The connectional organization of the cortico-thalamic system of the cat.

Data on connections between the areas of the cerebral cortex and nuclei of the thalamus are too complicated to analyse with naked intuition. Indeed, the complexity of connection data is one of the major challenges facing neuroanatomy. Recently, systematic methods have been developed and applied to the analysis of the connectivity in the cerebral cortex. These approaches have shed light on the gross organization of the cortical network, have made it possible to test systematically theories of cortical organization, and have guided new electrophysiological studies. This paper extends the approach to investigate the organization of the entire cortico-thalamic network. An extensive collation of connection tracing studies revealed approximately 1500 extrinsic connections between the cortical areas and thalamic nuclei of the cat cerebral hemisphere. Around 850 connections linked 53 cortical areas with each other, and around 650 connections linked the cortical areas with 42 thalamic nuclei. Non-metric multidimensional scaling, optimal set analysis and non-parametric cluster analysis were used to study global connectivity and the 'place' of individual structures within the overall scheme. Thalamic nuclei and cortical areas were in intimate connectional association. Connectivity defined four major thalamo-cortical systems. These included three broadly hierarchical sensory or sensory/motor systems (visual and auditory systems and a single system containing both somatosensory and motor structures). The highest stations of these sensory/motor systems were associated with a fourth processing system composed of prefrontal, cingulate, insular and parahippocampal cortex and associated thalamic nuclei (the 'fronto-limbic system'). The association between fronto-limbic and somato-motor systems was particularly close.     

Connectivity of ectopic neurons in the molecular layer of the somatosensory cortex in autoimmune mice

Approximately 50% of New Zealand Black mice (NZB/BINJ) and 80% of NXSM-D/EiJ mice prenatally develop neocortical layer I ectopias, mostly in somatosensory cortices. These cortical anomalies are similar to those seen in the brains of individuals with dyslexia. Neurofilament staining revealed a radial column of tightly packed fiber bundles in the layers underlying ectopias. This suggested that the connectivity of the ectopic neurons was aberrant. The present study used the tracers 1,1'-dioctadecyl- 3,3,3',3'-tetramethylindo- carbocyanine perchlorate (DiI) and biotinylated dextran amine (BDA) to more thoroughly explore the cortical and thalamic connectivity of the ectopias. DiI placement into ectopias again revealed a distinct bundle of fibers extending from the ectopic neurons to the deep cortical layers. This bundle split in the white matter with some fibers traveling to the corpus callosum and others to the internal capsule. Thalamic connections were concentrated in the ventrobasal com- plex (VB) and posterior thalamic nucleus group (Po). Injections of BDA into VB revealed reciprocal connections between VB and the ectopic cortical neurons. Ipsilateral corticocortical projections were seen between ectopias in primary somatosensory and motor and secondary somatosensory cortices, but no contralateral connections of the ectopic neurons were seen. These findings confirm the notion that layer I ectopias are anomalously connected by comparison to neurons in homologous cortex, which may underlie widespread dysfunction of brains containing ectopias.     

Differential gene expression between sensory neocortical areas: potential roles for Ten_m3 and Bcl6 in patterning visual and somatosensory pathways

Adult neocortical areas are characterized by marked differences in cytoarchitecture and connectivity that underlie their functional roles. The molecular determinants of these differences are largely unknown. We performed a microarray analysis to identify molecules that define the somatosensory and visual areas during the time when afferent and efferent projections are forming. We identified 122 molecules that are differentially expressed between the regions and confirmed by quantitative polymerase chain reaction 95% of the 20 genes tested. Two genes were chosen for further investigation: Bcl6 and Ten_m3. Bcl6 was highly expressed in the superficial cortical plate corresponding to developing layer IV of somatosensory cortex at postnatal day (P) 0. This had diminished by P3, but strong expression was found in layer V pyramidal cells by P7 and was maintained until adulthood. Retrograde tracing showed that Bcl6 is expressed in corticospinal neurons. Ten_m3 was expressed in a graded pattern within layer V of caudal cortex that corresponds well with visual cortex. Retrograde tracing and immunostaining showed that Ten_m3 is highly expressed along axonal tracts of projection neurons of the developing visual pathway. Overexpression demonstrated that Ten_m3 promotes homophilic adhesion and neurite outgrowth in vivo. This suggests an important role for Ten_m3 in the development of the visual pathway.     

