Publications by authors named "Henry Kennedy"

68 Publications

A dopamine gradient controls access to distributed working memory in the large-scale monkey cortex.

Neuron 2021 Sep 15. Epub 2021 Sep 15.

Center for Neural Science, New York University, New York, NY 10003, USA. Electronic address:

Dopamine is required for working memory, but how it modulates the large-scale cortex is unknown. Here, we report that dopamine receptor density per neuron, measured by autoradiography, displays a macroscopic gradient along the macaque cortical hierarchy. This gradient is incorporated in a connectome-based large-scale cortex model endowed with multiple neuron types. The model captures an inverted U-shaped dependence of working memory on dopamine and spatial patterns of persistent activity observed in over 90 experimental studies. Moreover, we show that dopamine is crucial for filtering out irrelevant stimuli by enhancing inhibition from dendrite-targeting interneurons. Our model revealed that an activity-silent memory trace can be realized by facilitation of inter-areal connections and that adjusting cortical dopamine induces a switch from this internal memory state to distributed persistent activity. Our work represents a cross-level understanding from molecules and cell types to recurrent circuit dynamics underlying a core cognitive function distributed across the primate cortex.
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http://dx.doi.org/10.1016/j.neuron.2021.08.024DOI Listing
September 2021

Rare long-range cortical connections enhance human information processing.

Curr Biol 2021 Aug 18. Epub 2021 Aug 18.

Centre for Eudaimonia and Human Flourishing, Linacre College, University of Oxford, Oxford, UK; Department of Psychiatry, University of Oxford, Oxford, UK; Center for Music in the Brain, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address:

What are the key topological features of connectivity critically relevant for generating the dynamics underlying efficient cortical function? A candidate feature that has recently emerged is that the connectivity of the mammalian cortex follows an exponential distance rule, which includes a small proportion of long-range high-weight anatomical exceptions to this rule. Whole-brain modeling of large-scale human neuroimaging data in 1,003 participants offers the unique opportunity to create two models, with and without long-range exceptions, and explicitly study their functional consequences. We found that rare long-range exceptions are crucial for significantly improving information processing. Furthermore, modeling in a simplified ring architecture shows that this improvement is greatly enhanced by the turbulent regime found in empirical neuroimaging data. Overall, the results provide strong empirical evidence for the immense functional benefits of long-range exceptions combined with turbulence for information processing.
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http://dx.doi.org/10.1016/j.cub.2021.07.064DOI Listing
August 2021

The Role of Unimodal Feedback Pathways in Gender Perception During Activation of Voice and Face Areas.

Front Syst Neurosci 2021 28;15:669256. Epub 2021 May 28.

Univ Lyon, Université Claude Bernard Lyon 1, INSERM, Stem Cell and Brain Research Institute U1208, Bron, France.

Cross-modal effects provide a model framework for investigating hierarchical inter-areal processing, particularly, under conditions where unimodal cortical areas receive contextual feedback from other modalities. Here, using complementary behavioral and brain imaging techniques, we investigated the functional networks participating in face and voice processing during gender perception, a high-level feature of voice and face perception. Within the framework of a signal detection decision model, Maximum likelihood conjoint measurement (MLCM) was used to estimate the contributions of the face and voice to gender comparisons between pairs of audio-visual stimuli in which the face and voice were independently modulated. Top-down contributions were varied by instructing participants to make judgments based on the gender of either the face, the voice or both modalities ( = 12 for each task). Estimated face and voice contributions to the judgments of the stimulus pairs were not independent; both contributed to all tasks, but their respective weights varied over a 40-fold range due to top-down influences. Models that best described the modal contributions required the inclusion of two different top-down interactions: (i) an interaction that depended on gender congruence across modalities (i.e., difference between face and voice modalities for each stimulus); (ii) an interaction that depended on the within modalities' gender magnitude. The significance of these interactions was task dependent. Specifically, gender congruence interaction was significant for the face and voice tasks while the gender magnitude interaction was significant for the face and stimulus tasks. Subsequently, we used the same stimuli and related tasks in a functional magnetic resonance imaging (fMRI) paradigm ( = 12) to explore the neural correlates of these perceptual processes, analyzed with Dynamic Causal Modeling (DCM) and Bayesian Model Selection. Results revealed changes in effective connectivity between the unimodal Fusiform Face Area (FFA) and Temporal Voice Area (TVA) in a fashion that paralleled the face and voice behavioral interactions observed in the psychophysical data. These findings explore the role in perception of multiple unimodal parallel feedback pathways.
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http://dx.doi.org/10.3389/fnsys.2021.669256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194406PMC
May 2021

The nonhuman primate neuroimaging and neuroanatomy project.

