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 ¢rst 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 ¢rst 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.

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The structural and functional organization of the human cingulate cortex is an ongoing focus; however, human imaging studies continue to use the century-old Brodmann concept of a two region cingulate cortex. Recently, a four-region neurobiological model was proposed based on structural, circuitry, and functional imaging observations. It encompasses the anterior cingulate, midcingulate, posterior cingulate, and retrosplenial cortices (ACC, MCC, PCC, and RSC, respectively). For the first time, this study performs multireceptor autoradiography of 15 neurotransmitter receptor ligands and multivariate statistics on human whole brain postmortem samples covering the entire cingulate cortex. We evaluated the validity of Brodmann's duality concept and of the four-region model using a hierarchical clustering analysis of receptor binding according to the degree of similarity of each area's receptor architecture. We could not find support for Brodmann's dual cingulate concept, because the anterior part of his area 24 has significantly higher AMPA, kainate, GABA(B), benzodiazepine, and M(3) but lower NMDA and GABA(A) binding site densities than the posterior part. The hierarchical clustering analysis distinguished ACC, MCC, PCC, and RSC as independent regions. The ACC has highest AMPA, kainate, alpha(2), 5-HT(1A), and D(1) but lowest GABA(A) densities. The MCC has lowest AMPA, kainate, alpha(2), and D(1) densities. Area 25 in ACC is similar in receptor-architecture to MCC, particularly the NMDA, GABA(A), GABA(B), and M(2) receptors. The PCC and RSC differ in the higher M(1) and alpha(1) but lower M(3) densities of PCC. Thus, multireceptor autoradiography supports the four-region neurobiological model of the cingulate cortex.

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.

A novel map of Broca's language region is proposed based on transmitter receptor distributions as functionally relevant molecular markers. It sheds new light on the relation between anatomy and functional segregation.

Functional imaging studies identified a motion-sensitive area (V5/MT+) in the vicinity of the posterior branch of the inferior temporal sulcus that has no correlate in any classical cytoarchitectonic map. The aim of the present study was to identify a cytoarchitectonic correlate of this region in 10 human postmortem brains and to provide a probability map of this area. Observer-independent mapping revealed an area, hOc5 (h for human, Oc for occipital lobe), that has a broad layer III, a high cell density in layer II/III, and a low one in layer V. Most of area hOc5 is found in the depths of the anterior occipital sulcus and the anterior parts of either the inferior lateral occipital or the inferior occipital sulcus. After 3-dimensional reconstruction and registration to a standard reference space, a probability map of the area measured the individual variability of its size and location. The mean spatial locations of area hOc5 are -43, -73, 10 (left) and 49, -70, 11 (right). The locations and their relationships to sulci strongly suggest that hOc5 is the cytoarchitectonic correlate of human V5/MT+. This hypothesis was supported by comparing the cytoarchitectonic probabilistic map with results from a functional imaging study.

Anterior cingulate cortex (ACC) is involved in emotion, emotional expression, mood and autonomic regulation in contrast to midcingulate cortex, which regulates response selection via cognitive and skeletomotor mechanisms. Although a subgenual part of ACC (sACC) may be vulnerable in depression and area 25 is cytologically unique, there are no assessments that contrast this region to pregenual ACC (pACC); both include parts of areas 32, 24, and 33 and the cingulate sulcus extends rostral to the corpus callosum and might contain area 24c. Independent verifications of cytoarchitectural differences among subregions, areas and laminar binding was undertaken with an observer-interactive approach and multireceptor autoradiography. Areas 24a and 24b have pregenual (p24a, p24b) and subgenual (s24a, s24b) components and subgenual areas have a very thin layer III. Area 24c is rostral to the genu (p24c) and has dorsal (pd24c) and ventral (pv24c) parts. Area pd24c has more and larger neurofilament-expressing neurons in layer Va and neurons in Vb form aggregates in area pv24c rather than solitary pyramids as in pd24c. Area pd24c occupies both banks of the cingulate sulcus with pv24c on the ventral bank. Layer III distinguishes these areas with pd24cd having many larger neurofilament-expressing neurons and a richer dendritic plexus in the entire layer III. Area 32 has pregenual (p32) and subgenual (s32) components. Layer II in s32 is of particular note because it has a neuron dense IIa and sparse IIb. Area 25 is comprised of anterior (25a) and posterior (25p) parts; 25p has the thinnest layer III in the cingulate gyrus and larger and more dense neurons in layer II. Area 33 continues around the genu and ventrally to encompass the full caudal extent of area 25. The multivariate, observer-interactive method accurately identified all borders except those of area 25. Finally, sACC has significantly higher GABA A , GABA B , BZ, α 1 , and 5-HT 1A densities than pACC. The GABA B , BZ and α 1 binding in the cingulate sulcus confirms the subdivision of area pd24c into ventral and dorsal components. Receptor binding also supports subdivision of area 25 with 25a containing significantly higher AMPA, kainate, NMDA, GABA A , Corresponding author: Nicola Palomero-Gallagher, Institute of Neurosciences and Biophysics -Medicine, Research Centre Jülich, 52425 Jülich, Germany, Phone: +49-2461-614790, e-mail: E-mail: n.palomero-gallagher@fz-juelich.de. Publisher's Disclaimer: Author Disclaimer Brent A. Vogt, Ph.D. (May 2008) The NIH requires open access to research it supports and it accepts word documents for such a purpose. Although open access is supposed to play a double role in grant progress, The present document is not submitted as progress. Only the final and high quality publication will be submitted as progress. Consult the journal of publication for this progress. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGABA B , and α 1 receptor densities than area 25p. In conclusion, ACC is ...

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