Interoperable atlases of the human brain.

The last two decades have seen an unprecedented development of human brain mapping approaches at various spatial and temporal scales. Together, these have provided a large fundus of information on many different aspects of the human brain including micro- and macrostructural segregation, regional specialization of function, connectivity, and temporal dynamics. Atlases are central in order to integrate such diverse information in a topographically meaningful way. It is noteworthy, that the brain mapping field has been developed along several major lines such as structure vs. function, postmortem vs. in vivo, individual features of the brain vs. population-based aspects, or slow vs. fast dynamics. In order to understand human brain organization, however, it seems inevitable that these different lines are integrated and combined into a multimodal human brain model. To this aim, we held a workshop to determine the constraints of a multi-modal human brain model that are needed to enable (i) an integration of different spatial and temporal scales and data modalities into a common reference system, and (ii) efficient data exchange and analysis. As detailed in this report, to arrive at fully interoperable atlases of the human brain will still require much work at the frontiers of data acquisition, analysis, and representation. Among them, the latter may provide the most challenging task, in particular when it comes to representing features of vastly different scales of space, time and abstraction. The potential benefits of such endeavor, however, clearly outweigh the problems, as only such kind of multi-modal human brain atlas may provide a starting point from which the complex relationships between structure, function, and connectivity may be explored.

A weighted and directed interareal connectivity matrix for macaque cerebral cortex.

Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation <1 log unit, range 5 log units). The connectivity profile for each area conformed to a lognormal distribution, where a majority of projections are moderate or weak in strength. In the G29 × 29 interareal subgraph, two-thirds of the connections that can exist do exist. Analysis of the smallest set of areas that collects links from all 91 nodes of the G29 × 91 subgraph (dominating set analysis) confirms the dense (66%) structure of the cortical matrix. The G29 × 29 subgraph suggests an unexpectedly high incidence of unidirectional links. The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans. It will also inform future modeling studies that explore the regularities of cortical networks.

The Human Connectome Project: a data acquisition perspective.

The Human Connectome Project (HCP) is an ambitious 5-year effort to characterize brain connectivity and function and their variability in healthy adults. This review summarizes the data acquisition plans being implemented by a consortium of HCP investigators who will study a population of 1200 subjects (twins and their non-twin siblings) using multiple imaging modalities along with extensive behavioral and genetic data. The imaging modalities will include diffusion imaging (dMRI), resting-state fMRI (R-fMRI), task-evoked fMRI (T-fMRI), T1- and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography and electroencephalography (MEG/EEG). Given the importance of obtaining the best possible data quality, we discuss the efforts underway during the first two years of the grant (Phase I) to refine and optimize many aspects of HCP data acquisition, including a new 7T scanner, a customized 3T scanner, and improved MR pulse sequences.

The future of the human connectome.

The opportunity to explore the human connectome using cutting-edge neuroimaging methods has elicited widespread interest. How far will the field be able to progress in deciphering long-distance connectivity patterns and in relating differences in connectivity to phenotypic characteristics in health and disease? We discuss the daunting nature of this challenge in relation to specific complexities of brain circuitry and known limitations of in vivo imaging methods. We also discuss the excellent prospects for continuing improvements in data acquisition and analysis. Accordingly, we are optimistic that major insights will emerge from human connectomics in the coming decade.

Weight consistency specifies regularities of macaque cortical networks.

To what extent cortical pathways show significant weight differences and whether these differences are consistent across animals (thereby comprising robust connectivity profiles) is an important and unresolved neuroanatomical issue. Here we report a quantitative retrograde tracer analysis in the cynomolgus macaque monkey of the weight consistency of the afferents of cortical areas across brains via calculation of a weight index (fraction of labeled neurons, FLN). Injection in 8 cortical areas (3 occipital plus 5 in the other lobes) revealed a consistent pattern: small subcortical input (1.3% cumulative FLN), high local intrinsic connectivity (80% FLN), high-input form neighboring areas (15% cumulative FLN), and weak long-range corticocortical connectivity (3% cumulative FLN). Corticocortical FLN values of projections to areas V1, V2, and V4 showed heavy-tailed, lognormal distributions spanning 5 orders of magnitude that were consistent, demonstrating significant connectivity profiles. These results indicate that 1) connection weight heterogeneity plays an important role in determining cortical network specificity, 2) high investment in local projections highlights the importance of local processing, and 3) transmission of information across multiple hierarchy levels mainly involves pathways having low FLN values.

