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Flat mapping based cortical surface registration constrained by manually traced sulcal curves has been widely used for inter subject comparisons of neuroanatomical data. Even for an experienced neuroanatomist, manual sulcal tracing can be quite time consuming, with the cost increasing with the number of sulcal curves used for registration. We present a method for estimation of an optimal subset of size N(C) from N possible candidate sulcal curves that minimizes a mean squared error metric over all combinations of N(C) curves. The resulting procedure allows us to estimate a subset with a reduced number of curves to be traced as part of the registration procedure leading to optimal use of manual labeling effort for registration. To minimize the error metric we analyze the correlation structure of the errors in the sulcal curves by modeling them as a multivariate Gaussian distribution. For a given subset of sulci used as constraints in surface registration, the proposed model estimates registration error based on the correlation structure of the sulcal errors. The optimal subset of constraint curves consists of the N(C) sulci that jointly minimize the estimated error variance for the subset of unconstrained curves conditioned on the N(C) constraint curves. The optimal subsets of sulci are presented and the estimated and actual registration errors for these subsets are computed., (Copyright 2009 Elsevier Inc. All rights reserved.)

Group analysis of structure or function in cerebral cortex typically involves, as a first step, the alignment of cortices. A surface-based approach to this problem treats the cortex as a convoluted surface and coregisters across subjects so that cortical landmarks or features are aligned. This registration can be performed using curves representing sulcal fundi and gyral crowns to constrain the mapping. Alternatively, registration can be based on the alignment of curvature metrics computed over the entire cortical surface. The former approach typically involves some degree of user interaction in defining the sulcal and gyral landmarks while the latter methods can be completely automated. Here we introduce a cortical delineation protocol consisting of 26 consistent landmarks spanning the entire cortical surface. We then compare the performance of a landmark-based registration method that uses this protocol with that of two automatic methods implemented in the software packages FreeSurfer and BrainVoyager. We compare performance in terms of discrepancy maps between the different methods, the accuracy with which regions of interest are aligned, and the ability of the automated methods to correctly align standard cortical landmarks. Our results show similar performance for ROIs in the perisylvian region for the landmark-based method and FreeSurfer. However, the discrepancy maps showed larger variability between methods in occipital and frontal cortex and automated methods often produce misalignment of standard cortical landmarks. Consequently, selection of the registration approach should consider the importance of accurate sulcal alignment for the specific task for which coregistration is being performed. When automatic methods are used, the users should ensure that sulci in regions of interest in their studies are adequately aligned before proceeding with subsequent analysis., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Spatial transformation of MR brain images is a standard tool used in automated anatomical parcellation and other quantitative and qualitative methods to assess brain tissue volume, composition, and distribution. Despite widespread use, the quantitative effects of spatial transformation on regional brain volume estimates have been little studied. We report on the effects of transformation on regional brain volumes of 38 (17M, 21F) manually parcellated brains. After tracing in native space, regions of interest were transformed using a classic piecewise-linear Talairach transformation (Tal) or a nonlinear registration (AIR 5th order nonlinear algorithm, 158 parameters) to one of three Talairach-based templates: 1) Tal50, constructed from 50 Talairach-transformed normal brains, 2) the MNI 305 atlas, 3) IA38, constructed from MNI305-transformed scans of the 38 subjects used in this study. Native volumes were compared to the transformed volumes. We found that: 1) significant group-level differences can be obtained in transformed data sets that are in the opposite direction of effects obtained in native space; 2) the effects of transformation are heterogeneous across brain regions, even after covarying for total brain volume and age; 3) volumetric intra-class correlations between native and transformed brains differ by registration method and template choice, region, and tissue type; and 4) transformed brains produced hippocampus and corpus callosum volume proportions that were significantly different from those obtained in native space. Our results suggest that region-based volumetric differences uncovered by spatial-transformation-based methods should be replicated in native-space brains, and that meta-analyses should take into account whether volumes are determined using spatially-transformed images and/or specific automated methods.