Neuroimage 2021 04 20;229:117726. Epub 2021 Jan 20.

Department of Neuroscience, Washington University Medical School, St Louis, MO USA.

Multi-modal neuroimaging projects such as the Human Connectome Project (HCP) and UK Biobank are advancing our understanding of human brain architecture, function, connectivity, and their variability across individuals using high-quality non-invasive data from many subjects. Such efforts depend upon the accuracy of non-invasive brain imaging measures. However, 'ground truth' validation of connectivity using invasive tracers is not feasible in humans. Studies using nonhuman primates (NHPs) enable comparisons between invasive and non-invasive measures, including exploration of how "functional connectivity" from fMRI and "tractographic connectivity" from diffusion MRI compare with long-distance connections measured using tract tracing. Our NonHuman Primate Neuroimaging & Neuroanatomy Project (NHP_NNP) is an international effort (6 laboratories in 5 countries) to: (i) acquire and analyze high-quality multi-modal brain imaging data of macaque and marmoset monkeys using protocols and methods adapted from the HCP; (ii) acquire quantitative invasive tract-tracing data for cortical and subcortical projections to cortical areas; and (iii) map the distributions of different brain cell types with immunocytochemical stains to better define brain areal boundaries. We are acquiring high-resolution structural, functional, and diffusion MRI data together with behavioral measures from over 100 individual macaques and marmosets in order to generate non-invasive measures of brain architecture such as myelin and cortical thickness maps, as well as functional and diffusion tractography-based connectomes. We are using classical and next-generation anatomical tracers to generate quantitative connectivity maps based on brain-wide counting of labeled cortical and subcortical neurons, providing ground truth measures of connectivity. Advanced statistical modeling techniques address the consistency of both kinds of data across individuals, allowing comparison of tracer-based and non-invasive MRI-based connectivity measures. We aim to develop improved cortical and subcortical areal atlases by combining histological and imaging methods. Finally, we are collecting genetic and sociality-associated behavioral data in all animals in an effort to understand how genetic variation shapes the connectome and behavior.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079967PMC
April 2021

Brain connectomes come of age.

Curr Opin Neurobiol 2020 12 1;65:152-161. Epub 2020 Dec 1.

Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France; Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences (CAS) Key Laboratory of Primate Neurobiology, CAS, Shanghai 200031, China.

Databases of consistent, directed- and weighted inter-areal connectivity for mouse, macaque and marmoset monkeys have recently become available and begun to be used to build structural and dynamical models. A structural hierarchy can be defined based by laminar patterns of cortical connections. A large-scale dynamical model of the macaque cortex endowed with a laminar structure accounts for empirically observed frequency-modulated interplay between bottom-up and top-down processes. Signal propagation in the model with spiking neurons displays a threshold of stimulus amplitude for the activity to gain access to the prefrontal cortex, reminiscent of the ignition phenomenon associated with conscious perception. These two examples illustrate how connectomics inform structurally based dynamic models of multi-regional brain systems. Theory raises novel questions for future anatomical and physiological empirical research, in a back-and-forth collaboration between experimentalists and theorists. Directed- and weighted inter-areal cortical connectivity matrices of macaque, marmoset and mouse exhibit similarities as well as marked differences. The new connectomic data provide quantitative information for structural and dynamical modeling of multi-regional cortical circuit providing insight to the global cortical function. Quantification of cortical hierarchy guides investigations of interplay between bottom-up and top-down information processes.
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http://dx.doi.org/10.1016/j.conb.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770070PMC
December 2020

Radial Migration Dynamics Is Modulated in a Laminar and Area-Specific Manner During Primate Corticogenesis.

Front Cell Dev Biol 2020 16;8:588814. Epub 2020 Oct 16.

University of Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.