Intrinsic functional architecture in the anaesthetized monkey brain.

The traditional approach to studying brain function is to measure physiological responses to controlled sensory, motor and cognitive paradigms. However, most of the brain's energy consumption is devoted to ongoing metabolic activity not clearly associated with any particular stimulus or behaviour. Functional magnetic resonance imaging studies in humans aimed at understanding this ongoing activity have shown that spontaneous fluctuations of the blood-oxygen-level-dependent signal occur continuously in the resting state. In humans, these fluctuations are temporally coherent within widely distributed cortical systems that recapitulate the functional architecture of responses evoked by experimentally administered tasks. Here, we show that the same phenomenon is present in anaesthetized monkeys even at anaesthetic levels known to induce profound loss of consciousness. We specifically demonstrate coherent spontaneous fluctuations within three well known systems (oculomotor, somatomotor and visual) and the 'default' system, a set of brain regions thought by some to support uniquely human capabilities. Our results indicate that coherent system fluctuations probably reflect an evolutionarily conserved aspect of brain functional organization that transcends levels of consciousness.

A graphical anatomical database of neural connectivity.

We describe a graphical anatomical database program, called XANAT (so named because it was developed under the X window system in UNIX), that allows the results of numerous studies on neuroanatomical connections to be stored, compared and analysed in a standardized format. Data are entered into the database by drawing injection and label sites from a particular tracer study directly onto canonical representations of the neuroanatomical structures of interest, along with providing descriptive text information. Searches may then be performed on the data by querying the database graphically, for example by specifying a region of interest within the brain for which connectivity information is desired, or via text information, such as keywords describing a particular brain region, or an author name or reference. Analyses may also be performed by accumulating data across multiple studies and displaying a colour-coded map that graphically represents the total evidence for connectivity between regions. Thus, data may be studied and compared free of areal boundaries (which often vary from one laboratory to the next), and instead with respect to standard landmarks, such as the position relative to well-known neuro-anatomical substrates or stereotaxic coordinates. If desired, areal boundaries may also be defined by the user to facilitate the interpretation of results. We demonstrate the application of the database to the analysis of pulvinar-cortical connections in the macaque monkey, for which the results of over 120 neuro-anatomical experiments were entered into the database. We show how these techniques can be used to elucidate connectivity trends and patterns that may otherwise go unnoticed.

'The surface management system' (SuMS) database: a surface-based database to aid cortical surface reconstruction, visualization and analysis.

Surface reconstructions of the cerebral cortex are increasingly widely used in the analysis and visualization of cortical structure, function and connectivity. From a neuroinformatics perspective, dealing with surface-related data poses a number of challenges. These include the multiplicity of configurations in which surfaces are routinely viewed (e.g. inflated maps, spheres and flat maps), plus the diversity of experimental data that can be represented on any given surface. To address these challenges, we have developed a surface management system (SuMS) that allows automated storage and retrieval of complex surface-related datasets. SuMS provides a systematic framework for the classification, storage and retrieval of many types of surface-related data and associated volume data. Within this classification framework, it serves as a version-control system capable of handling large numbers of surface and volume datasets. With built-in database management system support, SuMS provides rapid search and retrieval capabilities across all the datasets, while also incorporating multiple security levels to regulate access. SuMS is implemented in Java and can be accessed via a Web interface (WebSuMS) or using downloaded client software. Thus, SuMS is well positioned to act as a multiplatform, multi-user 'surface request broker' for the neuroscience community.

