Hierarchy is a major organizational principle of the cortex and underscores modern computational ... more Hierarchy is a major organizational principle of the cortex and underscores modern computational theories of cortical function. Consideration of the role of the local microcircuit in the amplification of inputs, leads to the argument that distance dependent changes in the laminar profiles of connectivity constitute the structural signatures of hierarchy. Statistical modeling of these signatures demonstrates that inputs from multiple hierarchical levels to their target areas show remarkable consistency, allowing the construction of a cortical hierarchy based on a principle of hierarchical distance. The statistical modeling that is applied to structure can also be applied to laminar differences in the oscillatory coherence between areas thereby determining a functional hierarchy of the cortex. Close examination of the anatomy of inter-areal connectivity reveals a dual counterstream architecture with well-defined distance-dependent feedback and feedforward pathways in both the supra- a...
Background: The cerebral cortex is divisible into many individual areas, each exhibiting distinct... more Background: The cerebral cortex is divisible into many individual areas, each exhibiting distinct connectivity profi les, architecture, and physiological characteristics. Interactions among cortical areas underlie higher sensory, motor, and cognitive functions. Graph theory provides an important framework for understanding network properties of the interareal weighted and directed connectiv-ity matrix reported in recent studies. Advances: We derive an exponential distance rule that predicts many binary and weighted features of the cortical network, including effi ciency of information transfer, the high specifi city of long-distance compared to short-distance connections, wire length minimization, and the existence of a highly interconnected cortical core. We propose a bow-tie representation of the cortex, which combines these features with hierarchical processing. Outlook: The exponential distance rule has important implications for understanding scaling prop-erties of the cortex a...
What is the relationship between anatomical connection strength and rhythmic synchronization? Sim... more What is the relationship between anatomical connection strength and rhythmic synchronization? Simultaneous recordings of 15 cortical areas in two macaque monkeys show that interareal networks are functionally organized in spatially distinct modules with specific synchronization frequencies, i.e. frequency-specific functional connectomes. We relate the functional interactions between 91 area pairs to their anatomical connection strength defined in a separate cohort of twenty six subjects. This reveals that anatomical connection strength predicts rhythmic synchronization and vice-versa, in a manner that is specific for frequency bands and for the feedforward versus feedback direction, even if interareal distances are taken into account. These results further our understanding of structure-function relationships in large-scale networks covering different modality-specific brain regions and provide strong constraints on mechanistic models of brain function. Because this approach can be ...
The segregation of callosal and association pathways in the developing visual cortex of the monke... more The segregation of callosal and association pathways in the developing visual cortex of the monkey was studied using the retrograde tracers fast blue and diamidino yellow. Quantitative analysis of the laminar distribution of labeled callosal and association neurons made it possible to reveal the shifting pattern of connections that characterizes the development of these two pathways. In the adult, callosal neurons are restricted to supragranular layers, where they are concentrated at the bottom of layer 3. Association neurons are located both in infra- and supragranular layers. Supragranular layer association neurons are concentrated in layer 2, with limited spread into layer 3 so that there is little overlap with callosal neurons. In the immature brain, callosal neurons are characterized by a tangential distribution that is more widespread than in the adult, while their laminar distribution undergoes little developmental change. Association neurons show two types of changes in thei...
Interactions between top-down and bottom-up processes in the cerebral cortex hold the key to unde... more Interactions between top-down and bottom-up processes in the cerebral cortex hold the key to understanding predictive coding, executive control and a gamut of other brain functions. The underlying circuit mechanism, however, remains poorly understood and represents a major challenge in neuroscience. In the present work we tackled this problem using a large-scale computational model of the primate cortex constrained by new directed and weighted connectivity data. In our model, the interplay between feedforward and feedback signaling depends on the cortical laminar structure and involves complex dynamics across multiple (intra-laminar, inter-laminar, inter-areal and whole cortex) scales. The model was tested by reproducing, and shedding insights into, a wide range of neurophysiological findings about frequency-dependent interactions between visual cortical areas: feedforward pathways are associated with enhanced gamma (30-70 Hz) oscillations, whereas feedback projections selectively m...
