping, is also described using the macaque central sulcus and adjacent superior parietal lobule as a second, biologically independent example. Algorithm-based mapping procedures, however, are not limited to these two architectural modalities, but can be applied to all images in which a laminar cortical pattern can be detected and quantified, e.g. myeloarchitectonic and in vivo high resolution MR imaging. Defining cortical borders, based on changes in cortical lamination in high resolution, in vivo structural MR images will result in a rapid increase of our knowledge on the structural parcellation of the human cerebral cortex.

Imaging of copper, zinc, and other elements in thin section of human brain samples (hippocampus) by laser ablation inductively coupled plasma mass spectrometry.

Laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS) was used to produce images of element distribution in 20-microm thin sections of human brain tissue. The sample surface was scanned (raster area approximately 80 mm(2)) with a focused laser beam (wavelength 213 nm, diameter of laser crater 50 microm, and laser power density 3 x 10(9) W cm(-2)) in a cooled laser ablation chamber developed for these measurements. The laser ablation system was coupled to a double-focusing sector field ICPMS. Ion intensities of 31P+, 32S+, 56Fe+, 63Cu+, 64Zn+, 232Th+, and 238U+ were measured within the area of interest of the human brain tissue (hippocampus) by LA-ICPMS. The quantitative determination of copper, zinc, uranium, and thorium distribution in thin slices of the human hippocampus was performed using matrix-matched laboratory standards. In addition, a new arrangement in solution-based calibration using a micronebulizer, which was inserted directly into the laser ablation chamber, was applied for validation of synthetic laboratory standard. The mass spectrometric analysis yielded an inhomogeneous distribution (layered structure) for P, S, Cu, and Zn in thin brain sections of the hippocampus. In contrast, Th and U are more homogeneously distributed at a low-concentration level with detection limits in the low-nanogram per gram range. The unique analytical capability and the limits of LA-ICPMS will be demonstrated for the imaging of element distribution in thin cross sections of brain tissue from the hippocampus. LA-ICPMS provides new information on the spatial element distribution of the layered structure in thin sections of brain tissues from the hippocampus.

Architectonics of the human cerebral cortex and transmitter receptor fingerprints: reconciling functional neuroanatomy and neurochemistry.

The density of transmitter receptors varies between different locations in the human cerebral cortex. We hypothesized that this variation may reflect the cyto- and myeloarchitectonical as well as the functional organisation of the cortex. We compared data from different imaging modalities (postmortem studies: cyto- and myeloarchitecture, quantitative in vitro receptor autoradiography; in vivo studies: PET receptor neuroimaging) in order to test our hypothesis. The regional and laminar distribution of the densities of numerous receptor types representing all classical transmitter systems as well as the adenosine system are visualized and measured in different cortical areas. The receptor distribution patterns segregate motor, primary sensory, unimodal sensory, multimodal association and other functionally identified cortical areas from each other. Areas of similar function show similar receptor fingerprints and differ from those with other properties. Thus, receptor distribution patterns reflect an organisational structure strictly correlated with the architectonics and functions of the human cerebral cortex.

The influence of explicit instructions and stimulus material on lateral frontal responses to an encoding task.

In this functional magnetic resonance imaging study, we explored the effects of both stimulus material and encoding task demands on activation in lateral prefrontal cortex (PFC). Two factors were manipulated: material type and task instructions. Subjects encoded words or abstract figures (factor 1: stimulus type) and were required to make either a meaning-based or a form-based (letter or shape) decision about each stimulus (factor 2: task instructions). Abstract figures engendered significantly higher levels of right PFC activity than did words. This effect was seen for meaning-based and form-based processing tasks and was significantly greater for the former. We did not observe a differential response of left lateral PFC to verbal and pictorial material. A double dissociation, however, was found within left PFC. A ventrolateral region (within left inferior frontal gyrus) showed the highest levels of activity when words were processed according to their meaning whereas activity in a more dorsolateral region (within left middle frontal gyrus) was greatest when words were processed according to their form (constituent letters). We have therefore observed a main effect of material type in producing lateralized activation of frontal lobes, although the strength of this effect is sensitive to the nature of the task that subjects are asked to perform. Left-side lateral PFC activity is also sensitive to task instructions but this effect was specific to verbal material. The complex patterns of frontal effect counsel against any simple dichotomy of frontal function at the level of either material or task type.

Multimodal characterisation of cortical areas by multivariate analyses of receptor binding and connectivity data.

