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C C Hilgetag

Publications and source records attributed to C C Hilgetag.

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Uniformity, specificity and variability of corticocortical connectivity.

In many studies of the mammalian brain, subjective assessments of connectivity patterns and connection strengths have been used to subdivide the cortex into separate but linked areas and to make deductions about the flow of information through the cortical network. Here we describe the results of applying statistical analyses to quantitative corticocortical connection data, and the conclusions that can be drawn from such quantitative approaches. Injections of the tracer WGA-HRP were made into different visual areas either side of the middle suprasylvian sulcus (MSS) in 11 adult cats. Retrogradely labelled cells produced by these injections were counted in selected coronal sections taken at regularly spaced intervals (1 mm) through the entire visual cortex, and their cumulative sums and relative proportions in each of 16 recognized visual cortical areas were computed. The surface dimensions of these areas were measured in each cat, from contour lines made on enlarged drawings of the same sections. A total of 116,149 labelled neurons were assigned to all visual cortical areas in the 11 cats, with 5212 others excluded because of their uncertain location. The distribution of relative connection strengths, that is, the percentage of labelled cells per cortical area, was evaluated using non-parametric cluster analyses and Monte Carlo simulation, and relationships between connection strength and area size were examined by linear regression. The absolute size of each visual cortical area was uniform across individual cats, whereas the strengths of connections between the same area pairs were extremely variable for injections in different animals. The overall distribution of labelling strengths for corticocortical connections was continuous and monotonic, rather than inherently clustered, with the highest frequencies presented by the absent (zero density) and the very-low-density connections. These two categories could not, on analytical grounds, be separated from each other. Thus it seems that any subjective description of corticocortical connectivity strengths by ordinal classes (such as 'absent', 'weak', 'moderate' or 'strong') imposes a categorization on the data, rather than recognizes a structure inherent in the data themselves. Despite the great variability of connections, similarities in the distribution profiles for the relative strengths of labelled cells in all areas could be used to identify clusters of different injection sites in the MSS. This supported the conclusion that there are four connectionally distinct subdivisions of this cortex, corresponding to areas 21a, PMLS and AMLS (in the medial bank) and to area PLLS (in the lateral bank). Even for tracer deposits in the same cortical subdivision, however, the strength of connections projecting to the site from other cortical areas varied greatly across injection in different individual animals. We further demonstrated that, on average, the strength of connections originating from any given cortical area was positively and linearly correlated with the size of its surface dimensions. When analysed by specific injection site location, however, this relationship was shown to hold for the individual connections to the medial bank MSS areas, but not for connections leading to the lateral bank area. The data suggest that connectivity of the cat's visual cortex possesses a number of uniform global features, which are locally organized in such a way as to give each cortical area unique characteristics.

Age Factors

Hierarchical organization of macaque and cat cortical sensory systems explored with a novel network processor.

Neuroanatomists have described a large number of connections between the various structures of monkey and cat cortical sensory systems. Because of the complexity of the connection data, analysis is required to unravel what principles of organization they imply. To date, analysis of laminar origin and termination connection data to reveal hierarchical relationships between the cortical areas has been the most widely acknowledged approach. We programmed a network processor that searches for optimal hierarchical orderings of cortical areas given known hierarchical constraints and rules for their interpretation. For all cortical systems and all cost functions, the processor found a multitude of equally low-cost hierarchies. Laminar hierarchical constraints that are presently available in the anatomical literature were therefore insufficient to constrain a unique ordering for any of the sensory systems we analysed. Hierarchical orderings of the monkey visual system that have been widely reported, but which were derived by hand, were not among the optimal orderings. All the cortical systems we studied displayed a significant degree of hierarchical organization, and the anatomical constraints from the monkey visual and somato-motor systems were satisfied with very few constraint violations in the optimal hierarchies. The visual and somato-motor systems in that animal were therefore surprisingly strictly hierarchical. Most inconsistencies between the constraints and the hierarchical relationships in the optimal structures for the visual system were related to connections of area FST (fundus of superior temporal sulcus). We found that the hierarchical solutions could be further improved by assuming that FST consists of two areas, which differ in the nature of their projections. Indeed, we found that perfect hierarchical arrangements of the primate visual system, without any violation of anatomical constraints, could be obtained under two reasonable conditions, namely the subdivision of FST into two distinct areas, whose connectivity we predict, and the abolition of at least one of the less reliable rule constraints. Our analyses showed that the future collection of the same type of laminar constraints, or the inclusion of new hierarchical constraints from thalamocortical connections, will not resolve the problem of multiple optimal hierarchical representations for the primate visual system. Further data, however, may help to specify the relative ordering of some more areas. This indeterminacy of the visual hierarchy is in part due to the reported absence of some connections between cortical areas. These absences are consistent with limited cross-talk between differentiated processing streams in the system. Hence, hierarchical representation of the visual system is affected by, and must take into account, other organizational features, such as processing streams.

