Defining neuroplasticity.

Neuroplasticity, i.e., the modifiability of the brain, is different in development and adulthood. The first includes changes in: (i) neurogenesis and control of neuron number; (ii) neuronal migration; (iii) differentiation of the somato-dendritic and axonal phenotypes; (iv) formation of connections; (v) cytoarchitectonic differentiation. These changes are often interrelated and can lead to: (vi) system-wide modifications of brain structure as well as to (vii) acquisition of specific functions such as ocular dominance or language. Myelination appears to be plastic both in development and adulthood, at least, in rodents. Adult neuroplasticity is limited, and is mainly expressed as changes in the strength of excitatory and inhibitory synapses while the attempts to regenerate connections have met with limited success. The outcomes of neuroplasticity are not necessarily adaptive, but can also be the cause of neurological and psychiatric pathologies.

The functional characterization of callosal connections.

The brain operates through the synaptic interaction of distant neurons within flexible, often heterogeneous, distributed systems. Histological studies have detailed the connections between distant neurons, but their functional characterization deserves further exploration. Studies performed on the corpus callosum in animals and humans are unique in that they capitalize on results obtained from several neuroscience disciplines. Such data inspire a new interpretation of the function of callosal connections and delineate a novel road map, thus paving the way toward a general theory of cortico-cortical connectivity. Here we suggest that callosal axons can drive their post-synaptic targets preferentially when coupled to other inputs endowing the cortical network with a high degree of conditionality. This might depend on several factors, such as their pattern of convergence-divergence, the excitatory and inhibitory operation mode, the range of conduction velocities, the variety of homotopic and heterotopic projections and, finally, the state-dependency of their firing. We propose that, in addition to direct stimulation of post-synaptic targets, callosal axons often play a conditional driving or modulatory role, which depends on task contingencies, as documented by several recent studies.

Bundle-Specific Axon Diameter Index as a New Contrast to Differentiate White Matter Tracts.

In the central nervous system of primates, several pathways are characterized by different spectra of axon diameters. In vivo methods, based on diffusion-weighted magnetic resonance imaging, can provide axon diameter index estimates non-invasively. However, such methods report voxel-wise estimates, which vary from voxel-to-voxel for the same white matter bundle due to partial volume contributions from other pathways having different microstructure properties. Here, we propose a novel microstructure-informed tractography approach, COMMITAxSize, to resolve axon diameter index estimates at the streamline level, thus making the estimates invariant along trajectories. Compared to previously proposed voxel-wise methods, our formulation allows the estimation of a distinct axon diameter index value for each streamline, directly, furnishing a complementary measure to the existing calculation of the mean value along the bundle. We demonstrate the favourable performance of our approach comparing our estimates with existing histologically-derived measurements performed in the corpus callosum and the posterior limb of the internal capsule. Overall, our method provides a more robust estimation of the axon diameter index of pathways by jointly estimating the microstructure properties of the tissue and the macroscopic organisation of the white matter connectivity.

The Complex Hodological Architecture of the Macaque Dorsal Intraparietal Areas as Emerging from Neural Tracers and DW-MRI Tractography.

In macaque monkeys, dorsal intraparietal areas are involved in several daily visuomotor actions. However, their border and sources of cortical afferents remain loosely defined. Combining retrograde histologic tracing and MRI diffusion-based tractography, we found a complex hodology of the dorsal bank of the intraparietal sulcus (db-IPS), which can be subdivided into a rostral intraparietal area PEip, projecting to the spinal cord, and a caudal medial intraparietal area MIP lacking such projections. Both include an anterior and a posterior sector, emerging from their ipsilateral, gradient-like connectivity profiles. As tractography estimations, we used the cross-sectional area of the white matter bundles connecting each area with other parietal and frontal regions, after selecting regions of interest (ROIs) corresponding to the injection sites of neural tracers. For most connections, we found a significant correlation between the proportions of cells projecting to all sectors of PEip and MIP along the continuum of the db-IPS and tractography. The latter also revealed "false positive" but plausible connections awaiting histologic validation.

On the cortical connectivity in the macaque brain: A comparison of diffusion tractography and histological tracing data.