The orderly radial migration of cortical neurons from their birthplace in the germinal zones to their final destination in the cortical plate is a prerequisite for the functional assembly of microcircuits in the neocortex. Rodent and primate corticogenesis differ both quantitatively and qualitatively, particularly with respect to the generation of neurons of the supragranular layers. Marked area differences in the outer subventricular zone progenitor cell density impact the radial glia scaffold compactness which is likely to induce area differences in radial migration strategy. Here, we describe specific features of radial migration in the non-human primate, including the absence of the premigratory multipolar stage found in rodents. approaches in the embryonic macaque monkey visual cortex, show that migrating neurons destined for supragranular and infragranular layers exhibit significant differences in morphology and velocity. Migrating neurons destined for the supragranular layers show a more complex bipolar morphology and higher motility rates than do infragranular neurons. There are area differences in the gross morphology and membrane growth behavior of the tip of the leading process. In the subplate compartment migrating neurons destined for the supragranular layers of presumptive area 17 exhibit radial constrained trajectories and leading processes with filopodia, which contrast with the meandering trajectories and leading processes capped by lamellipodia observed in the migrating neurons destined for presumptive area 18. Together these results present evidence that migrating neurons may exhibit autonomy and in addition show marked area-specific differences. We hypothesize that the low motility and high radial trajectory of area 17 migrating neurons contribute to the unique structural features of this area.
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http://dx.doi.org/10.3389/fcell.2020.588814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596244PMC
October 2020

Determinants of primate neurogenesis and the deployment of top-down generative networks in the cortical hierarchy.

Curr Opin Neurobiol 2021 02 21;66:69-76. Epub 2020 Oct 21.

University of Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron 69500, France. Electronic address:

What I cannot create I do not understand - Richard Feynman 1978 Because primate cortical development exhibits numerous specific features, the mouse is an imperfect model for human cortical development. Expansion of supragranular neurons is an evolutionary feature characterizing the primate cortex. Increased production of supragranular neurons is supported by a germinal zone innovation of the primate cortex: the Outer SubVentricular Zone, which along with supragranular neurons constitute privileged targets of primate brain-specific gene evolution. The resulting cell-type diversity of human supragranular neurons link cell and molecular evolutionary changes in progenitors with the emergence of distinctive architectural features in the primate cortex. We propose that these changes are required for the expansion of the primate cortical hierarchy deploying top-down generative networks with potentially important consequences for the neurobiology of human psychiatric disorders.
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http://dx.doi.org/10.1016/j.conb.2020.09.012DOI Listing
February 2021

Cortical hierarchy, dual counterstream architecture and the importance of top-down generative networks.

Neuroimage 2021 01 21;225:117479. Epub 2020 Oct 21.

Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France; Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences (CAS) Key Laboratory of Primate Neurobiology, CAS, Shanghai 200031, China. Electronic address:

Hierarchy is a major organizational principle of the cortex and underscores modern computational theories of cortical function. The local microcircuit amplifies long-distance inter-areal input, which show distance-dependent changes in their laminar profiles. Statistical modeling of these changes in laminar profiles 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- and infragranular layers, suggesting a multiplicity of feedback pathways with well-defined functional properties. These findings are consistent with feedback connections providing a generative network involved in a wide range of cognitive functions. A dynamical model constrained by connectivity data sheds insight into the experimentally observed signatures of frequency-dependent Granger causality for feedforward versus feedback signaling. Concerted experiments capitalizing on recent technical advances and combining tract-tracing, high-resolution fMRI, optogenetics and mathematical modeling hold the promise of a much improved understanding of lamina-constrained mechanisms of neural computation and cognition. However, because inter-areal interactions involve cortical layers that have been the target of important evolutionary changes in the primate lineage, these investigations will need to include human and non-human primate comparisons.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244994PMC
January 2021

Evolution of the human brain.

Science 2020 07;369(6503):506-507

University of Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France.

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http://dx.doi.org/10.1126/science.abd1840DOI Listing
July 2020

Towards HCP-Style macaque connectomes: 24-Channel 3T multi-array coil, MRI sequences and preprocessing.

Neuroimage 2020 07 8;215:116800. Epub 2020 Apr 8.

Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan. Electronic address:

Macaque monkeys are an important animal model where invasive investigations can lead to a better understanding of the cortical organization of primates including humans. However, the tools and methods for noninvasive image acquisition (e.g. MRI RF coils and pulse sequence protocols) and image data preprocessing have lagged behind those developed for humans. To resolve the structural and functional characteristics of the smaller macaque brain, high spatial, temporal, and angular resolutions combined with high signal-to-noise ratio are required to ensure good image quality. To address these challenges, we developed a macaque 24-channel receive coil for 3-T MRI with parallel imaging capabilities. This coil enables adaptation of the Human Connectome Project (HCP) image acquisition protocols to the in-vivo macaque brain. In addition, we adapted HCP preprocessing methods to the macaque brain, including spatial minimal preprocessing of structural, functional MRI (fMRI), and diffusion MRI (dMRI). The coil provides the necessary high signal-to-noise ratio and high efficiency in data acquisition, allowing four- and five-fold accelerations for dMRI and fMRI. Automated FreeSurfer segmentation of cortex, reconstruction of cortical surface, removal of artefacts and nuisance signals in fMRI, and distortion correction of dMRI all performed well, and the overall quality of basic neurobiological measures was comparable with those for the HCP. Analyses of functional connectivity in fMRI revealed high sensitivity as compared with those from publicly shared datasets. Tractography-based connectivity estimates correlated with tracer connectivity similarly to that achieved using ex-vivo dMRI. The resulting HCP-style in vivo macaque MRI data show considerable promise for analyzing cortical architecture and functional and structural connectivity using advanced methods that have previously only been available in studies of the human brain.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116593PMC
July 2020