Mammals show a wide range of brain sizes, reflecting adaptation to diverse habitats. Comparing in... more Mammals show a wide range of brain sizes, reflecting adaptation to diverse habitats. Comparing interareal cortical networks across brains of different sizes and mammalian orders provides robust information on evolutionarily preserved features and species-specific processing modalities. However, these networks are spatially embedded, directed, and weighted, making comparisons challenging. Using tract tracing data from macaque and mouse, we show the existence of a general organizational principle based on an exponential distance rule (EDR) and cortical geometry, enabling network comparisons within the same model framework. These comparisons reveal the existence of network invariants between mouse and macaque, exemplified in graph motif profiles and connection similarity indices, but also significant differences, such as fractionally smaller and much weaker long-distance connections in the macaque than in mouse. The latter lends credence to the prediction that long-distance cortico-cor...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jun 22, 2016
Tractography based on diffusion MRI offers the promise of characterizing many aspects of long-dis... more Tractography based on diffusion MRI offers the promise of characterizing many aspects of long-distance connectivity in the brain, but requires quantitative validation to assess its strengths and limitations. Here, we evaluate tractography's ability to estimate the presence and strength of connections between areas of macaque neocortex by comparing its results with published data from retrograde tracer injections. Probabilistic tractography was performed on high-quality postmortem diffusion imaging scans from two Old World monkey brains. Tractography connection weights were estimated using a fractional scaling method based on normalized streamline density. We found a correlation between log-transformed tractography and tracer connection weights of r = 0.59, twice that reported in a recent study on the macaque. Using a novel method to estimate interareal connection lengths from tractography streamlines, we regressed out the distance dependence of connection strength and found that...
Primate visual cortex is hierarchically organized. Bottom-up and top-down influences are exerted ... more Primate visual cortex is hierarchically organized. Bottom-up and top-down influences are exerted through distinct frequency channels, as was recently revealed in macaques by correlating inter-areal influences with laminar anatomical projection patterns. Because this anatomical data cannot be obtained in human subjects, we selected seven homologous macaque and human visual areas, and we correlated the macaque laminar projection patterns to human inter-areal directed influences as measured with magnetoencephalography. We show that influences along feedforward projections predominate in the gamma band, whereas influences along feedback projections predominate in the alpha-beta band. Rhythmic inter-areal influences constrain a functional hierarchy of the seven homologous human visual areas that is in close agreement with the respective macaque anatomical hierarchy. Rhythmic influences allow an extension of the hierarchy to 26 human visual areas including uniquely human brain areas. Hier...
We developed a large-scale dynamical model of the macaque neocortex based on recent quantitative ... more We developed a large-scale dynamical model of the macaque neocortex based on recent quantitative connectivity data. A hierarchy of timescales naturally emerges from this system: sensory areas show brief, transient responses to input (appropriate for sensory processing), whereas association areas integrate inputs over time and exhibit persistent activity (suitable for decision-making and working memory). The model displays multiple temporal hierarchies, as evidenced by contrasting responses to visual and somatosensory stimulation. Moreover, slower prefrontal and temporal areas have a disproportionate impact on global brain dynamics. These findings establish for the first time a circuit mechanism for "temporal receptive windows" that are progressively enlarged along the cortical hierarchy, extend the concept of working memory from local to large circuits, and suggest a re-interpretation of functional connectivity measures.
Evolutionary expansion and complexification of the primate cerebral cortex are largely linked to ... more Evolutionary expansion and complexification of the primate cerebral cortex are largely linked to the emergence of the outer subventricular zone (OSVZ), a uniquely structured germinal zone that generates the expanded primate supragranular layers. The primate OSVZ departs from rodent germinal zones in that it includes a higher diversity of precursor types, inter-related in bidirectional non-hierarchical lineages. In addition, primate-specific regulatory mechanisms are operating in primate cortical precursors via the occurrence of novel miRNAs. Here, we propose that the origin and evolutionary importance of the OSVZ is related to genetic changes in multiple regulatory loops and that cell-cycle regulation is a favored target for evolutionary adaptation of the cortex.