Diffusion-weighted magnetic resonance imaging (DW-MRI) tractography is a non-invasive tool to probe neural connections and the structure of the white matter. It has been applied successfully in studies of neurological disorders and normal connectivity. Recent work has revealed that tractography produces a high incidence of false-positive connections, often from "bottleneck" white matter configurations. The rich literature in histological connectivity analysis studies in the macaque monkey enables quantitative evaluation of the performance of tractography algorithms. In this study, we use the intricate connections of frontal, cingulate, and parietal areas, well established by the anatomical literature, to derive a symmetrical histological connectivity matrix composed of 59 cortical areas. We evaluate the performance of fifteen diffusion tractography algorithms, including global, deterministic, and probabilistic state-of-the-art methods for the connectivity predictions of 1711 distinct pairs of areas, among which 680 are reported connected by the literature. The diffusion connectivity analysis was performed on a different ex-vivo macaque brain, acquired using multi-shell DW-MRI protocol, at high spatial and angular resolutions. Across all tested algorithms, the true-positive and true-negative connections were dominant over false-positive and false-negative connections, respectively. Moreover, three-quarters of streamlines had endpoints location in agreement with histological data, on average. Furthermore, probabilistic streamline tractography algorithms show the best performances in predicting which areas are connected. Altogether, we propose a method for quantitative evaluation of tractography algorithms, which aims at improving the sensitivity and the specificity of diffusion-based connectivity analysis. Overall, those results confirm the usefulness of tractography in predicting connectivity, although errors are produced. Many of the errors result from bottleneck white matter configurations near the cortical grey matter and should be the target of future implementation of methods.

The Target of Exuberant Projections in Development.

In addition to neuronal death and elimination of synapses, the production of transient, exuberant axons, and axonal branches is a general phenomenon in development across species and systems. To understand what drives the decision of which axons are maintained and which are eliminated, it is important to monitor the interaction of juvenile axons at their target. As old and more recent work show, unlike what is claimed by Ribeiro Gomez et al. (2019), in the cerebral cortex, both classes of axons branch in the white matter near the target; axons destined to be maintained massively invade the gray matter where they develop terminal arbors and synapses. Axons destined to elimination remain in the white matter although a few transient, exploratory branches can enter the cortex. Axonal behavior and fate seem dictated by positional information probably conveyed by thalamic afferents and activity. Unlike what is suggested by Ribeiro Gomez et al. (2019), axonal selection should not be confused with synaptic reduction, which is a later event with minor or no impact on the topography of the connection.

Cortical and thalamic connectivity of occipital visual cortical areas 17, 18, 19, and 21 of the domestic ferret (Mustela putorius furo).

The present study describes the ipsilateral and contralateral corticocortical and corticothalamic connectivity of the occipital visual areas 17, 18, 19, and 21 in the ferret using standard anatomical tract-tracing methods. In line with previous studies of mammalian visual cortex connectivity, substantially more anterograde and retrograde label was present in the hemisphere ipsilateral to the injection site compared to the contralateral hemisphere. Ipsilateral reciprocal connectivity was the strongest within the occipital visual areas, while weaker connectivity strength was observed in the temporal, suprasylvian, and parietal visual areas. Callosal connectivity tended to be strongest in the homotopic cortical areas, and revealed a similar areal distribution to that observed in the ipsilateral hemisphere, although often less widespread across cortical areas. Ipsilateral reciprocal connectivity was observed throughout the visual nuclei of the dorsal thalamus, with no contralateral connections to the visual thalamus being observed. The current study, along with previous studies of connectivity in the cat, identified the posteromedial lateral suprasylvian visual area (PMLS) as a distinct network hub external to the occipital visual areas in carnivores, implicating PMLS as a potential gateway to the parietal cortex for dorsal stream processing. These data will also contribute to a macro connectome database of the ferret brain, providing essential data for connectomics analyses and cross-species analyses of connectomes and brain connectivity matrices, as well as providing data relevant to additional studies of cortical connectivity across mammals and the evolution of cortical connectivity variation.

Cortical and thalamic connectivity of temporal visual cortical areas 20a and 20b of the domestic ferret (Mustela putorius furo).

