Biology subjects

Kennedy, H.

Publications and source records attributed to Kennedy, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Iterative co-creation of harmonized human and non-human primate cellular and structural ontologies and 3D common coordinate frameworks for the basal ganglia

A major goal of the BRAIN Initiative Cell Atlas Network (BICAN) is to create a suite of foundational reference cell atlases and associated standards for human and non-human primate brains. Central to this goal is the creation of cross-species harmonized cellular taxonomies and structural parcellations with formal ontologies that can be mapped into 3D reference frameworks bridging neuroimaging and cellular and histological resolutions. We describe here an iterative approach, focused initially on the basal ganglia, to co-create structural and cellular ontologies in human, macaque and marmoset brains, including a Harmonized Ontology of Mammalian Brain Anatomy (HOMBA), and to map and refine structural parcellations into neuroimaging-based common coordinate frameworks. These references provide the framework for documenting and mapping all experimental sampling in BICAN, allowing analyses of cellular and molecular variation as a function of topographic position, and enabling comparisons of cellular, molecular and neuroimaging-based functional variation within and between primate species. HighlightsO_LIA hierarchical Harmonized Ontology of Mammalian Brain Anatomy (HOMBA) covering 2348 structures C_LIO_LIHOMBA-annotated 3D common coordinate frameworks (CCFs) of the basal ganglia across species C_LIO_LIHistologically informed 3D parcellation/atlas of 280 human subcortical structures indexed by HOMBA C_LIO_LIMapping and integration of structural, cellular and functional data with HOMBA and CCFs C_LI

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bioRxiv2025

Three cortical streams for somatosensory information processing

AbstractThe somatosensory cortex processes information hierarchically, transforming sensory input into appropriate responses. This hierarchy, in turn, provides a fundamental principle for the organization of anatomical and functional properties across the somatosensory cortex. While the local somatosensory hierarchy has been studied, a comprehensive model that fully illustrates somatosensory information transmission in fine detail remains lacking. In this study, we examine multimodal connectivity patterns of the entire macaque somatosensory cortex by integrating the information from receptor covariance (RC) and structural (SC) or functional connectivity (FC). Our findings not only reveal the hierarchical relationships but also propose a model of somatosensory processing streams. In this model, area 3bl serves as the initial cortical stage for somatosensory signals, projecting to areas 3al, 1, and 2. From there, somatosensory signals follow three major pathways: ventrally to the SII complex, medially to the medial SI and TSA, and posteriorly to somatosensory association areas in the parietal lobe. Further analysis shows that RC is not only closely linked to SC and FC but in addition displays unique characteristics that likely relate to the hierarchical processing across sensory modalities. This study deepens our understanding of brain connectivity patterns across different modalities and links the structural, chemoarchitectonic, and functional organization of the macaque somatosensory cortex.

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bioRxiv2024

Charting Cortical-Layer Specific Area Boundaries Using Gibbs Ringing Attenuated T1w/T2w-FLAIR Myelin MRI

Cortical areas have traditionally been defined by their distinctive layer cyto- and/or myelo- architecture using postmortem histology. Recent studies have delineated many areas by measuring overall cortical myelin content and its spatial gradients using the T1w/T2w ratio MRI in living primates, including humans. While T1w/T2w studies of areal transitions might benefit from using the layer profile of this myelin-related contrast, a significant confound is Gibbs ringing artefact, which produces signal fluctuations resembling cortical layers. Here, we address these issues with a novel approach using cortical layer thickness-adjusted T1w/T2w-FLAIR imaging, which effectively cancels out Gibbs ringing artefacts while enhancing intra-cortical myelin contrast. Whole-brain MRI measures were mapped onto twelve equivolumetric layers, and layer-specific sharp myeloarchitectonic transitions were identified using spatial gradients resulting in a putative 182 area/subarea partition of the macaque cerebral cortex. The myelin maps exhibit notably high homology with those in humans, suggesting cortical myelin shares a similar developmental program across species. Comparison with histological Gallyas myelin stains explains over 80% of the variance in the laminar T1w/T2w-FLAIR profiles, substantiating the validity of the method. Altogether, our approach provides a novel, noninvasive means for precision mapping layer myeloarchitecture in the primate cerebral cortex, advancing the pioneering work of classical neuroanatomists.

