Hartmut Mohlberg

A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data.

Correlating the activation foci identified in functional imaging studies of the human brain with structural (e.g., cytoarchitectonic) information on the activated areas is a major methodological challenge for neuroscience research. We here present a new approach to make use of three-dimensional probabilistic cytoarchitectonic maps, as obtained from the analysis of human post-mortem brains, for correlating microscopical, anatomical and functional imaging data of the cerebral cortex. We introduce a new, MATLAB based toolbox for the SPM2 software package which enables the integration of probabilistic cytoarchitectonic maps and results of functional imaging studies. The toolbox includes the functionality for the construction of summary maps combining probability of several cortical areas by finding the most probable assignment of each voxel to one of these areas. Its main feature is to provide several measures defining the degree of correspondence between architectonic areas and functional foci. The software, together with the presently available probability maps, is available as open source software to the neuroimaging community. This new toolbox provides an easy-to-use tool for the integrated analysis of functional and anatomical data in a common reference space.

Broca's region revisited: cytoarchitecture and intersubject variability.

The sizes of Brodmanns areas 44 and 45 (Brocas speech region) and their extent in relation to macroscopic landmarks and surrounding areas differ considerably among the available cytoarchitectonic maps. Such variability may be due to intersubject differences in anatomy, observer‐dependent discrepancies in cytoarchitectonic mapping, or both. Because a reliable definition of cytoarchitectonic borders is important for interpreting functional imaging data, we mapped areas 44 and 45 by means of an observer‐independent technique. In 10 human brains, the laminar distributions of cell densities were measured vertical to the cortical surface in serial coronal sections stained for perikarya. Thousands of density profiles were obtained. Cytoarchitectonic borders were defined as statistically significant changes in laminar patterns. The analysis of the three‐dimensional reconstructed brains and the two areas showed that cytoarchitectonic borders did not consistently coincide with sulcal contours. Therefore, macroscopic features are not reliable landmarks of cytoarchitectonic borders. Intersubject variability in the cytoarchitecture of areas 44 and 45 was significantly greater than cytoarchitectonic differences between these areas in individual brains. Although the volumes of area 44 differed across subjects by up to a factor of 10, area 44 but not area 45 was left‐over‐right asymmetrical in all brains. All five male but only three of five female brains had significantly higher cell densities on the left than on the right side. Such hemispheric and gender differences were not detected in area 45. These morphologic asymmetries of area 44 provide a putative correlate of the functional lateralization of speech production. J. Comp. Neurol. 412:319–341, 1999.

Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex : intersubject variability and probability maps

Probabilistic maps of neocortical areas and subcortical fiber tracts, warped to a common reference brain, have been published using microscopic architectonic parcellations in ten human postmortem brains. The maps have been successfully applied as topographical references for the anatomical localization of activations observed in functional imaging studies. Here, for the first time, we present stereotaxic, probabilistic maps of the hippocampus, the amygdala and the entorhinal cortex and some of their subdivisions. Cytoarchitectonic mapping was performed in serial, cell-body stained histological sections. The positions and the extent of cytoarchitectonically defined structures were traced in digitized histological sections, 3-D reconstructed and warped to the reference space of the MNI single subject brain using both linear and non-linear elastic tools of alignment. The probability maps and volumes of all structures were calculated. The precise localization of the borders of the mapped regions cannot be predicted consistently by macroanatomical landmarks. Many borders, e.g. between the subiculum and entorhinal cortex, subiculum and Cornu ammonis, and amygdala and hippocampus, do not match sulcal landmarks such as the bottom of a sulcus. Only microscopic observation enables the precise localization of the borders of these brain regions. The superposition of the cytoarchitectonic maps in the common spatial reference system shows a considerably lower degree of intersubject variability in size and position of the allocortical structures and nuclei than the previously delineated neocortical areas. For the first time, the present observations provide cytoarchitectonically verified maps of the human amygdala, hippocampus and entorhinal cortex, which take into account the stereotaxic position of the brain structures as well as intersubject variability. We believe that these maps are efficient tools for the precise microstructural localization of fMRI, PET and anatomical MR data, both in healthy and pathologically altered brains.

Brodmann's Areas 17 and 18 Brought into Stereotaxic Space—Where and How Variable?

Studies on structural-functional associations in the visual system require precise information on the location and variability of Brodmanns areas 17 and 18. Usually, these studies are based on the Talairach atlas, which does not rely on cytoarchitectonic observations, but on comparisons of macroscopic features in the Talairach brain and Brodmanns drawing. In addition, in this atlas are found only the approximate positions of cytoarchitectonic areas and not the exact borders. We have cytoarchitectonically mapped both areas in 10 human brains and marked their borders in corresponding computerized images. Borders were defined on the basis of quantitative cytoarchitecture and multivariate statistics. In addition to borders of areas 17 and 18, subparcellations within both areas were found. The cytoarchitectonically defined areas were 3-D reconstructed and transferred into the stereotaxic space of the standard reference brain. Surface rendering of the brains revealed high individual variability in size and shape of the areas and in the relationship to the free surface and sulci. Ranges and centers of gravity of both areas were calculated in Talairach coordinates. The positions of areas 17 and 18 in the stereotaxic space differed between the hemispheres. Both areas reached significantly more caudal and medial positions on the left than on the right. Probability maps were created in which the degree of overlap in each stereotaxic position was quantified. These maps of areas 17 and 18 are the first of their kind and contain precise stereotaxic information on both interhemispheric and interindividual differences.