Cerebral cortical folding, parcellation, and connectivity in humans, nonhuman primates, and mice.

Proc Natl Acad Sci U S A 2019 Dec 23. Epub 2019 Dec 23.

Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110.

Advances in neuroimaging and neuroanatomy have yielded major insights concerning fundamental principles of cortical organization and evolution, thus speaking to how well different species serve as models for human brain function in health and disease. Here, we focus on cortical folding, parcellation, and connectivity in mice, marmosets, macaques, and humans. Cortical folding patterns vary dramatically across species, and individual variability in cortical folding increases with cortical surface area. Such issues are best analyzed using surface-based approaches that respect the topology of the cortical sheet. Many aspects of cortical organization can be revealed using 1 type of information (modality) at a time, such as maps of cortical myelin content. However, accurate delineation of the entire mosaic of cortical areas requires a multimodal approach using information about function, architecture, connectivity, and topographic organization. Comparisons across the 4 aforementioned species reveal dramatic differences in the total number and arrangement of cortical areas, particularly between rodents and primates. Hemispheric variability and bilateral asymmetry are most pronounced in humans, which we evaluated using a high-quality multimodal parcellation of hundreds of individuals. Asymmetries include modest differences in areal size but not in areal identity. Analyses of cortical connectivity using anatomical tracers reveal highly distributed connectivity and a wide range of connection weights in monkeys and mice; indirect measures using functional MRI suggest a similar pattern in humans. Altogether, a multifaceted but integrated approach to exploring cortical organization in primate and nonprimate species provides complementary advantages and perspectives.
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http://dx.doi.org/10.1073/pnas.1902299116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936571PMC
December 2019

Unique Features of Subcortical Circuits in a Macaque Model of Congenital Blindness.

Cereb Cortex 2020 03;30(3):1407-1421

Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France.

There is an extensive modification of the functional organization of the brain in the congenital blind human, although there is little understanding of the structural underpinnings of these changes. The visual system of macaque has been extensively characterized both anatomically and functionally. We have taken advantage of this to examine the influence of congenital blindness in a macaque model of developmental anophthalmia. Developmental anophthalmia in macaque effectively removes the normal influence of the thalamus on cortical development leading to an induced "hybrid cortex (HC)" combining features of primary visual and extrastriate cortex. Here we show that retrograde tracers injected in early visual areas, including HC, reveal a drastic reduction of cortical projections of the reduced lateral geniculate nucleus. In addition, there is an important expansion of projections from the pulvinar complex to the HC, compared to the controls. These findings show that the functional consequences of congenital blindness need to be considered in terms of both modifications of the interareal cortical network and the ascending visual pathways.
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http://dx.doi.org/10.1093/cercor/bhz175DOI Listing
March 2020

Refinement of the Primate Corticospinal Pathway During Prenatal Development.

Cereb Cortex 2020 03;30(2):656-671

Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute, Bron, France.

Perturbation of the developmental refinement of the corticospinal (CS) pathway leads to motor disorders. While non-primate developmental refinement is well documented, in primates invasive investigations of the developing CS pathway have been confined to neonatal and postnatal stages when refinement is relatively modest. Here, we investigated the developmental changes in the distribution of CS projection neurons in cynomolgus monkey (Macaca fascicularis). Injections of retrograde tracer at cervical levels of the spinal cord at embryonic day (E) 95 and E105 show that: (i) areal distribution of back-labeled neurons is more extensive than in the neonate and dense labeling is found in prefrontal, limbic, temporal, and occipital cortex; (ii) distributions of contralateral and ipsilateral projecting CS neurons are comparable in terms of location and numbers of labeled neurons, in contrast to the adult where the contralateral projection is an order of magnitude higher than the ipsilateral projection. Findings from one largely restricted injection suggest a hitherto unsuspected early innervation of the gray matter. In the fetus there was in addition dense labeling in the central nucleus of the amygdala, the hypothalamus, the subthalamic nucleus, and the adjacent region of the zona incerta, subcortical structures with only minor projections in the adult control.
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http://dx.doi.org/10.1093/cercor/bhz116DOI Listing
March 2020

The sensory thalamus and visual midbrain in mouse lemurs.