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bioRxiv2024

A principled approach to community detection in interareal cortical networks

Interareal structural connectivity explored by tract-tracing reveals super-dense, weighted, directed, and spatially embedded complex networks. These properties make the extraction and alignment of the community structure of these networks with brain function challenging. Here, we overcome these difficulties using a principled, information theoretic approach that distinguishes connectivity profiles using the Hellinger distance. Applying it to retrograde tract-tracing data in the macaque, we show that the cortex at the interareal level is organized into a nested hierarchy of link-communities alongside a node-community hierarchy. We find that the [1/2]-Renyi divergence of connection profiles, a non-linear transform of the Hellinger metric, follows a Weibull-like distribution and scales linearly with interareal distances, establishing a quantitative expression between functional organization and cortical geometry. Finally, we show that the loop entropy along the hierarchy is maximized at a community description level that is neither excessively detailed, nor non-specific, defining a "Goldilocks" level that we hypothesize, is optimal for system-wide efficient information processing. Author SummaryUnderstanding how functional organization emerges from connectivity alone is a central challenge in neuroscience. The cortex forms a dense network, making it difficult to identify meaningful groups of areas using standard methods. Here, we introduce a principled information-theoretical approach that compares the connectivity patterns of brain areas to uncover their community structure and organization. By first detecting the link communities and then deriving the grouping of areas from it, our method reveals a hierarchical structure based on patterns of reciprocal communication. Applied to the retrograde tract-tracing database of the macaque cortical network, this approach identifies communities that share similar interaction patterns, offering new insights into large-scale brain organization. More broadly, it provides a general framework for analyzing complex networks with dense, directed, and weighted connections.

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bioRxiv2023

Modulation of motion signals across the visual cortical hierarchy during bistable perception

Top-down influences play a central role in perception. In multi-stable sensory phenomena subjective interpretation fluctuates spontaneously over time and the perceptual switches reflect internally driven representations engaging perceptual decision-making. Using functional magnetic resonance imaging (fMRI), we investigated how perceptual states are represented across early visual areas during perception of a bistable moving plaid. While subjects maintained central fixation, perception of the stimulus--two superimposed, obliquely oriented moving gratings--spontaneously alternated between component motion (2 gratings sliding obliquely over each other) and pattern motion (a single coherent pattern moving laterally). Direction-selective clusters were reliably modulated by perceptual state across both early (V1) and higher-order (V2 and the human medial temporal complex (hMT+)) visual regions. Pattern modulation was significantly stronger in primary visual cortex (V1) than in higher-order areas, suggesting that coherent percept formation engages mechanisms beyond simple bottom-up feature integration. Enhanced V1 modulation points to a prominent role for top-down influences from higher-order regions, consistent with predictive coding frameworks in which higher-level areas convey predictions to lower levels to disambiguate sensory input and drive perceptual inference under ambiguous conditions. Eye tracking confirmed that reflexive eye movement direction did not predict perceptual state, excluding an oculomotor confound. Interpretation of the results in light of current knowledge of the physiology of motion integration in early visual areas suggests circuits at which feedback would be predicted to act.

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bioRxiv2022

Retinotopic organization of feedback projections in primate early visual cortex: implications for active vision

Feedback connections play a major role in many theories of brain function. Previous studies of feedback connections to early visual areas have mainly concentrated on the representation of central visual fields. Here, injections of tracers at different eccentricities in areas V1 and V2 revealed retinotopically organized feedback. Peripheral injections revealed projections from 15 areas that are not labeled by central injections. Connection strengths for the majority of projections vary significantly with eccentricity in a systematic fashion with respect to distance and origin; whereas projections to central and upper visual fields are significantly stronger from ventral stream areas, peripheral and lower field projections are stronger from the dorsal stream. Non-invasive functional connectivity suggests a similar anatomical organization in humans. These features are discussed with respect to the cognitive and perceptual roles of these feedback pathways.