Algorithms

Anatomical connectivity defines the organization of clusters of cortical areas in the macaque monkey and the cat.

The number of different cortical structures in mammalian brains and the number of extrinsic fibres linking these regions are both large. As with any complex system, systematic analysis is required to draw reliable conclusions about the organization of the complex neural networks comprising these numerous elements. One aspect of organization that has long been suspected is that cortical networks are organized into 'streams' or 'systems'. Here we report computational analyses capable of showing whether clusters of strongly interconnected areas are aspects of the global organization of cortical systems in macaque and cat. We used two different approaches to analyse compilations of corticocortical connection data from the macaque and the cat. The first approach, optimal set analysis, employed an explicit definition of a neural 'system' or 'stream', which was based on differential connectivity. We defined a two-component cost function that described the cost of the global cluster arrangement of areas in terms of the areas' connectivity within and between candidate clusters. Optimal cluster arrangements of cortical areas were then selected computationally from the very many possible arrangements, using an evolutionary optimization algorithm. The second approach, non-parametric cluster analysis (NPCA), grouped cortical areas on the basis of their proximity in multidimensional scaling representations. We used non-metric multidimensional scaling to represent the cortical connectivity structures metrically in two and five dimensions. NPCA then analysed these representations to determine the nature of the clusters for a wide range of different cluster shape parameters. The results from both approaches largely agreed. They showed that macaque and cat cortices are organized into densely intra-connected clusters of areas, and identified the constituent members of the clusters. These clusters reflected functionally specialized sets of cortical areas, suggesting that structure and function are closely linked at this gross, systems level.

Algorithms

Computational analysis of functional connectivity between areas of primate cerebral cortex.

Recent analyses of association fibre networks in the primate cerebral cortex have revealed a small number of densely intra-connected and hierarchically organized structural systems. Corresponding analyses of data on functional connectivity are required to establish the significance of these structural systems. We therefore built up a relational database by systematically collating published data on the spread of activity after strychnine-induced disinhibition in the macaque cerebral cortex in vivo. After mapping these data to two different parcellation schemes, we used three independent methods of analysis which demonstrate that the cortical network of functional interactions is not homogeneous, but shows a clear segregation into functional assemblies of mutually interacting areas. The assemblies suggest a principal division of the cortex into visual, somatomotor and orbito-temporo-insular systems, while motor and somatosensory areas are inseparably interrelated. These results are largely compatible with corresponding analyses of structural data of mammalian cerebral cortex, and deliver the first functional evidence for 'small-world' architecture of primate cerebral cortex.

Animals

On imputing function to structure from the behavioural effects of brain lesions.