J Comp Neurol 2019 10 8;527(15):2599-2611. Epub 2019 Apr 8.

Department of Psychology, Vanderbilt University, Nashville, Tennessee.

Mouse lemurs are the smallest of extant primates and are thought to resemble early primates in many ways. We provide histological descriptions of the major sensory nuclei of the dorsal thalamus and the superior colliculus (SC) of mouse lemurs (Microcebus murinus). The dorsal lateral geniculate nucleus has the six layers typical of strepsirrhine primates, with matching pairs of magnocellular, parvocellular, and koniocellular layers, one of each pair for each eye. Unlike most primates, magnocellular and parvocellular layers exhibit only small differences in cell size. All layers express vesicular glutamate transporter 2 (VGLUT2), reflecting terminations of retinal inputs, and the expression of VGLUT2 is much less dense in the koniocellular layers. Parvalbumin is densely expressed in all layers, while SMI-32 is densely expressed only in the magnocellular layers. The adjoining pulvinar complex has a posterior nucleus with strong VGLUT2 expression, reflecting terminations from the SC. The SC is laminated with dense expression of VGLUT2 in the upper superficial gray layer, reflecting terminations from the retina. The ventral (MGNv), medial, and dorsal divisions of the medial geniculate complex are only moderately differentiated, although patches of dense VGLUT2 expression are found along the outer border of MGNv. The ventroposterior nucleus has darkly stained cells in Nissl stained sections, and narrow septa separating patchy regions of dense VGLUT2 expression that likely represent different body parts. Overall, these structures resemble those in other strepsirrhine primates, although they are smaller, with the sensory nuclei appearing to occupy proportionately more of the dorsal thalamus than in larger primates.
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http://dx.doi.org/10.1002/cne.24693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688912PMC
October 2019

Bridging the Gap between Mechanics and Genetics in Cortical Folding: ECM as a Major Driving Force.

Neuron 2018 08;99(4):625-627

Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France. Electronic address:

Folding of the cerebral cortex results from interrelated biological and mechanical processes that are incompletely understood. In this issue, Long et al. identify the key roles of HAPLN1, lumican, collagen I, and HA in relationship with changes in tissue stiffness.
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http://dx.doi.org/10.1016/j.neuron.2018.08.012DOI Listing
August 2018

Neural circuits for long-range color filling-in.

Neuroimage 2018 11 3;181:30-43. Epub 2018 Jul 3.

Univ Lyon, Université, Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500, Bron, France. Electronic address:

Surface color appearance depends on both local surface chromaticity and global context. How are these inter-dependencies supported by cortical networks? Combining functional imaging and psychophysics, we examined if color from long-range filling-in engages distinct pathways from responses caused by a field of uniform chromaticity. We find that color from filling-in is best classified and best correlated with appearance by two dorsal areas, V3A and V3B/KO. In contrast, a field of uniform chromaticity is best classified by ventral areas hV4 and LO. Dynamic causal modeling revealed feedback modulation from area V3A to areas V1 and LO for filling-in, contrasting with feedback from LO modulating areas V1 and V3A for a matched uniform chromaticity. These results indicate a dorsal stream role in color filling-in via feedback modulation of area V1 coupled with a cross-stream modulation of ventral areas suggesting that local and contextual influences on color appearance engage distinct neural networks.
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http://dx.doi.org/10.1016/j.neuroimage.2018.06.083DOI Listing
November 2018

How Areal Specification Shapes the Local and Interareal Circuits in a Macaque Model of Congenital Blindness.

Cereb Cortex 2018 08;28(8):3017-3034

Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.

There is little understanding of the structural underpinnings of the functional reorganization of the cortex in the congenitally blind human. Taking advantage of the extensive characterization of the macaque visual system, we examine in macaque the influence of congenital blindness resulting from the removal of the retina during in utero development. This effectively removes the normal influence of the thalamus on cortical development leading to an induced hybrid cortex (HC) combining features of primary visual and extrastriate cortex. Retrograde tracers injected in HC reveal a local, intrinsic connectivity characteristic of higher order areas and show that the HC receives a uniquely strong, purely feedforward projection from striate cortex but no ectopic inputs, except from subiculum, and entorhinal cortex. Statistical modeling of quantitative connectivity data shows that HC is relatively high in the cortical hierarchy and receives a reinforced input from ventral stream areas while the overall organization of the functional streams are conserved. The directed and weighted anophthalmic cortical graph from the present study can be used to construct dynamic and structural models. These findings show how the sensory periphery governs cortical phenotype and reveal the importance of developmental arealization for understanding the functional reorganization in congenital blindness.
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http://dx.doi.org/10.1093/cercor/bhy125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041985PMC
August 2018

Architectonic features and relative locations of primary sensory and related areas of neocortex in mouse lemurs.