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bioRxiv2021

Rare long-range cortical connections enhance information processing

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 modelling of large-scale human neuroimaging data in 1003 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, modelling 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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bioRxiv2020

Neural stem cells restore motor and cognitive function in a macaque model of Parkinson's disease

Parkinsons disease (PD) evolves over an extended and variable period in humans; several years prior to the onset of classical motor symptoms, cognitive deficits as well as sleep and biological rhythm disorders develop and worsen with disease progression, significantly impacting the quality of life of patients. The gold standard MPTP macaque model of PD recapitulates the progression of motor and non-motor symptoms over contracted periods of time. Here, this multidisciplinary and multiparametric study follows, in five animals, the steady progression of motor and non-motor symptoms and describes their reversal following bilateral grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration into the host environment as well as with in-vivo levels of striatal dopaminergic innervation and function. Given inter-individuality of disease progression and recovery the present study underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation and provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian non-human primates. One Sentence SummaryEmpirical evidence that cell therapy efficiently reverts cognitive and clinical motor symptoms in the non-human primate model of Parkinsons disease.

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bioRxiv2020

The role of anatomical connection strength for interareal communication in macaque cortex

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 adapted to non-invasive techniques, it promises to open new perspectives on the functional organization of the human brain.

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bioRxiv2020

Predictability of cortical-cortical connections in the mammalian brain

Despite a five-order magnitude range in size, the mammalian brain exhibits many shared anatomical and functional characteristics that should translate into cortical network commonalities. Here we develop a framework employing machine learning to quantify the degree of predictability of the weighted interareal cortical matrix. Data were obtained with retrograde tract-tracing experiments supplemented by projection length measurements. Using this framework with consistent and edge-complete empirical datasets in the macaque and mouse cortex, we show that there is significant amount of predictability embedded in the interareal cortical networks of both species. At the binary level, links are predictable with an Area Under the ROC curve of at least 0.8 for the macaque. At the weighted level, strengths of the medium and strong links are predictable with at least 85-90% accuracy in mouse and 70-80% in macaque, whereas weak links are not predictable in either species. These observations suggest that the formation and evolution of the cortical network at the mesoscale is to a large extent, rule-based, motivating further research on the architectural invariants of the cortical connectome.

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bioRxiv2020

A dopamine gradient controls access to distributed working memory in monkey cortex

Dopamine is critical for working memory. However, its effects throughout the large-scale primate cortex are poorly understood. Here we report that dopamine receptor density per neuron, measured by receptor autoradiography in the macaque monkey cortex, displays a macroscopic gradient along the cortical hierarchy. We developed a connectome- and biophysically-based model for distributed working memory that incorporates multiple neuron types and a dopamine gradient. The model captures an inverted U-shaped dependence of working memory on dopamine. The spatial distribution of mnemonic persistent activity matches that observed in over 90 experimental studies. We show that dopamine filters out irrelevant stimuli by enhancing inhibition of pyramidal cell dendrites. The level of cortical dopamine can also determine whether memory encoding is through persistent activity or an internal synaptic state. Taken together, our work represents a cross-level understanding that links molecules, cell types, recurrent circuit dynamics and a core cognitive function distributed across the cortex.

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bioRxiv2020

Cortical Hierarchy and The Dual Counterstream Architecture.

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 shed insights 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 primates comparisons. PlanO_LIIntroduction C_LIO_LIHierarchy - signatures of inputs to the local circuits. C_LIO_LIModels of hierarchy C_LIO_LIHierarchy - input consistency C_LIO_LIDual stream architecture. C_LIO_LIFunctional characteristics of FF and FB pathways. C_LIO_LIThe predictive brain and the importance of top-down generative networks. C_LIO_LIConclusion. C_LI

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bioRxiv2020

Canonical and noncanonical features of the mouse visual cortical hierarchy

Neocortical circuit computations underlying active vision are performed by a distributed network of reciprocally connected, functionally specialized areas. Mouse visual cortex is a dense, hierarchically organized network, comprising subnetworks that form preferentially interconnected processing streams. To determine the detailed layout of the mouse visual hierarchy, laminar patterns formed by interareal axonal projections, originating in each of ten visual areas were analyzed. Reciprocally connected pairs of areas, and shared targets of pairs of source areas, exhibited structural features consistent with a hierarchical organization. Beta regression analyses, which estimated a continuous measure of hierarchical distance, indicated that the network comprises multiple hierarchies embedded within overlapping processing levels. Single unit recordings showed that within each processing stream, receptive field sizes typically increased with increasing hierarchical level; however, ventral stream areas showed overall larger receptive field diameters. Together, the results reveal canonical and noncanonical hierarchical network motifs in mouse visual cortex.