What is the link, if any, between the patterns of connections in the brain and the behavioural effects of localized brain lesions? We explored this question in four related ways. First, we investigated the distribution of activity decrements that followed simulated damage to elements of the thalamocortical network, using integrative mechanisms that have recently been used to successfully relate connection data to information on the spread of activation, and to account simultaneously for a variety of lesion effects. Second, we examined the consequences of the patterns of decrement seen in the simulation for each type of inference that has been employed to impute function to structure on the basis of the effects of brain lesions. Every variety of conventional inference, including double dissociation, readily misattributed function to structure. Third, we tried to derive a more reliable framework of inference for imputing function to structure, by clarifying concepts of function, and exploring a more formal framework, in which knowledge of connectivity is necessary but insufficient, based on concepts capable of mathematical specification. Fourth, we applied this framework to inferences about function relating to a simple network that reproduces intact, lesioned and paradoxically restored orientating behaviour. Lesion effects could be used to recover detailed and reliable information on which structures contributed to particular functions in this simple network. Finally, we explored how the effects of brain lesions and this formal approach could be used in conjunction with information from multiple neuroscience methodologies to develop a practical and reliable approach to inferring the functional roles of brain structures.

Behavior

A solution to the binding problem? Information processing.

The brain effortlessly recombines information about the shape, colour, motion and so on of objects in the visual scene, but how it does so is not known. Synchronous neuronal firing has seemed an attractive solution to this problem, but new results and theoretical insights cast doubt on its functional role.

Evoked Potentials, Visual

Non-metric multidimensional scaling in the analysis of neuroanatomical connection data and the organization of the primate cortical visual system.

Neuroanatomists have established that the various gross structures of the brain are divided into a large number of different processing regions and have catalogued a large number of connections between these regions. The connectional data derived from neuroanatomical studies are complex, and reliable conclusions about the organization of brain systems cannot be drawn from considering them without some supporting analysis. Recognition of this problem has recently led to the application of a variety of techniques to the analysis of connection data. One of the techniques that we previously employed, non-metric multidimensional scaling (NMDS), appears to have revealed important aspects of the organization of the central nervous system, such as the gross organization of the whole cortical network in two species. We present here a detailed treatment of methodological aspects of the application of NMDS to connection data. We first examine in detail the particular properties of neuroanatomical connection data. Second, we consider the details of NMDS and discuss the propriety of different possible NMDS approaches. Third, we present results of the analyses of connection data from the primate visual system, and discuss their interpretation. Fourth, we study independent analyses of the organization of the visual system, and examine the relation between the results of these analyses and those from NMDS. Fifth, we investigate quantitatively the performance of a number of data transformation and conditioning procedures, as well as tied and untied NMDS analysis of untransformed low-level data, to determine how well NMDS can recover known metric parameters from artificial data. We then re-analyse real connectivity data with the most successful methods at removing the effects of sparsity, to ensure that this aspect of data structure does not obscure others. Finally, we summarize the evidence on the connectional organization of the primate visual system, and discuss the reliability of NMDS analyses of neuroanatomical connection data.

Animals

The connectional organization of the cortico-thalamic system of the cat.

Data on connections between the areas of the cerebral cortex and nuclei of the thalamus are too complicated to analyse with naked intuition. Indeed, the complexity of connection data is one of the major challenges facing neuroanatomy. Recently, systematic methods have been developed and applied to the analysis of the connectivity in the cerebral cortex. These approaches have shed light on the gross organization of the cortical network, have made it possible to test systematically theories of cortical organization, and have guided new electrophysiological studies. This paper extends the approach to investigate the organization of the entire cortico-thalamic network. An extensive collation of connection tracing studies revealed approximately 1500 extrinsic connections between the cortical areas and thalamic nuclei of the cat cerebral hemisphere. Around 850 connections linked 53 cortical areas with each other, and around 650 connections linked the cortical areas with 42 thalamic nuclei. Non-metric multidimensional scaling, optimal set analysis and non-parametric cluster analysis were used to study global connectivity and the 'place' of individual structures within the overall scheme. Thalamic nuclei and cortical areas were in intimate connectional association. Connectivity defined four major thalamo-cortical systems. These included three broadly hierarchical sensory or sensory/motor systems (visual and auditory systems and a single system containing both somatosensory and motor structures). The highest stations of these sensory/motor systems were associated with a fourth processing system composed of prefrontal, cingulate, insular and parahippocampal cortex and associated thalamic nuclei (the 'fronto-limbic system'). The association between fronto-limbic and somato-motor systems was particularly close.

Animals