It is generally agreed that information flow through the cortex is constrained by a hierarchical ... more It is generally agreed that information flow through the cortex is constrained by a hierarchical architecture. Lack of precise data on areal connectivity leads to indeterminacy of existing models. The authors introduce two quantitative parameters (SLN and FLN) that hold the promise of resolving such indeterminacy. In the visual system, using a very incomplete database, provisional hierarchies are in line with the recent proposal of higher functions of area V1 and suggest a hitherto unsuspected central function of the frontal eye field.
Small-world networks provide an appealing description of cortical architecture owing to their cap... more Small-world networks provide an appealing description of cortical architecture owing to their capacity for integration and segregation combined with an economy of connectivity. Previous reports of low-density interareal graphs and apparent small-world properties are challenged by data that reveal high-density cortical graphs in which economy of connections is achieved by weight heterogeneity and distance-weight correlations. These properties define a model that predicts many binary and weighted features of the cortical network including a core-periphery, a typical feature of self-organizing information processing systems. Feedback and feedforward pathways between areas exhibit a dual counterstream organization, and their integration into local circuits constrains cortical computation. Here, we propose a bow-tie representation of interareal architecture derived from the hierarchical laminar weights of pathways between the high-efficiency dense core and periphery.
Proceedings of the National Academy of Sciences, 2009
The link between cortical precursors G1 duration (TG1) and their mode of division remains a major... more The link between cortical precursors G1 duration (TG1) and their mode of division remains a major unresolved issue of potential importance for regulating corticogenesis. Here, we induced a 25% reduction in TG1 in mouse cortical precursors via forced expression of cyclin D1 and cyclin E1. We found that in utero electroporation-mediated gene transfer transfects a cohort of synchronously cycling precursors, necessitating alternative methods of measuring cell-cycle phases to those classical used. TG1 reduction promotes cell-cycle reentry at the expense of differentiation and increases the self-renewal capacities of Pax6 precursors as well as of Tbr2 basal precursors (BPs). A population level analysis reveals sequential and lineage-specific effects, showing that TG1 reduction: ( i ) promotes Pax6 self-renewing proliferative divisions before promoting divisions wherein Pax6 precursors generate Tbr2 BPs and ( ii ) promotes self-renewing proliferative divisions of Tbr2 precursors at the exp...
Hierarchy is a major organizational principle of the cortex and underscores modern computational ... more Hierarchy is a major organizational principle of the cortex and underscores modern computational theories of cortical function. Consideration of the role of the local microcircuit in the amplification of inputs, leads to the argument that distance dependent changes in the laminar profiles of connectivity constitute the structural signatures of hierarchy. Statistical modeling of these signatures demonstrates that inputs from multiple hierarchical levels to their target areas show remarkable consistency, allowing the construction of a cortical hierarchy based on a principle of hierarchical distance. The statistical modeling that is applied to structure can also be applied to laminar differences in the oscillatory coherence between areas thereby determining a functional hierarchy of the cortex. Close examination of the anatomy of inter-areal connectivity reveals a dual counterstream architecture with well-defined distance-dependent feedback and feedforward pathways in both the supra- a...
Background: The cerebral cortex is divisible into many individual areas, each exhibiting distinct... more Background: The cerebral cortex is divisible into many individual areas, each exhibiting distinct connectivity profi les, architecture, and physiological characteristics. Interactions among cortical areas underlie higher sensory, motor, and cognitive functions. Graph theory provides an important framework for understanding network properties of the interareal weighted and directed connectiv-ity matrix reported in recent studies. Advances: We derive an exponential distance rule that predicts many binary and weighted features of the cortical network, including effi ciency of information transfer, the high specifi city of long-distance compared to short-distance connections, wire length minimization, and the existence of a highly interconnected cortical core. We propose a bow-tie representation of the cortex, which combines these features with hierarchical processing. Outlook: The exponential distance rule has important implications for understanding scaling prop-erties of the cortex a...
What is the relationship between anatomical connection strength and rhythmic synchronization? Sim... more What is the relationship between anatomical connection strength and rhythmic synchronization? Simultaneous recordings of 15 cortical areas in two macaque monkeys show that interareal networks are functionally organized in spatially distinct modules with specific synchronization frequencies, i.e. frequency-specific functional connectomes. We relate the functional interactions between 91 area pairs to their anatomical connection strength defined in a separate cohort of twenty six subjects. This reveals that anatomical connection strength predicts rhythmic synchronization and vice-versa, in a manner that is specific for frequency bands and for the feedforward versus feedback direction, even if interareal distances are taken into account. These results further our understanding of structure-function relationships in large-scale networks covering different modality-specific brain regions and provide strong constraints on mechanistic models of brain function. Because this approach can be ...