Lesion overlap difference maps have been used in studies designed to test anatomical hypotheses regarding brain systems critical for various cognitive and behavioral tasks, including naming and recognition of concrete entities [Damasio, H., Tranel, D., Grabowski, T., Adolphs, R., Damasio, A., 2004. Neural systems behind word and concept retrieval. Cognition 92, 179-229]. To date, the interpretation of these results has focused on areas of maximum lesion overlap differences. Here we explore formal methods for statistical thresholding and power analysis. We derive exact voxel-wise statistics describing the behavior of lesion overlap difference maps and lesion proportion difference maps under the null hypothesis of no association between lesion and deficit, and we apply the statistics to a large subset of the subjects previously reported in [Damasio, H., Tranel, D., Grabowski, T., Adolphs, R., Damasio, A., 2004. Neural systems behind word and concept retrieval. Cognition 92, 179-229], in order to reassess the lesion correlates of deficits in naming and recognition for five categories of concrete entities. The thresholded maps confirmed many of the results reported previously, but also revealed some differences. Differences in spatial distribution of the lesion correlates of impaired naming of unique versus nonunique entities were confirmed in the inferotemporal region (IT), although overlapping components across categories became apparent in left IT. Additionally, the left inferior frontal gyrus (IFG) was implicated in naming both categories of nonunique natural entities (animals and fruits/vegetables). In corresponding power analyses, we estimated where significant effects could be found under an assumption of maximal effect size given the observed spatial distribution of lesions. Such "effective coverage maps" are valuable for the interpretation of the results, notably because of heterogeneity in lesion coverage encountered in lesion studies. We strongly suggest that when inferential statistics are used in voxel-wise lesion-deficit statistical mapping, these or other power maps be included in the reports.

Rather than specifying spatial relations with a closed-class set of prepositions, American Sign Language (ASL) encodes spatial relations using space itself via classifier constructions. In these constructions, handshape morphemes specify object type, and the position of the hands in signing space schematically represents the spatial relation between objects. A [15O]water PET study was conducted to investigate the neural regions engaged during the production of English prepositions and ASL locative classifier constructions in hearing subjects with deaf parents (ASL-English bilinguals). Ten subjects viewed line drawings depicting a spatial relation between two objects and were asked to produce either an ASL locative classifier construction or an English preposition that described the spatial relation. The comparison task was to name the figure object (colored red) in either ASL or in English. Describing spatial relations in either ASL or English engaged parietal cortex bilaterally. However, an interaction analysis revealed that right superior parietal cortex was engaged to a greater extent for ASL than for English. We propose that right parietal cortex is involved in the visual-motoric transformation required for ASL. The production of both English prepositions and ASL nouns engaged Broca's area to a greater extent than ASL classifier constructions. We suggest that Broca's area is not engaged because these constructions do not involve retrieval of the name of an object or the name of a spatial relation. Finally, under the same task conditions, only left parietal activation was observed for monolingual English speakers producing spatial prepositions (H. Damasio et al., 2001, NeuroImage, 13). We conclude that the right hemisphere activation observed for ASL-English bilinguals was due to their life-long experience with spatial language in ASL.

Voxel-based morphometry (VBM) is an automated statistical technique used to detect regional differences in tissue density and tissue amount based on spatially standardized structural magnetic resonance (MR) images. Developed initially to discern differences between groups of subjects, VBM is now being used to characterize structural abnormalities in individual brains. While VBM performance has been qualitatively assessed for this purpose, to date no quantitative validation study has been performed. This study evaluated several commonly used variants of VBM for detecting structural differences at the individual level by assessing their performance in MR images of 10 subjects with stable focal brain lesions. Results were quantitatively compared to expert tracings of the lesions, the current gold standard for lesion detection and delineation. Additionally, analyses using two sets of simulated lesion data were performed to examine the relative impact of the underlying processing steps on VBM results. Performance metrics revealed that (1) for this application, VBM had low sensitivity; (2) detection sensitivity was altered by model parameterization; (3) underperformance was due to the adverse influence of lesions on the preprocessing steps and to insufficient statistical power; and (4) VBM could not satisfactorily delineate the spatial extent of lesions, even in simulations that avoided preprocessing artifacts. In its current form, VBM is not a suitable stand-alone technique for detecting or spatially characterizing focal lesions.