Cortical areas are regarded as fundamental structural and functional units within the information processing networks of the brain. Their properties have been described extensively by cyto-, myelo- and chemoarchitectonics, cortical and extracortical connectivity patterns, receptive field mapping, activation properties, lesion effects, and other structural and functional characteristics. Systematic integrative approaches aiming at multimodal characterisations of cortical areas or at the delineation of global features of the cortical network, however, are still scarce and usually limited to a single data modality, such as cytoarchitectonical or tract tracing data. Here we describe a methodological framework for the systematic evaluation, comparison and integration of different data modalities from the brain and demonstrate its practical application and significance in the analysis of receptor binding and connectivity data within the motor and visual cortices of macaque monkeys. The framework builds on algorithmic methods to convert data between different cortical parcellation schemes, as well as on statistical techniques for the exploration of multivariate data sets comprising data of different types and scales. Thereby, we establish a relationship between intrinsic area properties as expressed by quantitative receptor binding, and extrinsic inter-area communication, which relies on anatomical connectivity. Our analyses provide preliminary evidence for a good correspondence of these two data types in the motor cortex, and their partial discrepancy in the visual cortex, raising hypotheses about the different organisational aspects highlighted by receptors and connectivity. The methodological framework presented here is flexible enough to accommodate a wide range of further data modalities, and is specific enough to permit novel insights and predictions concerning brain organisation. Thus, this approach promises to be very useful in the endeavour to characterise multimodal structure-function relationships in the brain.

A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM).

Motivated by the vast amount of information that is rapidly accumulating about the human brain in digital form, we embarked upon a program in 1992 to develop a four-dimensional probabilistic atlas and reference system for the human brain. Through an International Consortium for Brain Mapping (ICBM) a dataset is being collected that includes 7000 subjects between the ages of eighteen and ninety years and including 342 mono- and dizygotic twins. Data on each subject includes detailed demographic, clinical, behavioural and imaging information. DNA has been collected for genotyping from 5800 subjects. A component of the programme uses post-mortem tissue to determine the probabilistic distribution of microscopic cyto- and chemoarchitectural regions in the human brain. This, combined with macroscopic information about structure and function derived from subjects in vivo, provides the first large scale opportunity to gain meaningful insights into the concordance or discordance in micro- and macroscopic structure and function. The philosophy, strategy, algorithm development, data acquisition techniques and validation methods are described in this report along with database structures. Examples of results are described for the normal adult human brain as well as examples in patients with Alzheimer's disease and multiple sclerosis. The ability to quantify the variance of the human brain as a function of age in a large population of subjects for whom data is also available about their genetic composition and behaviour will allow for the first assessment of cerebral genotype-phenotype-behavioural correlations in humans to take place in a population this large. This approach and its application should provide new insights and opportunities for investigators interested in basic neuroscience, clinical diagnostics and the evaluation of neuropsychiatric disorders in patients.

A four-dimensional probabilistic atlas of the human brain.

The authors describe the development of a four-dimensional atlas and reference system that includes both macroscopic and microscopic information on structure and function of the human brain in persons between the ages of 18 and 90 years. Given the presumed large but previously unquantified degree of structural and functional variance among normal persons in the human population, the basis for this atlas and reference system is probabilistic. Through the efforts of the International Consortium for Brain Mapping (ICBM), 7,000 subjects will be included in the initial phase of database and atlas development. For each subject, detailed demographic, clinical, behavioral, and imaging information is being collected. In addition, 5,800 subjects will contribute DNA for the purpose of determining genotype- phenotype-behavioral correlations. The process of developing the strategies, algorithms, data collection methods, validation approaches, database structures, and distribution of results is described in this report. Examples of applications of the approach are described for the normal brain in both adults and children as well as in patients with schizophrenia. This project should provide new insights into the relationship between microscopic and macroscopic structure and function in the human brain and should have important implications in basic neuroscience, clinical diagnostics, and cerebral disorders.

Cyto-, myelo-, and receptor architectonics of the human parietal cortex.

Various cyto- and myeloarchitectonic maps of the human parietal cortex have been published since the beginning of the past century. However, the parietal lobe remains an uncharted region, since these anatomical findings fail to explain the much greater areal differentiation, especially in the posterior parietal cortex, which has recently been revealed by functional imaging studies. This lack of congruence does not imply a total lack of correspondence between anatomical and functional data, since several practically forgotten architectonic studies published during the first 5 decades of the past century demonstrate a much more differentiated map of the parietal cortex than the popular map of Brodmann and others. Moreover, recent receptor-architectonic studies also demonstrate a detailed architectonic pattern the functional aspects of which will be explored in the near future.

A stereological approach to human cortical architecture: identification and delineation of cortical areas.

Stereology offers a variety of procedures to analyze quantitatively the regional and laminar organization in cytoarchitectonically defined areas of the human cerebral cortex. Conventional anatomical atlases are of little help in localizing specific cortical areas, since most of them are based on a single brain and use highly observer-dependent criteria for the delineation of cortical areas. In consequence, numerous cortical maps exist which greatly differ with respect to number, position, size and extent of cortical areas. We describe a novel algorithm-based procedure for the delineation of cortical areas, which exploits the automated estimation of volume densities of cortical cell bodies. Spatial sampling of the laminar pattern is performed with density profiles, followed by multivariate analysis of the profiles' shape, which locates the cytoarchitectonic borders between neighboring cortical areas at sites where the laminar pattern changes significantly. The borders are then mapped to a human brain atlas system comprising tools for three dimensional reconstruction, visualization and morphometric analysis. A sample of brains with labeled cortical areas is warped into the reference brain of the atlas system in order to generate a population map of the cortical areas, which describes the intersubject variability in spatial conformation of cortical areas. These population maps provide a novel tool for the interpretation of images obtained with functional imaging techniques.