An integrated software suite for surface-based analyses of cerebral cortex.

The authors describe and illustrate an integrated trio of software programs for carrying out surface-based analyses of cerebral cortex. The first component of this trio, SureFit (Surface Reconstruction by Filtering and Intensity Transformations), is used primarily for cortical segmentation, volume visualization, surface generation, and the mapping of functional neuroimaging data onto surfaces. The second component, Caret (Computerized Anatomical Reconstruction and Editing Tool Kit), provides a wide range of surface visualization and analysis options as well as capabilities for surface flattening, surface-based deformation, and other surface manipulations. The third component, SuMS (Surface Management System), is a database and associated user interface for surface-related data. It provides for efficient insertion, searching, and extraction of surface and volume data from the database.

Mapping visual cortex in monkeys and humans using surface-based atlases.

We have used surface-based atlases of the cerebral cortex to analyze the functional organization of visual cortex in humans and macaque monkeys. The macaque atlas contains multiple partitioning schemes for visual cortex, including a probabilistic atlas of visual areas derived from a recent architectonic study, plus summary schemes that reflect a combination of physiological and anatomical evidence. The human atlas includes a probabilistic map of eight topographically organized visual areas recently mapped using functional MRI. To facilitate comparisons between species, we used surface-based warping to bring functional and geographic landmarks on the macaque map into register with corresponding landmarks on the human map. The results suggest that extrastriate visual cortex outside the known topographically organized areas is dramatically expanded in human compared to macaque cortex, particularly in the parietal lobe.

Mapping of architectonic subdivisions in the macaque monkey, with emphasis on parieto-occipital cortex.

The intraparietal sulcus (IPS) of the macaque monkey contains numerous areas associated with different aspects of cortical function, including motor control as well as visual, somatosensory, vestibular, and possibly auditory processing. This study focuses largely on the architectonic organization of areas within and near the IPS, but also examines remaining portions of the hemisphere with which the IPS is interconnected. We charted the location of up to 72 architectonically distinct areas plus numerous architectonic zones in individuals over a region covering most of the cortical hemisphere. Identified cortical subdivisions (areas plus zones) were represented on computationally generated flat maps in relation to gyral and sulcal geography, thereby facilitating the analysis of consistent as well as variable aspects of the sizes and relative positions of subdivisions across animals. Using myelin and Nissl stains, plus immunohistochemical staining with the SMI-32 antibody, 17 architectonic subdivisions were identified that are largely or entirely contained in the intraparietal and parieto-occipital sulci. This includes four newly identified zones: a heavily myelinated lateral occipitoparietal zone, termed LOP; a strongly SMI-32 immunoreactive zone termed 7t (near the tip of the IPS); plus medial and lateral subdivisions (VIPm and VIPl) of ventral intraparietal area (VIP), which was previously regarded as an anatomically homogeneous area. Within the superior temporal sulcus, we identified a densely myelinated zone termed the dorso-posterior subdivision of the medial superior temporal area (MSTdp) that bordered middle temporal area (MT). We charted the extent of numerous other architectonically defined subdivisions throughout the cortical hemisphere by using criteria largely based on previous studies, but in some instances involving revised or expanded identification criteria.

Corticocortical connections of visual, sensorimotor, and multimodal processing areas in the parietal lobe of the macaque monkey.