The present study describes the ipsilateral and contralateral corticocortical and corticothalamic connectivity of the temporal visual areas 20a and 20b in the ferret using standard anatomical tract-tracing methods. The two temporal visual areas are strongly interconnected, but area 20a is primarily connected to the occipital visual areas, whereas area 20b maintains more widespread connections with the occipital, parietal and suprasylvian visual areas and the secondary auditory cortex. The callosal connectivity, although homotopic, consists mainly of very weak anterograde labeling which was more widespread in area 20a than area 20b. Although areas 20a and 20b are well connected with the visual dorsal thalamus, the injection into area 20a resulted in more anterograde label, whereas more retrograde label was observed in the visual thalamus following the injection into area 20b. Most interestingly, comparisons to previous connectional studies of cat areas 20a and 20b reveal a common pattern of connectivity of the temporal visual cortex in carnivores, where the posterior parietal cortex and the central temporal region (PMLS) provide network points required for dorsal and ventral stream interaction enroute to integration in the prefrontal cortex. This pattern of network connectivity is not dissimilar to that observed in primates, which highlights the ferret as a useful animal model to understand visual sensory integration between the dorsal and ventral streams. The data generated will also contribute to a connectomics database, to facilitate cross species analysis of brain connectomes and wiring principles of the brain.

Cortical and thalamic connectivity of posterior parietal visual cortical areas PPc and PPr of the domestic ferret (Mustela putorius furo).

The present study describes the ipsilateral and contralateral cortico-cortical and cortico-thalamic connectivity of the parietal visual areas, posterior parietal caudal cortical area (PPc) and posterior parietal rostral cortical area (PPr), in the ferret using standard anatomical tract-tracing methods. The two divisions of posterior parietal cortex of the ferret are strongly interconnected, however area PPc shows stronger connectivity with the occipital and suprasylvian visual cortex, while area PPr shows stronger connectivity with the somatomotor cortex, reflecting the functional specificity of these two areas. This pattern of connectivity is mirrored in the contralateral callosal connections. In addition, PPc and PPr are connected with the visual and somatomotor nuclei of the dorsal thalamus. Numerous connectional similarities exist between the posterior parietal cortex of the ferret (PPc and PPr) and the cat (area 7 and 5), indicative of the homology of these areas within the Carnivora. These findings highlight the existence of a frontoparietal network as a shared feature of the organization of parietal cortex across Euarchontoglires and Laurasiatherians, with the degree of expression varying in relation to the expansion and areal complexity of the posterior parietal cortex. This observation indicates that the ferret is a potentially valuable experimental model animal for understanding the evolution and function of the posterior parietal cortex and the frontoparietal network across mammals. The data generated will also contribute to a connectomics database, to further cross-species analyses of connectomes and illuminate wiring principles of cortical connectivity across mammals.

Diversity of Cortico-descending Projections: Histological and Diffusion MRI Characterization in the Monkey.

The axonal composition of cortical projections originating in premotor, supplementary motor (SMA), primary motor (a4), somatosensory and parietal areas and descending towards the brain stem and spinal cord was characterized in the monkey with histological tract tracing, electron microscopy (EM) and diffusion MRI (dMRI). These 3 approaches provided complementary information. Histology provided accurate assessment of axonal diameters and size of synaptic boutons. dMRI revealed the topography of the projections (tractography), notably in the internal capsule. From measurements of axon diameters axonal conduction velocities were computed. Each area communicates with different diameter axons and this generates a hierarchy of conduction delays in this order: a4 (the shortest), SMA, premotor (F7), parietal, somatosensory, premotor F4 (the longest). We provide new interpretations for i) the well-known different anatomical and electrophysiological estimates of conduction velocity; ii) why conduction delays are probably an essential component of the cortical motor command; and iii) how histological and dMRI tractography can be integrated.

Topological principles and developmental algorithms might refine diffusion tractography.