J Comp Neurol 2019 02 26;527(3):625-639. Epub 2018 Apr 26.

Department of Psychology, Vanderbilt University, Nashville, TN, 37240.

Mouse lemurs are the smallest of the living primates, and are members of the understudied radiation of strepsirrhine lemurs of Madagascar. They are thought to closely resemble the ancestral primates that gave rise to present day primates. Here we have used multiple histological and immunochemical methods to identify and characterize sensory areas of neocortex in four brains of adult lemurs obtained from a licensed breeding colony. We describe the laminar features for the primary visual area (V1), the secondary visual area (V2), the middle temporal visual area (MT) and area prostriata, somatosensory areas S1(3b), 3a, and area 1, the primary motor cortex (M1), and the primary auditory cortex (A1). V1 has "blobs" with "nonblob" surrounds, providing further evidence that this type of modular organization might have evolved early in the primate lineage to be retained in all extant primates. The laminar organization of V1 further supports the view that sublayers of layer 3 of primates have been commonly misidentified as sublayers of layer 4. S1 (area 3b) is proportionately wider than the elongated area observed in anthropoid primates, and has disruptions that may distinguish representations of the hand, face, teeth, and tongue. Primary auditory cortex is located in the upper temporal cortex and may include a rostral area, R, in addition to A1. The resulting architectonic maps of cortical areas in mouse lemurs can usefully guide future studies of cortical connectivity and function.
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http://dx.doi.org/10.1002/cne.24419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109619PMC
February 2019

The Mouse Cortical Connectome, Characterized by an Ultra-Dense Cortical Graph, Maintains Specificity by Distinct Connectivity Profiles.

Neuron 2018 02;97(3):698-715.e10

Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110-1093, USA. Electronic address:

The inter-areal wiring pattern of the mouse cerebral cortex was analyzed in relation to a refined parcellation of cortical areas. Twenty-seven retrograde tracer injections were made in 19 areas of a 47-area parcellation of the mouse neocortex. Flat mounts of the cortex and multiple histological markers enabled detailed counts of labeled neurons in individual areas. The observed log-normal distribution of connection weights to each cortical area spans 5 orders of magnitude and reveals a distinct connectivity profile for each area, analogous to that observed in macaques. The cortical network has a density of 97%, considerably higher than the 66% density reported in macaques. A weighted graph analysis reveals a similar global efficiency but weaker spatial clustering compared with that reported in macaques. The consistency, precision of the connectivity profile, density, and weighted graph analysis of the present data differ significantly from those obtained in earlier studies in the mouse.
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http://dx.doi.org/10.1016/j.neuron.2017.12.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958229PMC
February 2018

The logistics of afferent cortical specification in mice and men.

Semin Cell Dev Biol 2018 04 31;76:112-119. Epub 2017 Aug 31.

Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France. Electronic address:

The mechanisms shaping areal specification in the neocortex have been the focus of a sustained interest over the past three decades. Studies in rodents have provided insight in the interplay between intrinsic genetic mechanisms and extrinsic inputs relayed to the cortex by thalamocortical axons. Here we focus on the exploration of the developing primate visual system which points to embryonic thalamic axons exerting a profound, early instructive role on arealisation in the primate cortex, via an influence on cortical progenitor cell-cycle and mode of division.
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http://dx.doi.org/10.1016/j.semcdb.2017.08.047DOI Listing
April 2018

Feedforward and feedback frequency-dependent interactions in a large-scale laminar network of the primate cortex.

Sci Adv 2016 Nov 16;2(11):e1601335. Epub 2016 Nov 16.

Center for Neural Science, New York University (NYU), New York, NY 10003, USA.; NYU-East China Normal University Institute for Brain and Cognitive Science, NYU Shanghai, Shanghai, China.