The segregation of callosal and association pathways in the developing visual cortex of the monke... more The segregation of callosal and association pathways in the developing visual cortex of the monkey was studied using the retrograde tracers fast blue and diamidino yellow. Quantitative analysis of the laminar distribution of labeled callosal and association neurons made it possible to reveal the shifting pattern of connections that characterizes the development of these two pathways. In the adult, callosal neurons are restricted to supragranular layers, where they are concentrated at the bottom of layer 3. Association neurons are located both in infra- and supragranular layers. Supragranular layer association neurons are concentrated in layer 2, with limited spread into layer 3 so that there is little overlap with callosal neurons. In the immature brain, callosal neurons are characterized by a tangential distribution that is more widespread than in the adult, while their laminar distribution undergoes little developmental change. Association neurons show two types of changes in thei...
Interactions between top-down and bottom-up processes in the cerebral cortex hold the key to unde... more Interactions between top-down and bottom-up processes in the cerebral cortex hold the key to understanding predictive coding, executive control and a gamut of other brain functions. The underlying circuit mechanism, however, remains poorly understood and represents a major challenge in neuroscience. In the present work we tackled this problem using a large-scale computational model of the primate cortex constrained by new directed and weighted connectivity data. In our model, the interplay between feedforward and feedback signaling depends on the cortical laminar structure and involves complex dynamics across multiple (intra-laminar, inter-laminar, inter-areal and whole cortex) scales. The model was tested by reproducing, and shedding insights into, a wide range of neurophysiological findings about frequency-dependent interactions between visual cortical areas: feedforward pathways are associated with enhanced gamma (30-70 Hz) oscillations, whereas feedback projections selectively m...
Mammals show a wide range of brain sizes, reflecting adaptation to diverse habitats. Comparing in... more Mammals show a wide range of brain sizes, reflecting adaptation to diverse habitats. Comparing interareal cortical networks across brains of different sizes and mammalian orders provides robust information on evolutionarily preserved features and species-specific processing modalities. However, these networks are spatially embedded, directed, and weighted, making comparisons challenging. Using tract tracing data from macaque and mouse, we show the existence of a general organizational principle based on an exponential distance rule (EDR) and cortical geometry, enabling network comparisons within the same model framework. These comparisons reveal the existence of network invariants between mouse and macaque, exemplified in graph motif profiles and connection similarity indices, but also significant differences, such as fractionally smaller and much weaker long-distance connections in the macaque than in mouse. The latter lends credence to the prediction that long-distance cortico-cor...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jun 22, 2016
Tractography based on diffusion MRI offers the promise of characterizing many aspects of long-dis... more Tractography based on diffusion MRI offers the promise of characterizing many aspects of long-distance connectivity in the brain, but requires quantitative validation to assess its strengths and limitations. Here, we evaluate tractography's ability to estimate the presence and strength of connections between areas of macaque neocortex by comparing its results with published data from retrograde tracer injections. Probabilistic tractography was performed on high-quality postmortem diffusion imaging scans from two Old World monkey brains. Tractography connection weights were estimated using a fractional scaling method based on normalized streamline density. We found a correlation between log-transformed tractography and tracer connection weights of r = 0.59, twice that reported in a recent study on the macaque. Using a novel method to estimate interareal connection lengths from tractography streamlines, we regressed out the distance dependence of connection strength and found that...
Primate visual cortex is hierarchically organized. Bottom-up and top-down influences are exerted ... more Primate visual cortex is hierarchically organized. Bottom-up and top-down influences are exerted through distinct frequency channels, as was recently revealed in macaques by correlating inter-areal influences with laminar anatomical projection patterns. Because this anatomical data cannot be obtained in human subjects, we selected seven homologous macaque and human visual areas, and we correlated the macaque laminar projection patterns to human inter-areal directed influences as measured with magnetoencephalography. We show that influences along feedforward projections predominate in the gamma band, whereas influences along feedback projections predominate in the alpha-beta band. Rhythmic inter-areal influences constrain a functional hierarchy of the seven homologous human visual areas that is in close agreement with the respective macaque anatomical hierarchy. Rhythmic influences allow an extension of the hierarchy to 26 human visual areas including uniquely human brain areas. Hier...