A cross-cohort PET analysis was performed in 62 normal subjects (31 men and 31 women) to address the issue of whether men and women have different physiologic correlates of naming visually presented concrete entities. The subjects named nonunique concrete entities in one or more conceptual categories and also performed a face orientation decision task. A second analysis was performed in 24 additional subjects to assess whether there were gender effects related to the face orientation decision task and to constrain the interpretation of the first analysis. Male subjects engaged the left inferotemporal region and several other left hemisphere regions more than female subjects did during visual naming. Areas showing more activity in female subjects included the right inferior frontal gyrus and right precentral cortex, regions that were less active in visual naming than in the face orientation decision task. In other words, the male subjects engaged the latter regions less or deactivated them more than female subjects. The results can be interpreted as showing a greater modulation of activity in both hemispheres for men compared to women. Although the gender effects we found are smaller than the task effects, they are not negligible for the purposes of performing and interpreting functional imaging studies.

Normal subjects activate the left temporal polar cortex when they name persons, and subjects with damage to the left temporal pole due to left anterior temporal lobectomy are impaired in the retrieval of the proper names of persons. Eight such subjects were studied in a PET activation experiment to address the neural systems supporting their residual naming. We hypothesized that there would be increased activity, relative to normal controls, in the surround of the damaged region, the homologous right temporal pole, or both. Neither the group nor individual target subjects showed significantly increased activity in the lesion surround or in the right temporal pole. Several other regions that are activated by normals during the retrieval of the proper names of persons and which were undamaged in the target subjects (left anterior superior temporal sulcus, mesial frontal cortex, and anterior cingulate) were nevertheless significantly less activated by the target subjects, a finding that suggests that damage to the left temporal pole alters the function of a large-scale system needed for the retrieval of proper nouns. There was increased activity in early visual cortices, suggesting intensification of visual processing to compensate for the defective preferred name retrieval processing.

Using high resolution MRI scans and automated tissue segmentation, gray and white matter (GM, WM) volumes of the frontal, temporal, parietal, and occipital lobes, cingulate gyrus, and insula were calculated. Subjects included 23 male and 23 female healthy, right-handed subjects. For all structures, male volumes were greater than female, but the gray/white (G/W) ratio was consistently higher across structures in women than men. Sexual dimorphism was greater for WM than GM: most of the G/W ratio sex differences can be attributed to variation in WM volume. The corpus callosum, although larger in men, is less sexually dimorphic than the WM as a whole. Several regions demonstrate pair-wise asymmetries in G/W ratio and WM volume. Both the cingulate gyrus and insula exhibit strong asymmetries. The left cingulate gyrus is significantly larger than the right, and the G/W ratio of the left insula is significantly greater than that of the right. Although statistically significant sex differences and asymmetries are present at this level of analysis, we argue that researchers should be wary of ascribing cognitive functional significance to these patterns at this time. This is not to say, however, that these patterns are not important for understanding the natural history of the human brain, and its evolution and development.

A [(15)O]water PET experiment was conducted to investigate the neural regions engaged in processing constructions unique to signed languages: classifier predicates in which the position of the hands in signing space schematically represents spatial relations among objects. Ten deaf native signers viewed line drawings depicting a spatial relation between two objects (e.g., a cup on a table) and were asked either to produce a classifier construction or an American Sign Language (ASL) preposition that described the spatial relation or to name the figure object (colored red). Compared to naming objects, describing spatial relationships with classifier constructions engaged the supramarginal gyrus (SMG) within both hemispheres. Compared to naming objects, naming spatial relations with ASL prepositions engaged only the right SMG. Previous research indicates that retrieval of English prepositions engages both right and left SMG, but more inferiorly than for ASL classifier constructions. Compared to ASL prepositions, naming spatial relations with classifier constructions engaged left inferior temporal (IT) cortex, a region activated when naming concrete objects in either ASL or English. Left IT may be engaged because the handshapes in classifier constructions encode information about object type (e.g., flat surface). Overall, the results suggest more right hemisphere involvement when expressing spatial relations in ASL, perhaps because signing space is used to encode the spatial relationship between objects.

