Predictability of cortico-cortical connections in the mammalian brain.

Despite a five order of magnitude range in size, the brains of mammals share many anatomical and functional characteristics that translate into cortical network commonalities. Here we develop a machine learning framework to quantify the degree of predictability of the weighted interareal cortical matrix. Partial network connectivity data were obtained with retrograde tract-tracing experiments generated with a consistent methodology, supplemented by projection length measurements in a nonhuman primate (macaque) and a rodent (mouse). We show that there is a significant level 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. Weighted medium and strong links are predictable with an 85%-90% accuracy (mouse) and 70%-80% (macaque), whereas weak links are not predictable in either species. These observations reinforce earlier observations that the formation and evolution of the cortical network at the mesoscale is, to a large extent, rule based. Using the methodology presented here, we performed imputations on all area pairs, generating samples for the complete interareal network in both species. These are necessary for comparative studies of the connectome with minimal bias, both within and across species.

Color appearance of spatial patterns compared by direct estimation and conjoint measurement.

Perceptual scales of color saturation obtained by direct estimation (DE) and maximum likelihood conjoint measurement (MLCM) were compared for red checkerboard patterns and uniform red squares. For the DE task, observers were asked to rate the saturation level as a percentage, indicating the chromatic sensation for each pattern and contrast. For the MLCM procedure, observers judged on each trial which of two stimuli that varied in chromatic contrast and/or spatial pattern evoked the most salient color. In separate experiments, patterns varying only in luminance contrast were also tested. The MLCM data confirmed previous results reported with DE indicating that the slope of the checkerboard scale with cone contrast levels is steeper than that for the uniform square. Similar results were obtained with patterns modulated only in luminance. DE methods were relatively more variable within an observer, reflecting observer uncertainty, while MLCM scales showed greater relative variability across observers, perhaps reflecting individual differences in the appearance of the stimuli. MLCM provides a reliable scaling method, based only on ordinal judgments between pairs of stimuli and that provides less opportunity for subject-specific biases and strategies to intervene in perceptual judgements.

Comprehensive morphometric assessment of deltoid muscle development in children: A cross-sectional study.

BACKGROUND: Normative values for different morphometric parameters of muscle fibres during paediatric development, i.e. from 0 to 18 years, are currently unavailable. They would be of major importance to accurately evaluate pathological changes and could be used as reference biomarkers for evaluating treatment response in clinical trials, or physiological adjustments in sports or ageing. METHODS: Data were derived from 482 images with a total of 33 094 fibres from 10 µm cross-sections of snap-frozen muscle from 83 deltoid muscle biopsies from patients, 0-18 years, without neuromuscular pathology stained with ATPase 9.4. Data was acquired and analysed with patented image analysis algorithms from "CARPACCIO.cloud". Several parameters were extracted or calculated, including cross-sectional area (CSA), fibre type, circularity, as well as the Minimum diameter of Feret (MinFeret). FINDINGS: This study illustrates changes in quantitative parameters for muscle morphology over the course of paediatric development and the pivotal changes occurring around puberty. Only fibre size parameters (MinFeret, CSA) are dependent on gender, and only after puberty. All other parameters vary in a similar manner for females and males. The proportion of type 1 fibres is essentially constant from birth to age 10, decreasing to ≈40% by age 18. Circularity decreases with age, to plateau after age 10 for both fibre types. INTERPRETATION: Normative values and reference charts for muscle fibre types in this age range have been generated to allow comparison of data from patients in pathology laboratories working on neuromuscular diseases. FUNDING: BPI FRANCE, PULSALYS, Association de l'Institut de Myologie, French National Research Agency (ANR), LABEX CORTEX of Université de Lyon.

Seasonal Variation in Diurnal Rhythms of the Human Eye: Implications for Continuing Ocular Growth in Adolescents and Young Adults.

Purpose: To investigate the diurnal rhythms in the human eye in winter and summer in southeast Norway (latitude 60°N). Methods: Eight measures (epochs) of intraocular pressure, ocular biometry, and optical coherence tomography were obtained from healthy participants (17-24 years of age) on a mid-winter's day (n = 35; 6 hours of daylight at solstice) and on a day the following summer (n = 24; 18 hours of daylight at solstice). Participants wore an activity monitor 7 days before measurements. The epochs were scheduled relative to the individual's habitual wake and sleep time: two in the day (morning and midday) and six in the evening (every hour until and 1 hour after sleep time). Saliva was collected for melatonin. A linear mixed-effects model was used to determine significant diurnal variations, and a sinusoid with a 24-hour period was fitted to the data with a nonlinear mixed-effects model to estimate rhythmic statistics. Results: All parameters underwent significant diurnal variation in winter and summer (P < 0.002). A 1-hour phase advance was observed for melatonin and ocular axial length in the summer (P < 0.001). The degree of change in axial length was associated with axial length phase advance (R2 = 0.81, P < 0.001) and choroidal thickening (R2 = 0.54, P < 0.001) in summer. Conclusions: Diurnal rhythms in ocular biometry appear to be synchronized with melatonin secretion in both winter and summer, revealing seasonal variation of diurnal rhythms in young adult eyes. The association between axial length and seasonal changes in the phase relationships between ocular parameters and melatonin suggests a between-individual variation in adaptation to seasonal changes in ocular diurnal rhythms.

Human Foveal Cone and RPE Cell Topographies and Their Correspondence With Foveal Shape.