We developed a large-scale dynamical model of the macaque neocortex based on recent quantitative ... more We developed a large-scale dynamical model of the macaque neocortex based on recent quantitative connectivity data. A hierarchy of timescales naturally emerges from this system: sensory areas show brief, transient responses to input (appropriate for sensory processing), whereas association areas integrate inputs over time and exhibit persistent activity (suitable for decision-making and working memory). The model displays multiple temporal hierarchies, as evidenced by contrasting responses to visual and somatosensory stimulation. Moreover, slower prefrontal and temporal areas have a disproportionate impact on global brain dynamics. These findings establish for the first time a circuit mechanism for "temporal receptive windows" that are progressively enlarged along the cortical hierarchy, extend the concept of working memory from local to large circuits, and suggest a re-interpretation of functional connectivity measures.
Evolutionary expansion and complexification of the primate cerebral cortex are largely linked to ... more Evolutionary expansion and complexification of the primate cerebral cortex are largely linked to the emergence of the outer subventricular zone (OSVZ), a uniquely structured germinal zone that generates the expanded primate supragranular layers. The primate OSVZ departs from rodent germinal zones in that it includes a higher diversity of precursor types, inter-related in bidirectional non-hierarchical lineages. In addition, primate-specific regulatory mechanisms are operating in primate cortical precursors via the occurrence of novel miRNAs. Here, we propose that the origin and evolutionary importance of the OSVZ is related to genetic changes in multiple regulatory loops and that cell-cycle regulation is a favored target for evolutionary adaptation of the cortex.
It is generally agreed that information flow through the cortex is constrained by a hierarchical ... more It is generally agreed that information flow through the cortex is constrained by a hierarchical architecture. Lack of precise data on areal connectivity leads to indeterminacy of existing models. The authors introduce two quantitative parameters (SLN and FLN) that hold the promise of resolving such indeterminacy. In the visual system, using a very incomplete database, provisional hierarchies are in line with the recent proposal of higher functions of area V1 and suggest a hitherto unsuspected central function of the frontal eye field.
Small-world networks provide an appealing description of cortical architecture owing to their cap... more Small-world networks provide an appealing description of cortical architecture owing to their capacity for integration and segregation combined with an economy of connectivity. Previous reports of low-density interareal graphs and apparent small-world properties are challenged by data that reveal high-density cortical graphs in which economy of connections is achieved by weight heterogeneity and distance-weight correlations. These properties define a model that predicts many binary and weighted features of the cortical network including a core-periphery, a typical feature of self-organizing information processing systems. Feedback and feedforward pathways between areas exhibit a dual counterstream organization, and their integration into local circuits constrains cortical computation. Here, we propose a bow-tie representation of interareal architecture derived from the hierarchical laminar weights of pathways between the high-efficiency dense core and periphery.
Proceedings of the National Academy of Sciences, 2009
The link between cortical precursors G1 duration (TG1) and their mode of division remains a major... more The link between cortical precursors G1 duration (TG1) and their mode of division remains a major unresolved issue of potential importance for regulating corticogenesis. Here, we induced a 25% reduction in TG1 in mouse cortical precursors via forced expression of cyclin D1 and cyclin E1. We found that in utero electroporation-mediated gene transfer transfects a cohort of synchronously cycling precursors, necessitating alternative methods of measuring cell-cycle phases to those classical used. TG1 reduction promotes cell-cycle reentry at the expense of differentiation and increases the self-renewal capacities of Pax6 precursors as well as of Tbr2 basal precursors (BPs). A population level analysis reveals sequential and lineage-specific effects, showing that TG1 reduction: ( i ) promotes Pax6 self-renewing proliferative divisions before promoting divisions wherein Pax6 precursors generate Tbr2 BPs and ( ii ) promotes self-renewing proliferative divisions of Tbr2 precursors at the exp...
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