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.

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.

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.

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.

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.

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.

Information processing in the primate visual system: an integrated systems perspective.

The primate visual system contains dozens of distinct areas in the cerebral cortex and several major subcortical structures. These subdivisions are extensively interconnected in a distributed hierarchical network that contains several intertwined processing streams. A number of strategies are used for efficient information processing within this hierarchy. These include linear and nonlinear filtering, passage through information bottlenecks, and coordinated use of multiple types of information. In addition, dynamic regulation of information flow within and between visual areas may provide the computational flexibility needed for the visual system to perform a broad spectrum of tasks accurately and at high resolution.

Selectivity for polar, hyperbolic, and Cartesian gratings in macaque visual cortex.

The neural basis of pattern recognition is a central problem in visual neuroscience. Responses of single cells were recorded in area V4 of macaque monkey to three classes of periodic stimuli that are based on spatial derivative operators: polar (concentric and radial), hyperbolic, and conventional sinusoidal (Cartesian) gratings. Of 118 cells tested, 16 percent responded significantly more to polar or hyperbolic (non-Cartesian) gratings than to Cartesian gratings and only 8 percent showed a significant preference for Cartesian gratings. Among cells selective for non-Cartesian gratings, those that preferred concentric gratings were most common. Cells selective for non-Cartesian gratings may constitute an important intermediate stage in pattern recognition and the representation of surface shape.

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.

Visual cortex: cartography, connectivity, and concurrent processing.

The mammalian visual cortex contains a complex mosaic of areas that are richly connected with one another. Recent progress has advanced our understanding of both macroscopic and microscopic aspects of cortical organization, and of information flow within and between functionally specialized processing streams.

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.

Topographic organization of the middle temporal visual area in the macaque monkey: representational biases and the relationship to callosal connections and myeloarchitectonic boundaries.

We have used physiological and anatomical techniques to address three general issues concerning the topographic organization of the middle temporal visual area (MT) of the macaque monkey. First, we carried out a quantitative analysis of irregularities and asymmetries in the visual representation in MT. This analysis revealed a striking overemphasis on a restricted portion of the visual field that runs obliquely through the inferior contralateral quadrant and largely avoids both the horizontal meridian and the inferior vertical meridian. This corresponds to the portion of the visual field that would be maximally stimulated during visually guided hand movements. Second, the physiologically determined topographic organization of MT was compared to the pattern of callosal inputs in the same hemisphere, which are known to be distributed irregularly within MT. Callosal inputs tended to be densest near the representation of the vertical meridian, but there were numerous exceptions to this trend. Thus, topographic irregularities account for only part of the irregularities in callosal inputs to MT. Finally, comparison of these data with previous reports shows a strong correlation between body weight and the average size of MT. The representation in myeloarchitectonically defined MT was found to include much of the visual periphery, although it is unclear from our data whether this representation is invariably complete.

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.

Development of connections within and between areas V1 and V2 of macaque monkeys.

We have investigated the development of intrinsic and interareal connections in areas V1 and V2 of the macaque monkey using postmortem transport of the lipophilic fluorescent tracer diI, applied to brains fixed at different pre- and postnatal ages. Intrinsic connections in the deep layers of V1 are evident on embryonic day 108 (E108), but are not robust in the superficial layers until around E118, when migration is largely complete. Both intrinsic horizontal projections and extrinsic projections to V2 initially have a continuous distribution. Patchy projections are first evident in V1 around E145, the same age at which cytochrome oxidase blobs appear, presumably signaling the differentiation of the blob-dominated and interblob-dominated streams in the primary visual cortex. The magnocellular-dominated stream becomes distinct at earlier stages (by E122), as judged by connectional and histochemical criteria. In area V2, intrinsic connections initially (at E108) involve only deep layer cells and do not have a clustered organization. By E130, superficial layer cells are involved and the V2 intrinsic connections have a patchy distribution; by E145, an adult-like pattern is present. The projection from V2 to V1 passes through an early stage (up to E133) of originating principally from deep layer cells, and thereafter originating from superficial as well as deep layers. We found evidence for changes in dendritic morphology during development. Most notably, at E118, many neurons in layer 6 which are involved in intrinsic or interareal connections have dendrites that extend well into the superficial layers, even into layer 1, a characteristic not reported in the adult.

Lack of topography in the spinal cord projection to the rabbit soleus muscle.