Interactions between top-down and bottom-up processes in the cerebral cortex hold the key to understanding attentional processes, predictive coding, executive control, and a gamut of other brain functions. However, the underlying circuit mechanism remains poorly understood and represents a major challenge in neuroscience. We approached 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 (intralaminar, interlaminar, interareal, and whole cortex) scales. The model was tested by reproducing, as well as providing insights into, a wide range of neurophysiological findings about frequency-dependent interactions between visual cortical areas, including the observation that feedforward pathways are associated with enhanced gamma (30 to 70 Hz) oscillations, whereas feedback projections selectively modulate alpha/low-beta (8 to 15 Hz) oscillations. Furthermore, the model reproduces a functional hierarchy based on frequency-dependent Granger causality analysis of interareal signaling, as reported in recent monkey and human experiments, and suggests a mechanism for the observed context-dependent hierarchy dynamics. Together, this work highlights the necessity of multiscale approaches and provides a modeling platform for studies of large-scale brain circuit dynamics and functions.
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http://dx.doi.org/10.1126/sciadv.1601335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5262462PMC
November 2016

Spatial Embedding and Wiring Cost Constrain the Functional Layout of the Cortical Network of Rodents and Primates.

PLoS Biol 2016 07 21;14(7):e1002512. Epub 2016 Jul 21.

Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem-cell and Brain Research Institute U1208, Bron, France.

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-cortical connections could be very weak in the much-expanded human cortex, implying an increased susceptibility to disconnection syndromes such as Alzheimer disease and schizophrenia. Finally, our data from tracer experiments involving only gray matter connections in the primary visual areas of both species show that an EDR holds at local scales as well (within 1.5 mm), supporting the hypothesis that it is a universally valid property across all scales and, possibly, across the mammalian class.
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http://dx.doi.org/10.1371/journal.pbio.1002512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956175PMC
July 2016

Using Diffusion Tractography to Predict Cortical Connection Strength and Distance: A Quantitative Comparison with Tracers in the Monkey.

J Neurosci 2016 06;36(25):6758-70

Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri 63110.

Unlabelled: 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 the correlation between tractography and tracers remains positive, albeit substantially reduced. Altogether, these observations provide a valuable, data-driven perspective on both the strengths and limitations of tractography for analyzing interareal corticocortical connectivity in nonhuman primates and a framework for assessing future tractography methodological refinements objectively.

Significance Statement: Tractography based on diffusion MRI has great potential for a variety of applications, including estimation of comprehensive maps of neural connections in the brain ("connectomes"). Here, we describe methods to assess quantitatively tractography's performance in detecting interareal cortical connections and estimating connection strength by comparing it against published results using neuroanatomical tracers. We found the correlation of tractography's estimated connection strengths versus tracer to be twice that of a previous study. Using a novel method for calculating interareal cortical distances, we show that tractography-based estimates of connection strength have useful predictive power beyond just interareal separation. By freely sharing these methods and datasets, we provide a valuable resource for future studies in cortical connectomics.
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http://dx.doi.org/10.1523/JNEUROSCI.0493-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916250PMC
June 2016

Subtype-Specific Genes that Characterize Subpopulations of Callosal Projection Neurons in Mouse Identify Molecularly Homologous Populations in Macaque Cortex.

Cereb Cortex 2017 Mar;27(3):1817-1830

Department of Stem Cell and Regenerative Biology, Center for Brain Science, and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.

Callosal projection neurons (CPN) interconnect the neocortical hemispheres via the corpus callosum and are implicated in associative integration of multimodal information. CPN have undergone differential evolutionary elaboration, leading to increased diversity of cortical neurons-and more extensive and varied connections in neocortical gray and white matter-in primates compared with rodents. In mouse, distinct sets of genes are enriched in discrete subpopulations of CPN, indicating the molecular diversity of rodent CPN. Elements of rodent CPN functional and organizational diversity might thus be present in the further elaborated primate cortex. We address the hypothesis that genes controlling mouse CPN subtype diversity might reflect molecular patterns shared among mammals that arose prior to the divergence of rodents and primates. We find that, while early expression of the examined CPN-enriched genes, and postmigratory expression of these CPN-enriched genes in deep layers are highly conserved (e.g., Ptn, Nnmt, Cited2, Dkk3), in contrast, the examined genes expressed by superficial layer CPN show more variable levels of conservation (e.g., EphA3, Chn2). These results suggest that there has been evolutionarily differential retraction and elaboration of superficial layer CPN subpopulations between mouse and macaque, with independent derivation of novel populations in primates. Together, these data inform future studies regarding CPN subpopulations that are unique to primates and rodents, and indicate putative evolutionary relationships.
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http://dx.doi.org/10.1093/cercor/bhw023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317451PMC
March 2017

Brain structure and dynamics across scales: in search of rules.

Curr Opin Neurobiol 2016 04 8;37:92-98. Epub 2016 Feb 8.