The identification and reconstruction of axonal pathways in the living brain or "ex-vivo" is promising a revolution in connectivity studies bridging the gap from animal to human neuroanatomy with extensions to brain structural-functional correlates. Unfortunately, the methods suffer from juvenile drawbacks. In this perspective paper we mention several computational and developmental principles, which might stimulate a new generation of algorithms and a discussion bridging the neuroimaging and neuroanatomy communities.

Validation strategies for the interpretation of microstructure imaging using diffusion MRI.

Extracting microanatomical information beyond the image resolution of MRI would provide valuable tools for diagnostics and neuroscientific research. A number of mathematical models already suggest microstructural interpretations of diffusion MRI (dMRI) data. Examples of such microstructural features could be cell bodies and neurites, e.g. the axon's diameter or their orientational distribution for global connectivity analysis using tractography, and have previously only been possible to access through conventional histology of post mortem tissue or invasive biopsies. The prospect of gaining the same knowledge non-invasively from the whole living human brain could push the frontiers for the diagnosis of neurological and psychiatric diseases. It could also provide a general understanding of the development and natural variability in the healthy brain across a population. However, due to a limited image resolution, most of the dMRI measures are indirect estimations and may depend on the whole chain from experimental parameter settings to model assumptions and implementation. Here, we review current literature in this field and highlight the integrative work across anatomical length scales that is needed to validate and trust a new dMRI method. We encourage interdisciplinary collaborations and data sharing in regards to applying and developing new validation techniques to improve the specificity of future dMRI methods.

Network causality, axonal computations, and Poffenberger.

All brain operations are implemented by networks of neurons. Unfortunately, the networks underlying even the most elementary brain operations remain elusive. This is due to the complexity of the networks, their heterogeneity, and to the multiple computations performed by the axons. Poffenberger's paradigm is one example of a simple task aimed at characterizing the temporal properties of an interhemispheric network which has remained elusive to this day.

The Crossed Projection to the Striatum in Two Species of Monkey and in Humans: Behavioral and Evolutionary Significance.

The corpus callosum establishes the anatomical continuity between the 2 hemispheres and coordinates their activity. Using histological tracing, single axon reconstructions, and diffusion tractography, we describe a callosal projection to n caudatus and putamen in monkeys and humans. In both species, the origin of this projection is more restricted than that of the ipsilateral projection. In monkeys, it consists of thin axons (0.4-0.6 µm), appropriate for spatial and temporal dispersion of subliminal inputs. For prefrontal cortex, contralateral minus ipsilateral delays to striatum calculated from axon diameters and conduction distance are <2 ms in the monkey and, by extrapolation, <4 ms in humans. This delay corresponds to the performance in Poffenberger's paradigm, a classical attempt to estimate central conduction delays, with a neuropsychological task. In both species, callosal cortico-striatal projections originate from prefrontal, premotor, and motor areas. In humans, we discovered a new projection originating from superior parietal lobule, supramarginal, and superior temporal gyrus, regions engaged in language processing. This projection crosses in the isthmus the lesion of which was reported to dissociate syntax and prosody. The projection might originate from an overproduction of callosal projections in development, differentially pruned depending on species.

Axon diameter relates to synaptic bouton size: structural properties define computationally different types of cortical connections in primates.

Neural connections are implemented by axons of different diameters, whose spectrum increases depending on species and areas. Axon diameter determines conduction velocity and is proportional to the size of the cell body of origin. We describe that in motor, callosal connections of the monkey thick axons distribute larger boutons than thin axons, suggesting that faster axons also release more neurotransmitter at their termination, probably activating more powerfully their targets.

Organization and evolution of parieto-frontal processing streams in macaque monkeys and humans.

The functional organization of the parieto-frontal system is crucial for understanding cognitive-motor behavior and provides the basis for interpreting the consequences of parietal lesions in humans from a neurobiological perspective. The parieto-frontal connectivity defines some main information streams that, rather than being devoted to restricted functions, underlie a rich behavioral repertoire. Surprisingly, from macaque to humans, evolution has added only a few, new functional streams, increasing however their complexity and encoding power. In fact, the characterization of the conduction times of parietal and frontal areas to different target structures has recently opened a new window on cortical dynamics, suggesting that evolution has amplified the probability of dynamic interactions between the nodes of the network, thanks to communication patterns based on temporally-dispersed conduction delays. This might allow the representation of sensory-motor signals within multiple neural assemblies and reference frames, as to optimize sensory-motor remapping within an action space characterized by different and more complex demands across evolution.