Ina [(15)O] water PET experiment, 10 normal subjects retrieved words denoting actions (performed with or without an implement), and another 10 normal subjects retrieved words denoting the spatial relations between objects. Our objective was to test the following hypothesis: that the salient neural activity associated with naming actions and spatial relations occurs in left frontal operculum and left parietal association cortices, but not in the left inferotemporal cortices (IT) or in the right parietal association cortices. There were two control tasks, one requiring a decision on the orientation of unknown faces (a standard control task in our laboratory) and another requiring the retrieval of words denoting the concrete entities used in the action and spatial relations tasks. In accordance with the hypothesis, both naming actions and spatial relations (using the face orientation task as control activated the left frontal operculum; naming actions also activated the left parietal lobe. However, sectors of the left posterior IT were also engaged in both naming actions and spatial relations. When the naming of concrete entities was subtracted from the naming of actions performed with such entities, area MT in the posterior temporo-occipital region was activated bilaterally. On the other hand, when naming of the concrete entities was subtracted from the naming of spatial relations, left parietal activation was found, and when two tasks of naming spatial relations were contrasted to each other bilateral parietal activation was seen, right when abstract stimuli were used and left when concrete objects were used. The activity in posterior IT is thought to be related to object processing and possibly name retrieval at a subconscious level., (Copyright 2001 Academic Press.)

We describe and evaluate a practical, automated algorithm based on local statistical mixture modeling for segmenting single-channel, T1-weighted volumetric magnetic resonance images of the brain into gray matter, white matter, and cerebrospinal fluid. We employed a stereological sampling method to assess, prospectively, the performance of the method with respect to human experts on 10 normal T1-weighted brain scans acquired with a three-dimensional gradient echo pulse sequence. The overall kappa statistic for the concordance of the algorithm with the human experts was 0.806, while that among raters, excluding the algorithm, was 0.802. The algorithm had better agreement with the modal expert decision (kappa = 0.878). The algorithm could not be distinguished from the experts by this measure. We also validated the algorithm on a simulated MR scan of a digital brain phantom with known tissue composition. Global gray matter and white matter errors were 1% and <1%, respectively, and correlation coefficients with the underlying tissue model were 0.95 for gray matter, 0.98 for white matter, and 0.95 for cerebrospinal fluid. In both approaches to validation, we evaluated both local and global performance of the algorithm. Human experts generated slightly higher global gray matter proportion estimates on the test brain scans relative to the algorithm (3.7%) and on the simulated MR scan relative to the true tissue model (4.4%). The algorithm underestimated gray in some subcortical nuclei which contain admixed gray and white matter. We demonstrate the reliability of the method on individual 1 NEX data sets of the test subjects, and its insensitivity to the precise values of initial model parameters. The output of this algorithm is suitable for quantifying cerebral cortical tissue, using a commonly performed commercial pulse sequence., (Copyright 2000 Academic Press.)

Primary comparative data on the hominoid brain are scarce and major neuroanatomical differences between humans and apes have not yet been described satisfactorily, even at the gross level. Basic questions that involve the evolution of the human brain cannot be addressed adequately unless the brains of all extant hominoid species are analyzed. Contrary to the scarcity of original data, there is a rich literature on the topic of human brain evolution and several debates exist on the size of particular sectors of the brain, e.g., the frontal lobe. In this study we applied a non-invasive imaging technique (magnetic resonance) on living human, great ape and lesser ape subjects in order to investigate the overall size of the hominoid brain. The images were reconstructed in three dimensions and volumetric estimates were obtained for the brain and its main anatomical sectors, including the frontal and temporal lobes, the insula, the parieto-occipital sector and the cerebellum.A remarkable homogeneity is present in the relative size of many of the large sectors of the hominoid brain, but interspecific and intraspecific variation exists in certain parts of the brain. The human cerebellum is smaller than expected for an ape brain of human size. It is suggested that the cerebellum increased less than the cerebrum after the split of the human lineage from the African ancestral hominoid stock. In contrast, humans have a slightly larger temporal lobe and insula than expected, but differences are not statistically significant. Humans do not have a larger frontal lobe than expected for an ape brain of human size and gibbons have a relatively smaller frontal lobe than the rest of the hominoids. Given the fact that the frontal lobe in humans and great apes has similar relative size, it is parsimonious to suggest that the relative size of the whole of the frontal lobe has not changed significantly during hominid evolution in the Plio-Pleistocene., (Copyright 2000 Academic Press.)