The human inferior parietal cortex: Cytoarchitectonic parcellation and interindividual variability

The inferior parietal cortex (IPC) integrates information from different sensory modalities and plays an important role in a variety of higher cognitive functions. Brodmann (Brodmann, K., 1909. Vergleichende Lokalisationslehre der Grosshirnrinde. Barth, Leipzig) proposed a cytoarchitectonic subdivision of the IPC into only two cortical areas, a rostral (BA 40) and a caudal (BA 39) area. Although his scheme was repeatedly challenged by other observers, it is still used for the anatomical localization of functional imaging data. The apparent differences between all these cyto- and myeloarchitectonic maps may be caused partly by the observer-dependent procedure of defining cytoarchitectonic borders by pure visual inspection of histological sections and partly by the interindividual variability of cytoarchitecture. The present observations and the resulting cortical map of the IPC are based on quantitative, observer-independent definitions of cytoarchitectonic borders and take into account each areas topographical variability across brains. Ten human postmortem brains were scanned using an MRI 3-D FLASH sequence prior to histological processing. After embedding in paraffin, serial sections through whole brains were prepared, and the sections were stained for cell bodies. Following high-resolution digitization of sections containing the IPC, we defined the cytoarchitecture and borders of each cortical area of this brain region using a multivariate statistical analysis of laminar cell density profiles. In contrast to previous observations, we found seven cytoarchitectonic areas in the IPC: five in the rostral (covering the region of BA 40) and two in the caudal part (covering the region of BA 39). We observed considerable interindividual variability in the topography of each area. A consistent correspondence between macroanatomical landmarks and cytoarchitectonic borders was not found. This new cytoarchitectonic map of the human IPC demonstrates regional differences in the cortical microstructure that is suggestive of functional differentiation. Furthermore, the map is registered in three dimensions and thereby provides a robust anatomical base for interpreting functional imaging studies.

Analysis of neural mechanisms underlying verbal fluency in cytoarchitectonically defined stereotaxic space—The roles of Brodmann areas 44 and 45

We investigated neural activations underlying a verbal fluency task and cytoarchitectonic probabilistic maps of Brocas speech region (Brodmanns areas 44 and 45). To do so, we reanalyzed data from a previous functional magnetic resonance imaging (fMRI) [Brain 125 (2002) 1024] and from a cytoarchitectonic study [J. Comp. Neurol. 412 (1999) 319] and developed a method to combine both data sets. In the fMRI experiment, verbal fluency was investigated in 11 healthy volunteers, who covertly produced words from predefined categories. A factorial design was used with factors verbal class (semantic vs. overlearned fluency) and switching between categories (no vs. yes). fMRI data analysis employed SPM99 (Statistical Parametric Mapping). Cytoarchitectonic maps of areas 44 and 45 were derived from histologic sections of 10 postmortem brains. Both the in vivo fMRI and postmortem MR data were warped to a common reference brain using a new elastic warping tool. Cytoarchitectonic probability maps with stereotaxic information about intersubject variability were calculated for both areas and superimposed on the functional data, which showed the involvement of left hemisphere areas with verbal fluency relative to the baseline. Semantic relative to overlearned fluency showed greater involvement of left area 45 than of 44. Thus, although both areas participate in verbal fluency, they do so differentially. Left area 45 is more involved in semantic aspects of language processing, while area 44 is probably involved in high-level aspects of programming speech production per se. The combination of functional data analysis with a new elastic warping tool and cytoarchitectonic maps opens new perspectives for analyzing the cortical networks involved in language.

White matter fiber tracts of the human brain: three-dimensional mapping at microscopic resolution, topography and intersubject variability.