We studied the corticocortical connections of architectonically defined areas of parietal and temporoparietal cortex, with emphasis on areas in the intraparietal sulcus (IPS) that are implicated in visual and somatosensory integration. Retrograde tracers were injected into selected areas of the IPS, superior temporal sulcus, and parietal lobule. The distribution of labeled cells was charted in relation to architectonically defined borders throughout the hemisphere and displayed on computer-generated three-dimensional reconstructions and on cortical flat maps. Injections centered in the ventral intraparietal area (VIP) revealed a complex pattern of inputs from numerous visual, somatosensory, motor, and polysensory areas, and from presumed vestibular- and auditory-related areas. Sensorimotor projections were predominantly from the upper body representations of at least six somatotopically organized areas. In contrast, injections centered in the neighboring ventral lateral intraparietal area (LIPv) revealed inputs mainly from extrastriate visual areas, consistent with previous studies. The pattern of inputs to LIPv largely overlapped those to zone MSTdp, a newly described subdivision of the medial superior temporal area. These results, in conjunction with those from injections into other parietal areas (7a, 7b, and anterior intraparietal area), support the fine-grained architectonic partitioning of cortical areas described in the preceding study. They also support and extend previous evidence for multiple distributed networks that are implicated in multimodal integration, especially with regard to area VIP.

Response profiles to texture border patterns in area V1.

Cells in area V1 of the anesthetized macaque monkey were stimulated with large texture patterns composed of homogeneous regions of line elements (texels) with different orientations. To human observers, such patterns appear to segregate, with the percept of sharp boundaries between texture regions. Our objective was to investigate whether the boundaries are reflected in the responses of single cells in V1. We measured responses to individual texels at different distances from the texture border. For each cell, patterns of optimally or orthogonally orientated texels were adjusted so that only one texel fell into the receptive field and all other texels fell in the visually unresponsive regions outside. In 37 out of 156 neurons tested (24%), texels immediately adjacent to a texture border evoked reliably larger responses than identical texels farther away from the border. In 17 neurons (11%), responses to texels near the border were relatively reduced. Border enhancement effects were generally stronger than border attenuation effects. When tested with four different border configurations (two global orientations and two edge polarities), many cells showed reliable effects for only one or two configurations, consistent with cells encoding information about the orientation of the texture border or its location with respect to the segmented region. Across the sample, enhancement effects were similar for all texture borders. Modulation by the texture surround was predominantly suppressive; even the responses near texture borders were smaller than those to a single line. We compared these results with the results of a popout test in which the line in the receptive field was surrounded by homogeneous texture fields either orthogonal or parallel to the center line. The patterns of response modulation and the temporal onset of differential responses were similar in the two tests, suggesting that the two perceptual phenomena are mediated by similar neural mechanisms.

Selectivity for complex shapes in primate visual area V2.

To explore the role of visual area V2 in shape analysis, we studied the responses of neurons in area V2 of the alert macaque using a set of 128 grating and geometric line stimuli that varied in their shape characteristics and geometric complexity. Simple stimuli included oriented bars and sinusoidal gratings; complex stimuli included angles, arcs, circles, and intersecting lines, plus hyperbolic and polar gratings. We found that most V2 cells responded well to at least some of the complex stimuli, and in many V2 cells the most effective complex stimulus elicited a significantly larger response than the most effective bar or sinusoid. Approximately one-third of the V2 cells showed significant differential responsiveness to various complex shape characteristics, and many were also selective for the orientation, size, and/or spatial frequency of the preferred shape. These results indicate that V2 cells explicitly represent complex shape information and suggest specific types of higher order visual information that V2 cells extract from visual scenes.

Response modulation by texture surround in primate area V1: correlates of "popout" under anesthesia.

We studied the effects of contextual modulation in area V1 of anesthetized macaque monkeys. In 146 cells, responses to a single line over the center of the receptive field were compared with those to full texture patterns in which the center line was surrounded by similar lines at either the same orientation (uniform texture) or the orthogonal orientation (orientation contrast). On average, the responses to single lines were reduced by 42% when texture was presented in the surround. Uniform textures often produced stronger suppression (7% more, on average) so that lines with orientation contrast on average evoked larger responses than lines in uniform texture fields. This difference is correlated with perceptual differences between such stimuli, suggesting that physiological mechanisms contributing to the saliency ("popout") of textural stimuli operate, at least to some degree, even under anesthesia. Significant response modulation by the texture surround was seen in 112 cells (77%). Fifty-three cells (36%) responded differently to the two texture patterns; response preferences for orientation contrast (35 cells; 24%) were seen more often than preferences for uniform textures (18 cells; 12%). The remaining 59 cells (40%) were similarly suppressed by both texture surrounds. Detailed analysis of texture modulation revealed two major components of surround effects: (1) fast nonspecific ("general") suppression that occurred at about the same latency as excitatory responses and was found in all layers of striate cortex; and (2) differential response modulation that began about 60-70 ms after stimulus onset (about 15-20 ms after the onset of the excitatory response) and was less homogeneously distributed over cortical layers.