Different nitric oxide synthase inhibitors cause rapid and differential alterations in the ligand-binding capacity of transmitter receptors in the rat cerebral cortex.

Inhibitors of nitric oxide (NO) synthesis reduce postlesional neuronal death during reperfusion injury by reducing the NO-mediated increase in excitatory neurotransmitter-release. The protective effects of various NO-synthase (NOS) inhibitors differ due to their isoform selectivity. The effects of NO-mediated excessive neurotransmitter supply are transmitted via specific neurotransmitter receptors expressed by the target cells. We report changes in the ligand-binding of different excitatory and inhibitory neurotransmitter-receptors studied by in vitro receptor autoradiography after in vivo-application of NOS-inhibitors. Since the constitutively expressed neuronal NOS-I is area-specifically distributed within the rat cortex, numerous cortical areas were studied in non-lesioned rats, in order to analyze the area-specific effects of NOS-inhibitors. The results showed that the NOS-I-specific inhibitor 7-nitroindazole increased binding of 3H-muscimol, 3H-pirenzepine and 3H-kainate, whereas the less isoform-specific, general NOS-inhibitor L-nitroarginine increased binding of 3H-muscimol and 3H-AMPA in most cortical areas, leaving 3H-kainate binding almost unchanged. The water soluble L-nitroarginine-methylester caused similar effects to those of L-nitroarginine which changed over a period of chronic treatment. The inhibitory GABAA-receptors were increased after NOS-inhibition in most cortical areas, whereas binding of 3H-Oxotremorine-M (acetylcholine receptors), 3H-MK-801 (NMDA-receptors) and 3H-AMPA (AMPA receptors) was affected differently among the cortical areas. Strongest alterations of ligand-binding capacity after administration of NOS-inhibitors were seen in cortical areas known to contain the highest packing densities of NOS-I-positive interneurons such as the piriform and entorhinal cortices, indicating that, in normal animals, neurotransmission and probably cognitive information processing would be affected by the pharmacological modulation of nitric oxide production.

Receptor autoradiographic mapping of the mesial motor and premotor cortex of the macaque monkey.

This study analyzes regional and laminar distribution patterns of neurotransmitter binding sites in the motor areas of the macaque mesial frontal cortex. Differences in distribution patterns are compared with the cytoarchitectonic parcellation. Binding sites were analyzed with quantitative in vitro receptor autoradiography in unfixed brains of five macaque monkeys. Alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) binding sites were labeled with [3H]AMPA, [3H]kainate, and [3H]MK-801, respectively, muscarinic binding sites with [3H]pirenzepine or [3H]oxotremorine-M, noradrenergic binding sites with [3H]prazosin or [3H]UK-14304, gamma-aminobutyric acid (GABA)A binding sites with [3H]muscimol, and serotoninergic binding sites with [3H]ketanserine. Adjacent sections were stained with a modified Nissl method for cytoarchitectonic analysis. In the motor areas F1, F3, and F6, [3H]AMPA, [3H]pirenzepine, and [3H]oxotremorine-M binding was maximal in layers II, III, and V, and [3H]kainate binding was maximal in layers V and VI. Clear-cut changes in laminar distribution patterns of [3H]AMPA, [3H]kainate, and [3H]oxotremorine-M binding sites very closely matched corresponding cytoarchitectonic borders. Mean areal binding densities of all ligands to F1, F3, and F6 were plotted as polar plots for each area. A polygon was obtained for each area ("neurochemical fingerprint") when all the density values belonging to one area were connected with each other. The "neurochemical fingerprints" of F1, F3, and F6 were virtually identical in shape but increased in size from F1 to F6. This result reflects the functional similarity of these motor-related areas and possibly correlates with their differential involvement in motor control. Areas F1, F3, and F6 can thus be grouped into one "neurochemical family" of areas.

Quantitative analysis of sulci in the human cerebral cortex: development, regional heterogeneity, gender difference, asymmetry, intersubject variability and cortical architecture.

The degree of cortical folding (GI) and the relation between sulci and borders of cyto- and receptorarchitectonically defined areas were analyzed in postmortem human brains. The GI reaches adult levels (with highest values in the association cortices) around birth and does not decrease during aging. It shows a sex-dependent left-over-right asymmetry. Sulci and borders of architectonical areas coincide only in a few examples; thus, sulci are not generally valid landmarks of the microstructural organization of the cortex. Individual sulci were studied in 3D-reconstructed MRI sequences of living brains. A considerable intersubject variability of the distances between the sulcal surfaces of individual brains and their mean sulcal surfaces is apparent. The depth of the central sulcus varies with manual skill and handedness.