The position and extent of individual fiber tracts within the white matter of human brains can be identified in vivo using diffusion tensor imaging (DTI) and fiber tracking methods. Previous to this study, however, the lack of three-dimensional (3-D) probability maps precluded comparing the anatomical precision of MRI studies with microscopically defined fiber tracts in human postmortem brains. The present study provides 3-D registered maps of the topography, course and intersubject variability of major fiber tracts, which were identified at microscopic resolution. The analyzed tracts include the corticospinal tract, optic and acoustic radiations, fornix, cingulum, corpus callosum, superior longitudinal, superior and inferior occipito-frontal and uncinate fascicles; sources and targets of fiber tracts include the lateral and medial geniculate nuclei and mamillary bodies. Tracts and nuclei were identified in serial myelin-stained histological sections of ten postmortem brains. The sections were 3-D reconstructed and registered to a standardized stereotaxic space of an in vivo MR reference brain by means of linear and non-linear, elastic transformations. The individual fiber tracts and nuclei were superimposed in the reference space, and probability maps were generated as a quantitative measure of intersubject variability for each voxel of the stereotaxic space. This study presents the first stereotaxic atlas of the course, location and extent of fiber tracts and related nuclei based on microscopically defined localization and topographic data taken at multiple levels on each of the three orthogonal planes. The maps are useful for evaluating and identifying fiber bundles in DTI, for localizing subcortical lesions visible in anatomical MR images and for studying neuronal connectivity.

Interhemispheric asymmetry of the human motor cortex related to handedness and gender.

Most people are right-handed, preferring the right hand for skilled as well as unskilled activities, but a notable proportion are mixed-handed, preferring to use the right hand for some actions and the left hand for others. Assuming a structural/functional correlation in the motor system we tested whether asymmetries in hand performance in consistent right and left handers as well as in mixed handers are associated with anatomical asymmetries in the motor cortex. In vivo MR morphometry was used for analyzing interhemispheric asymmetry in the depth of the central sulcus in the region of cortical hand representation of 103 healthy subjects. Subjects were tested both for hand preference and hand performance. As expected, left-right differences in hand performance differed significantly between consistent right, consistent left and mixed handers and were independent on gender. Male consistent right handers showed a significant deeper central sulcus on the left hemisphere than on the right. Anatomical asymmetries decreased significantly from male consistent right over mixed to consistent left handers. Sixty two per cent of consistent left handers revealed a deeper central sulcus on the right than on the left hemisphere, but for the group as a whole this rightward asymmetry was not significant. No interhemispheric asymmetry was found in females. Thus, anatomical asymmetry was associated with handedness only in males, but not in females, suggesting sex differences in the cortical organization of hand movements.

The human inferior parietal lobule in stereotaxic space

Recently, a new cytoarchitectonic map of the human inferior parietal lobule (IPL) has been proposed, with the IPL consisting of seven cytoarchitectonically distinct areas (Caspers et al. in Neuroimage 33(2):430–448, 2006). The aim of the present study was to investigate the different aspects of variability of these IPL areas. As one aspect of variability, we analysed the topographical relationship between the localisation of the borders of the areas and macroanatomical landmarks. Although five areas occupy the surface supramarginal gyrus and two the angular gyrus, their borders cannot be reliably detected by means of macroanatomy. To account for variability in size and extent of the areas in stereotaxic space, cytoarchitectonic probabilistic maps have been calculated for each IPL area. Hemisphere- and gender-related differences have been investigated on basis of volumes of cytoarchitectonic areas. For one of them, area PFcm, a significant gender difference in volume was found with males having larger volumes than females; this difference exceeds that of gender differences in total brain volume. The different aspects of variability and volumetric asymmetry may underlie some of the well-known functional asymmetries in the IPL, observed, for example during fMRI experiments analysing spatial attention or motor attention, and planning. The cytoarchitectonic probabilistic maps of the seven IPL areas provide a robust anatomical reference and open new perspectives for further structure–function investigations of the human IPL.

Areas 3a, 3b, and 1 of human primary somatosensory cortex: 2. Spatial normalization to standard anatomical space

Interindividual topographical variability of cytoarchitectonically defined somatosensory areas 3a, 3b, and 1 was analyzed in the standard anatomical format of a computerized brain atlas. T1-weighted magnetic resonance images were obtained from 10 postmortem brains. The brains were serially sectioned at 20 mcm, sections were stained for cell bodies, and areas 3a, 3b, and 1 were defined with an observer-independent cytoarchitectonic technique. After correction of the sections for deformations due to histological processing, the 3-D reconstructed histological volumes of the individual brains and the volume representations of the cytoarchitectonic areas were adapted to the reference brain of a computerized atlas. Corresponding areas were superimposed in the 3-D space of the reference brain. These population maps describe, for each voxel, how many brains have a representation of one particular cytoarchitectonic area. Each areas extent is very variable across different brains, but representations of areas 3a, 3b, and 1 in >/=50% of the brains were found in the fundus of the central sulcus, its caudal bank, and on the crown of the postcentral gyrus, respectively. Volumes of interest (VOIs) were defined for each area in which >/=50% of the brains have a representation of that area. Despite close spatial relationship of areas 3a, 3b, and 1 in the postcentral gyrus, the three VOIs overlap by <1% of their volumes. Functional imaging data can now be brought into the same standard anatomical format, and changes in regional cerebral blood flow can be calculated in VOIs of areas 3a, 3b, and 1, which are derived from genuine cytoarchitectonic data.