Purpose: To characterize the association between foveal shape and cone and retinal pigment epithelium (RPE) cell topographies in healthy humans. Methods: Multimodal adaptive scanning light ophthalmoscopy and optical coherence tomography (OCT) were used to acquire images of foveal cones, RPE cells, and retinal layers in eyes of 23 healthy participants with normal foveas. Distributions of cone and RPE cell densities were fitted with nonlinear mixed-effects models. A linear mixed-effects model was used to examine the relationship between cone and RPE inter-cell distances and foveal shape as obtained from the OCT scans of retinal thickness. Results: The best-fit model to the cone densities was a power function with a nasal-temporal asymmetry. There was a significant linear relationship among cone and RPE cell spacing, foveal shape, and foveal cell topography. The model predictions of the central 10° show that the contributions of both the cones and RPE cells are necessary to account for foveal shape. Conclusions: The results indicate that there is a strong relationship between cone and RPE cell spacing and the shape of the human adolescent and adult fovea. This finding adds to the existing evidence of the critical role that the RPE serves in fetal foveal development and through adolescence, possibly via the imposition of constraints on the number and distribution of foveal cones.

Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease.

Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality-of-life of patients. Circadian-rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold-standard 6-methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) macaque model of PD recapitulates the progression of motor and nonmotor symptoms over contracted periods of time. Here, this multidisciplinary/multiparametric study follows, in five animals, the steady progression of motor and nonmotor symptoms and describes their reversal following 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, and in a subset of animals, with in vivo levels of striatal dopaminergic innervation and function. The present study provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian nonhuman primates and, given interindividuality of disease progression and recovery, underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation.

Hierarchical and nonhierarchical features of the mouse visual cortical network.

Neocortical computations underlying vision are performed by a distributed network of functionally specialized areas. Mouse visual cortex, a dense interareal network that exhibits hierarchical properties, comprises subnetworks interconnecting distinct processing streams. To determine the layout of the mouse visual hierarchy, we have evaluated the laminar patterns formed by interareal axonal projections originating in each of ten areas. Reciprocally connected pairs of areas exhibit feedforward/feedback relationships consistent with a hierarchical organization. Beta regression analyses, which estimate a continuous hierarchical distance measure, indicate that the network comprises multiple nonhierarchical circuits embedded in a hierarchical organization of overlapping levels. Single-unit recordings in anaesthetized mice show that receptive field sizes are generally consistent with the hierarchy, with the ventral stream exhibiting a stricter hierarchy than the dorsal stream. Together, the results provide an anatomical metric for hierarchical distance, and reveal both hierarchical and nonhierarchical motifs in mouse visual cortex.

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

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.

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

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 (N = 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 (N = 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.

The nonhuman primate neuroimaging and neuroanatomy project.

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.

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

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.

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

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. Ex vivo 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.

Adaptive Changes in Color Vision from Long-Term Filter Usage in Anomalous but Not Normal Trichromacy.

For over 150 years, spectrally selective filters have been proposed to improve the vision of observers with color vision deficiencies [1]. About 6% of males and <1% of females have anomalies in their gene arrays coded on the X chromosome that result in significantly decreased spectral separation between their middle- (M-) and long- (L-) wave sensitive cone photoreceptors [2]. These shifts alter individuals' color-matching and chromatic discrimination such that they are classified as anomalous trichromats [3, 4]. Broad-band spectrally selective filters proposed to improve the vision of color-deficient observers principally modify the illuminant and are largely ineffective in enhancing discrimination or perception because they do not sufficiently change the relative activity of M- and L-photoreceptors [5, 6]. Properly tailored notch filters, by contrast, might increase the difference of anomalous M- and L-cone signals. Here, we evaluated the effects of long-term usage of a commercial filter designed for this purpose on luminance and chromatic contrast response, estimated with a signal detection-based scaling method. We found that sustained use over two weeks was accompanied by increased chromatic contrast response in anomalous trichromats. Importantly, these improvements were observed when tested without the filters, thereby demonstrating an adaptive visual response. Normal observers and a placebo control showed no such changes in contrast response. These findings demonstrate a boosted chromatic response from exposure to enhanced chromatic contrasts in observers with reduced spectral discrimination. They invite the suggestion that modifications of photoreceptor signals activate a plastic post-receptoral substrate that could potentially be exploited for visual rehabilitation.

Suprathreshold contrast response in normal and anomalous trichromats.

Maximum likelihood difference scaling was used to measure suprathreshold contrast response difference scales for low-frequency Gabor patterns, modulated along luminance and L-M color directions in normal, protanomalous, and deuteranomalous observers. Based on a signal-detection model, perceptual scale values, parameterized as $ d^\prime $d', were estimated by maximum likelihood. The difference scales were well fit by a Michaelis-Menten model, permitting estimates of response and contrast gain parameters for each subject. Anomalous observers showed no significant differences in response or contrast gain from normal observers for luminance contrast. For chromatic modulation, however, anomalous observers displayed higher contrast and lower response gain compared to normal observers. These effects cannot be explained by simple pigment shift models, and they support a compensation mechanism to optimize the mapping of the input contrast range to the neural response range. A linear relation between response and contrast gain suggests a neural trade-off between them.

Measuring and Modeling Visual Appearance.

In studying visual perception, we seek to develop models of processing that accurately predict perceptual judgments. Much of this work is focused on judgments of discrimination, and there is a large literature concerning models of visual discrimination. There are, however, non-threshold visual judgments, such as judgments of the magnitude of differences between visual stimuli, that provide a means to bridge the gap between threshold and appearance. We describe two such models of suprathreshold judgments, maximum likelihood difference scaling and maximum likelihood conjoint measurement, and review recent literature that has exploited them.

Refinement of the Primate Corticospinal Pathway During Prenatal Development.

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.

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

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.

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.

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

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.