Several mammalian muscles in the limb and trunk receive topographically organized innervation from spinal cord motor neurons. Some muscles in which topographic innervation has been demonstrated have a sheet-like architecture; others are compartmentalized and/or have more than one origin. An interesting question is whether topography is related to these anatomical features, or whether it occurs as a general consequence of the development of innervation. To address this question, we examined the pattern of projections to the soleus muscle, which lacks these anatomical features. Intracellular recordings of endplate potentials in early and intermediate age rabbits were used to assess the spinal origin of inputs to two distinct regions of the muscle. Both regions were innervated by both rostral and caudal portions of the motor pool. These experiments also showed that individual muscle fibers frequently receive separate inputs arising from widely separated regions of the motor pool. In another set of experiments, physiological measurements of tension overlap in young, polyinnervated muscles showed that the relative positions of motor neurons in the spinal cord do not correlate with the extent to which motor units share muscle fibers. In a third set of experiments, motor neurons were retrogradely labeled following local injections of tracer into muscle. Small and large local injections resulted in comparably dispersed labeling of motor neurons within the motor pool. Moreover, the rostrocaudal position of labeled neurons was not correlated with the position of the injection site within the muscle. Together, these results provide evidence that the soleus muscle is not topographically innervated. Furthermore, an examination of several age groups suggests that the innervation pattern in this muscle is not altered by postnatal synapse elimination.

The specificity of re-innervation by identified sensory and motor neurons in the leech.

Re-innervation of skin and muscle by identified sensory and motor neurons in segmental ganglia of the leech was studied using physiological techniques. After lesions of peripheral nerves, sensory axons which re-innervated the skin always regained sensitivity to their original stimulus modality (touch, pressure or noxious stimuli). Motor neurons invariably re-innervated the appropriate type of body wall muscle, such as longitudinal or circular muscle layers. Both sensory and motor axons usually returned to the appropriate region of the body wall (dorsal, lateral, or ventral) when regenerating after a nerve crush or cut. This capacity was lost, however, when growth along old nerve branches was prevented by evulsing long segments of the nerve. Re-innervation usually occurred by way of growth of new axons all the way to the periphery, but in a few cases reconnection with the surviving distal segment of the original axon had taken place. The specificity of re-innervation can be accounted for by a combination of selective growth along appropriate nerve branches and specific interactions with target tissues.

Two-dimensional maps of the cerebral cortex.

A procedure is described for constructing two-dimensional, unfolded representations of the cerebral cortex. The technique is based on information contained in outlines of histological sections, and it allows an entire hemisphere to be represented on a single cortical map. Maps for different hemispheres from individuals of the same species are similar in size, shape, and organization, and their configuration is largely independent of the plane of sectioning used for reconstruction. Many types of information pertaining to the location and organization of different functional subdivisions can be displayed on cortical maps; representative applications of the technique to mapping cerebral cortex in the macaque and the cat are shown. Areal measurements on cortical maps correspond closely (generally within 20%) to actual surface areas in the intact hemisphere. Therefore, the maps can also be used to provide accurate determinations of the absolute and relative extent of various anatomical and functional subdivisions of the cortex.

Ventral posterior visual area of the macaque: visual topography and areal boundaries.

Using both physiological and anatomical techniques, we have studied the topographic organization of extrastriate visual cortex on the ventral surface of the occipital lobe in macaque monkeys. Our results show that a topographically organized representation of the superior contralateral quadrant of the visual field lies immediately anterior to the ventral half of V2. This area is organized in a mirror symmetric fashion to ventral V2: it shares a horizontal meridian representation with V2 and a representation of the superior vertical meridian forms its anterior border. A well-defined strip of callosal inputs runs along the vertical meridian representation, thereby providing a reliable anatomical marker for areal boundaries in ventral extrastriate cortex. We refer to this area as the ventral posterior area (VP) because it is, in all these respects, notably similar to VP in the owl monkey. Ventral V2 has strong reciprocal connections with VP, and the topography of the V2 projection agrees closely with the topography revealed in our physiological mapping experiments. The visual field representation in VP is strikingly anisotropic, with linear magnification factor being much larger along contours of constant polar angle than along contours of constant eccentricity.

Cortical connections of areas V3 and VP of macaque monkey extrastriate visual cortex.

The cortical connections of visual area 3 (V3) and the ventral posterior area (VP) in the macaque monkey were studied by using combinations of retrograde and anterograde tracers. Tracer injections were made into V3 or VP following electrophysiological recording in and near the target area. The pattern of ipsilateral cortical connections was analyzed in relation to the pattern of interhemispheric connections identified after transection of the corpus callosum. Both V3 and VP have major connections with areas V2, V3A, posterior intraparietal area (PIP), V4, middle temporal area (MT), medial superior temporal area (dorsal) (MSTd), and ventral intraparietal area (VIP). Their connections differ in several respects. Specifically, V3 has connections with areas V1 and V4 transitional area (V4t) that are absent for VP; VP has connections with areas ventral occipitotemporal area (VOT), dorsal prelunate area (DP), and visually responsive portion of temporal visual area F (VTF) that are absent or occur only rarely for V3. The laminar pattern of labelled terminals and retrogradely labeled cell bodies allowed assessment of the hierarchical relationships between areas V3 and VP and their various targets. Areas V1 and V2 are at a lower level than V3 and VP; all of the remaining areas are at a higher level. V3 receives major inputs from layer 4B of V1, suggesting an association with the magnocellular-dominated processing stream and a role in routing magnocellular-dominated information along pathways leading to both parietal and temporal lobes. The convergence and divergence of pathways involving V3 and VP underscores the distributed nature of hierarchical processing in the visual system.