Stem Cell and Brain Research Institute, INSERM U1208, 69500 Bron, France; Université de Lyon, Université Lyon I, 69003 Lyon, France.

Louis Henry Sullivan, the father of skyscrapers, famously stated 'Form ever follows function'. In this short review, we will focus on the relationship between form (structure) and function (dynamics) in the brain. We summarize recent advances on the quantification of directed- and weighted-mesoscopic connectivity of mammalian cortex, the exponential distance rule for mesoscopic and microscopic circuit wiring, a spatially embedded random model of inter-areal cortical networks, and a large-scale dynamical circuit model of money's cortex that gives rise to a hierarchy of timescales. These findings demonstrate that inter-areal cortical networks are dense (hence such concepts as 'small-world' need to be refined when applied to the brain), spatially dependent (therefore purely topological approach of graph theory has limited applicability) and heterogeneous (consequently cortical areas cannot be treated as identical 'nodes').
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http://dx.doi.org/10.1016/j.conb.2015.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029120PMC
April 2016

Alpha-Beta and Gamma Rhythms Subserve Feedback and Feedforward Influences among Human Visual Cortical Areas.

Neuron 2016 Jan;89(2):384-97

1Ernst Strungmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Deutschordenstraße 46, 60528 Frankfurt, Germany

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. Hierarchical levels of ventral- and dorsal-stream visual areas are differentially affected by inter-areal influences in the alpha-beta band.
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http://dx.doi.org/10.1016/j.neuron.2015.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871751PMC
January 2016

A Large-Scale Circuit Mechanism for Hierarchical Dynamical Processing in the Primate Cortex.

Neuron 2015 Oct 1;88(2):419-31. Epub 2015 Oct 1.

Center for Neural Science, New York University, New York, NY 10003, USA; NYU-ECNU Institute of Brain and Cognitive Science, NYU Shanghai, Shanghai 200122, China. Electronic address:

We developed a large-scale dynamical model of the macaque neocortex, which is based on recently acquired directed- and weighted-connectivity data from tract-tracing experiments, and which incorporates heterogeneity across areas. 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 versus somatosensory stimulation. Moreover, slower prefrontal and temporal areas have a disproportionate impact on global brain dynamics. These findings establish a circuit mechanism for "temporal receptive windows" that are progressively enlarged along the cortical hierarchy, suggest an extension of time integration in decision making from local to large circuits, and should prompt a re-evaluation of the analysis of functional connectivity (measured by fMRI or electroencephalography/magnetoencephalography) by taking into account inter-areal heterogeneity.
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http://dx.doi.org/10.1016/j.neuron.2015.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630024PMC
October 2015

Unsupervised lineage-based characterization of primate precursors reveals high proliferative and morphological diversity in the OSVZ.

J Comp Neurol 2016 Feb 7;524(3):535-63. Epub 2015 Jul 7.

Stem Cell and Brain Research Institute, INSERM U846, 69500, Bron, France.

Generation of the primate cortex is characterized by the diversity of cortical precursors and the complexity of their lineage relationships. Recent studies have reported miscellaneous precursor types based on observer classification of cell biology features including morphology, stemness, and proliferative behavior. Here we use an unsupervised machine learning method for Hidden Markov Trees (HMTs), which can be applied to large datasets to classify precursors on the basis of morphology, cell-cycle length, and behavior during mitosis. The unbiased lineage analysis automatically identifies cell types by applying a lineage-based clustering and model-learning algorithm to a macaque corticogenesis dataset. The algorithmic results validate previously reported observer classification of precursor types and show numerous advantages: It predicts a higher diversity of progenitors and numerous potential transitions between precursor types. The HMT model can be initialized to learn a user-defined number of distinct classes of precursors. This makes it possible to 1) reveal as yet undetected precursor types in view of exploring the significant features of precursors with respect to specific cellular processes; and 2) explore specific lineage features. For example, most precursors in the experimental dataset exhibit bidirectional transitions. Constraining the directionality in the HMT model leads to a reduction in precursor diversity following multiple divisions, thereby suggesting that one impact of bidirectionality in corticogenesis is to maintain precursor diversity. In this way we show that unsupervised lineage analysis provides a valuable methodology for investigating fundamental features of corticogenesis.
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http://dx.doi.org/10.1002/cne.23820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758405PMC
February 2016

The outer subventricular zone and primate-specific cortical complexification.

Neuron 2015 Feb;85(4):683-94

Neuroscience Research Institute and Dept Cellular Molecular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuron.2014.12.060DOI Listing
February 2015
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