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bioRxiv2020

Voice and Face Gender Perception engages multimodal integration via multiple feedback pathways.

Multimodal integration provides an ideal framework for investigating top-down influences in perceptual integration. Here, we investigate mechanisms and functional networks participating in face-voice multimodal integration during gender perception by using complementary behavioral (Maximum Likelihood Conjoint Measurement) and brain imaging (Dynamic Causal Modeling of fMRI data) techniques. Thirty-six subjects were instructed to judge pairs of face-voice stimuli either according to the gender of the face (face task), the voice (voice task) or the stimulus (stimulus task; no specific modality instruction given). Face and voice contributions to the tasks were not independent, as both modalities significantly contributed to all tasks. The top-down influences in each task could be modeled as a differential weighting of the contributions of each modality with an asymmetry in favor of the auditory modality in terms of magnitude of the effect. Additionally, we observed two independent interaction effects in the decision process that reflect both the coherence of the gender information across modalities and the magnitude of the gender difference from neutral. In a second experiment we investigated with functional MRI the modulation of effective connectivity between the Fusiform Face Area (FFA) and the Temporal Voice Area (TVA), two cortical areas implicated in face and voice processing. Twelve participants were presented with multimodal face-voice stimuli and instructed to attend either to face, voice or any gender information. We found specific changes in effective connectivity between these areas in the same conditions that generated behavioral interactions. Taken together, we interpret these results as converging evidence supporting the existence of multiple parallel hierarchical systems in multi-modal integration.

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bioRxiv2019

Unique Features of Sub-Cortical Circuits in A Macaque Model of Congenital Blindness

There is 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 the congenital blindness in macaque resulting from the removal of the retina during in utero development. 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 hybrid cortex reveals 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 hybrid cortex, 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 inter-areal cortical network and the ascending visual pathways.

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bioRxiv2019

Refinement of the primate corticospinal pathway during prenatal development

Perturbation of the developmental refinement of the corticospinal pathway leads to motor disorders. In non-primates developmental refinement is well documented, however in primates invasive investigations of the developing corticospinal pathway have been confined to neonatal and postnatal stages when refinement is relatively modest.\n\nHere, we investigated the developmental changes in the distribution of corticospinal projection neurons in cynomolgus monkey. Injections of retrograde tracer at the 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 contra- and ipsilateral projecting corticospinal 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.\n\nIn 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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bioRxiv2018

A Gene Regulatory Model of Cortical Neurogenesis

Sparse data describing mouse cortical neurogenesis were used to derive a model gene regulatory network (GRN) that is then able to control the quantitative cellular dynamics of the observed neurogenesis. Derivation of the network begins by estimating from the biological data a set of cell states and transition probabilities necessary to explain neurogenesis. We show that the stochastic transition between states can be implemented by the dynamics of a GRN comprising only 36 abstract genes. Finally, we demonstrate using detailed physical simulations of cell mitosis, and differentiation that this GRN is able to steer a population of neuroepithelial precursors through mitotic expansion and differentiation to form the quantitatively correct complex multicellular architectures of mouse cortical areas 3 and 6. We find that the same GRN is able to generate both areas though modulation of only one gene, suggesting that arealization of the cortical sheet may require only simple improvisations on a fundamental gene network. We conclude that even sparse phenotypic and cell lineage data can be used to infer fundamental properties of neurogenesis and its organization.\n\n1. HighlightsO_LIEstimation of the cell states and transition probabilities of neurogenesis from experimental data.\nC_LIO_LIDesign of an abstract gene regulatory network (GRN) whose dynamics implement cell states and their stochastic transitions.\nC_LIO_LIDetailed simulation of GRN-guided neurogenesis for mouse cortical areas 3 and 6.\nC_LIO_LIDifferent dynamics of neurogenesis of distinct cortical areas arise through modulation of only a single gene.\nC_LI\n\n2. In briefPfister et al. show how sparse phenotypic and cell lineage data can be used to infer a small abstract gene regulatory network (GRN), which, when inserted into model precursor cells, is able to control in a distributed manner the quantitative cellular dynamics of neocortical neurogenesis.

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bioRxiv2017

Neural circuits for long-range color filling-in

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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