The claustrum of the ferret: afferent and efferent connections to lower and higher order visual cortical areas.

The claustrum, a subcortical telencephalic structure, is known to be reciprocally interconnected to almost all cortical regions; however, a systematic analysis of claustrocortical connectivity with physiologically identified lower and higher order visual cortical areas has not been undertaken. In the current study we used biotinylated dextran amine to trace the connections of the ferret claustrum with lower (occipital areas 17, 18, 19 and 21) and higher (parietal and temporal areas posterior parietal caudal visual area (PPc), posterior parietal rostral visual area (PPr), 20a, 20b, anterior ectosylvian visual area (AEV)) order visual cortical areas. No connections between the claustrum and area 17 were observed. Occipital visual areas 18, 19 and 21 revealed a reciprocal connectivity mainly to the caudal part of the claustrum. After injection into parietal areas PPc and PPr labeled neurons and terminals were found throughout almost the entire rostrocaudal extent of the dorsal claustrum. Area 20b revealed reciprocal connections mainly to the caudal-ventral claustrum, although some labeled neurons and terminals were observed in the dorso-central claustrum. No projection from the claustrum to areas AEV and 20a could be observed, though projections from AEV and 20a to the claustrum were found. Only injections placed in areas PPr and AEV resulted in anterogradely labeled terminals in the contralateral claustrum. Our results suggest that lower order visual areas have clearly defined connectivity zones located in the caudal claustrum, whereas higher order visual areas, even if not sending and/or receiving projections from the entire claustrum, show a more widespread connectivity.

The diameter of cortical axons depends both on the area of origin and target.

In primates, different cortical areas send axons of different diameters into comparable tracts, notably the corpus callosum (Tomasi S, Caminiti R, Innocenti GM. 2012. Areal differences in diameter and length of corticofugal projections. Cereb Cortex. 22:1463-1472). We now explored if an area also sends axons of different diameters to different targets. We find that the parietal area PEc sends thicker axons to area 4 and 6, and thinner ones to the cingulate region (area 24). Areas 4 and 9, each sends axons of different diameters to the nucleus caudatus, to different levels of the internal capsule, and to the thalamus. The internal capsule receives the thickest axon, followed by thalamus and nucleus caudatus. The 2 areas (4 and 9) differ in the diameter and length of axons to corresponding targets. We calculated how diameter determines conduction velocity of the axons and together with pathway length determines transmission delays between different brain sites. We propose that projections from and within the cerebral cortex consist of a complex system of lines of communication with different geometrical and time computing properties.

Diameter, length, speed, and conduction delay of callosal axons in macaque monkeys and humans: comparing data from histology and magnetic resonance imaging diffusion tractography.

Three macaque monkeys and 13 healthy human volunteers underwent diffusion tensor MRI with a 3 Tesla scanner for diffusion tract tracing (DTT) reconstruction of callosal bundles from different areas. In six macaque monkeys and three human subjects, the length of fiber tracts was obtained from histological data and combined with information on the distribution of axon diameter, so as to estimate callosal conduction delays from different areas. The results showed that in monkeys, the spectrum of tract lengths obtained with DTT closely matches that estimated from histological reconstruction of axons labeled with an anterogradely transported tracer. For each sector of the callosum, we obtained very similar conduction delays regardless of whether conduction distance was obtained from tractography or from histological analysis of labeled axons. This direct validation of DTT measurements by histological methods in monkeys was a prerequisite for the computation of the callosal conduction distances and delays in humans, which we had previously obtained by extrapolating the length of callosal axons from that of the monkey, proportionally to the brain volumes in the two species. For this analysis, we used the distribution of axon diameters from four different sectors of the corpus callosum. As in monkeys, in humans the shortest callosal conduction delays were those of motor, somatosensory, and premotor areas; the longer ones were those of temporal, parietal, and visual areas. These results provide the first histological validation of anatomical data about connection length in the primate brain based on DTT imaging.