It has been shown that the retrieval of words denoting visually presented concrete entities engages neural systems in the left temporal lobe and that the precise pattern of activation within the temporal lobe depends in part on the conceptual category to which the entity belongs. Here, we used [15O]water positron emission tomography to test the hypothesis that the pattern of activation associated with word retrieval in left frontal lobe would also be related to conceptual category. The design entailed the performance of three tasks requiring the retrieval of words denoting animals, tools, and unique persons. The visual stimuli were presented at different rates, to produce equal performance success across categories, a feature which also had the effect of equalizing the proportion of scan time spent in mental search. All three word retrieval tasks activated the left inferior frontal gyrus, but they differed in their recruitment of two other premotor and prefrontal areas. Activity in a portion of the middle frontal gyrus, corresponding to Brodmann area 46, bore a linear relation to response latency and may index the extent of mental search. This region was most active when subjects named persons. Activity in the anterior bank of the precentral gyrus, along the inferior and middle frontal gyri, was most marked for naming tools. This region overlaps the area activated when subjects generate words for actions. We suggest that it is engaged by the retrieval of words denoting actions or objects with characteristic actions. The data presented here provide additional support for the notion that "nonclassical" language areas in extrasylvian frontal and temporal regions mediate word retrieval and that the pattern of their engagement relates to conceptual category.

Scenarios regarding the evolution of cognitive function in hominids depend largely on our understanding of the organization of the frontal lobes in extant humans and apes. The frontal lobe is involved in functions such as creative thinking, planning of future actions, decision making, artistic expression, aspects of emotional behavior, as well as working memory, language and motor control. It is often claimed that the frontal lobe is disproportionately larger in humans than in other species, but conflicting reports exist on this issue. The brain of the apes in particular remains largely unknown. In this report we measure the volume of the frontal lobe as a whole and of its main sectors (including cortex and immediately underlying white matter) in living humans, and in post-mortem brains of the chimpanzee, gorilla, orang-utan, gibbon and the macaque using three-dimensional reconstructions of magnetic resonance (MR) scans of the brain. On the basis of these data we suggest that although the absolute volume of the brain and the frontal lobe is largest in humans, the relative size of the frontal lobe is similar across hominoids, and that humans do not have a larger frontal lobe than expected from a primate brain of the human size. We also report that the relative size of the sectors of the frontal lobe (dorsal, mesial, orbital) is similar across the primate species studied. Our conclusions are preliminary, because the size of our sample, although larger than in previous studies, still remains small. With this caveat we conclude that the overall volume of the frontal lobe in hominids enlarged in absolute size along with the rest of the brain, but did not become relatively larger after the split of the human line from the ancestral African hominoid stock. Aspects other than relative volume of the frontal lobe have to be responsible for the cognitive specializations of the hominids.

A study of cognition emerging from a neurobiological perspective, as opposed to one emerging from a purely computational or psychological perspective, begins with observations of the human brain in normal and pathological states and is furthered by the investigation of hypotheses which are articulated using neuroanatomical nomenclature. Brainvox is an interactive three-dimensional brain imaging software package designed to permit such research through the support of the description and quantification of brain pathology in magnetic resonance images and of the experimental investigation of human cognition in lesion and functional imaging studies. Important general features of Brainvox, for these purposes, are: (1) adaptation of volume rendering for brain lesions and for corendered datasets; (2) shared memory architecture, which enables the user to identify and label anatomical structures, while inspecting the brain in multiple views simultaneously; (3) modular program design, including interlocking command-line utilities, which make Brainvox extensible and empower users without programming expertise to implement new analysis techniques through Unix shell scripting; and (4) full integration of three-dimensional tools for visualization with tools for analysis. Specific features include a new object templating technique (MAP-3) for studies of groups of brain-lesioned subjects, a complete and extensible suite of command-line processing utilities, a three-dimensional optimal graph-searching tool, and a method for planning PET slices and matching MR and PET slices (MP&#95;FIT).

Global amnesia after herpes simplex encephalitis has been typically associated with lesions of anterior and medial temporal lobe, inferior and medial frontal lobe, and insula. The neuropathologic correlates of this disease are usually considered to be bilateral and similar across cases. We describe a 27-year-old woman whose chronic amnesia and cerebral lesions after viral encephalitis indicate a different pattern. Two features distinguish her presentation: (1) markedly asymmetric lesions extensively involving the right temporal lobe but sparing almost all of the same structures on the left and (2) severe compromise of nonverbal learning and a nonverbal retrograde amnesia in contrast to disproportionately small impairments of verbal learning and retention. The findings suggest that encephalitis patients cannot be treated as a homogeneous group and that detailed analysis of variability in their anatomic lesions may be an important explanatory factor in neural accounts of these severe human amnesias.