A common network of functional areas for attention and eye movements.

Functional magnetic resonance imaging (fMRI) and surface-based representations of brain activity were used to compare the functional anatomy of two tasks, one involving covert shifts of attention to peripheral visual stimuli, the other involving both attentional and saccadic shifts to the same stimuli. Overlapping regional networks in parietal, frontal, and temporal lobes were active in both tasks. This anatomical overlap is consistent with the hypothesis that attentional and oculomotor processes are tightly integrated at the neural level.

Neural activity in areas V1, V2 and V4 during free viewing of natural scenes compared to controlled viewing.

Under natural viewing conditions primates make frequent exploratory eye movements across complex scenes. We recorded neural activity of 62 cells in visual areas V1, V2 and V4 in an awake behaving monkey that freely viewed natural images. About half of the cells studied showed a modulation in firing rate following some of the eye movements made during free viewing, though the proportions showing a discernible modulation varied across areas. These cells were also examined under controlled viewing conditions in which gratings or natural image patches were flashed in and around the classical receptive field while the animal performed a fixation task. Activity rates were generally highest with flashed gratings and lowest during free viewing. Flashed natural image patches evoked responses between these two extremes, and the responses were higher when the patches were confined to the classical receptive field than when they extended into the non-classical surround. Thus the reduction of activity during free viewing relative to that obtained with flashed gratings is partly attributable to natural images being less effective stimuli and partly to suppressive spatio-temporal neural mechanisms that are important during natural vision.

Neural activity in areas V1, V2 and V4 during free viewing of natural scenes compared to controlled viewing.

Under natural viewing conditions primates make frequent exploratory eye movements across complex scenes. We recorded neural activity of 62 cells in visual areas V1, V2 and V4 in an awake behaving monkey that freely viewed natural images. About half of the cells studied showed a modulation in firing rate following some of the eye movements made during free viewing, though the proportions showing a discernible modulation varied across areas. These cells were also examined under controlled viewing conditions in which gratings or natural image patches were flashed in and around the classical receptive field while the animal performed a fixation task. Activity rates were generally highest with flashed gratings and lowest during free viewing. Flashed natural image patches evoked responses between these two extremes, and the responses were higher when the patches were confined to the classical receptive field than when they extended into the non-classical surround. Thus the reduction of activity during free viewing relative to that obtained with flashed gratings is partly attributable to natural images being less effective stimuli and partly to suppressive spatio-temporal neural mechanisms that are important during natural vision.

Neural activity in areas V1, V2 and V4 during free viewing of natural scenes compared to controlled viewing.

Under natural viewing conditions primates make frequent exploratory eye movements across complex scenes. We recorded neural activity of 62 cells in visual areas V1, V2 and V4 in an awake behaving monkey that freely viewed natural images. About half of the cells studied showed a modulation in firing rate following some of the eye movements made during free viewing, though the proportions showing a discernible modulation varied across areas. These cells were also examined under controlled viewing conditions in which gratings or natural image patches were flashed in and around the classical receptive field while the animal performed a fixation task. Activity rates were generally highest with flashed gratings and lowest during free viewing. Flashed natural image patches evoked responses between these two extremes, and the responses were higher when the patches were confined to the classical receptive field than when they extended into the non-classical surround. Thus the reduction of activity during free viewing relative to that obtained with flashed gratings is partly attributable to natural images being less effective stimuli and partly to suppressive spatio-temporal neural mechanisms that are important during natural vision.