Weight consistency specifies regularities of macaque cortical networks

To what extent cortical pathways show significant weight differences and whether these differences are consistent across animals (thereby comprising robust connectivity profiles) is an important and unresolved neuroanatomical issue. Here we report a quantitative retrograde tracer analysis in the cynomolgus macaque monkey of the weight consistency of the afferents of cortical areas across brains via calculation of a weight index (fraction of labeled neurons, FLN). Injection in 8 cortical areas (3 occipital plus 5 in the other lobes) revealed a consistent pattern: small subcortical input (1.3% cumulative FLN), high local intrinsic connectivity (80% FLN), high-input form neighboring areas (15% cumulative FLN), and weak long-range corticocortical connectivity (3% cumulative FLN). Corticocortical FLN values of projections to areas V1, V2, and V4 showed heavy-tailed, lognormal distributions spanning 5 orders of magnitude that were consistent, demonstrating significant connectivity profiles. These results indicate that 1) connection weight heterogeneity plays an important role in determining cortical network specificity, 2) high investment in local projections highlights the importance of local processing, and 3) transmission of information across multiple hierarchy levels mainly involves pathways having low FLN values.     

Principles governing auditory cortex connections

Topographic maps are common constituents of the primary auditory, visual, and somatic sensory cortex. However, in most cortical areas, no such maps have yet been identified, posing a conceptual problem for theories of cortical function centered on topography. What principle guides the organization of these other areas? We investigated this issue in cat auditory cortex. The connectional topography of five tonotopic areas and eight non-tonotopic areas was assessed using retrograde tract tracing and quantified by three metrics: clustering, dispersion, and separation. Clustering measures the spatial density of labeled neurons, dispersion provides an index of their spread, and separation serves as a scaling metric. These parameters each show that all auditory cortical regions receive precise and equally topographic connections from thalamic, corticocortical, and commissural sources. This isotropic principle suggests a common substrate for coordinating communication across the cortex and may reflect common mechanisms related to the developmental patterning of connections. This unifying principle extends to auditory and prefrontal cortex, and perhaps to other neocortical areas.     

Early specification of the hierarchical organization of visual cortical areas in the macaque monkey

The laminar organization of cortico-cortical projection neurons (expressed by the percentage of supragranular projecting neurons - SLN%) characterizes cortical pathways as feedforward (FF) or feedback (FB) and determines the hierarchical ranking of cortical areas. There is evidence of a developmental reduction in SLN% of pathways to area V1. Here, by analyzing pre- and postnatal projections to area V4, we have been able to address whether developmental reductions of SLN% impact on information processing in the immature cortex. FB pathways to area V4 exhibit 28-84% reduction of SLN%. This contrasts with the FF projections, which show little or no SLN% reduction. However, SLN% values in the immature cortex allocated cortical areas to the same hierarchical levels as in the adult. The developmental reduction of SLN% is a widespread phenomenon in the neocortex and is a distinctive feature of FB pathways. Two mechanisms contribute to developmental changes in SLN%: (i) delayed ingrowth of axons into the cortical target from infragranular layer neurons and (ii) prolonged developmental reduction of the divergence of projections from supragranular layer neurons. The present results show that FF and FB projections exhibit different developmental processes and patterns of connections linking cortical areas and their hierarchical relations are established prenatally, independently of regressive phenomena.     

Comparison of Intrinsic Connectivity in Different Areas of Macaque Monkey Cerebral Cortex

We have used small injections of biocytin to label and comparepatterns of intreareal, laterally spreading projections of pyramidalneurons in a number of areas of macaque monkey cerebral cortex.In visual areas (V1, V2, and V4), somatosensory areas (3b, 1,and 2), and motor area 4, a punctate discontinuous pattern ofconnections is made from 200-µm-diameter biocytin injectionsin the superficial layers. In prefrontal cortex (areas 9 and46), stripe-like connectivity patterns are observed. In allareas of cortex examined, the width of the terminal-free gapsis closely scaled to the average diameter of terminal patches,or width of terminal stripes. In addition, both patch and gapdimensions match the average lateral spread of the dendriticfield of single pyramidal neurons in the superficial layersof the same cortical region. These architectural features ofthe connectional mosaics are constant despite a twofold differencein scale across cortical areas and different species. They thereforeappear to be fundamental features of cortical organization.A model is offered in which local circuit inhibitory "basket"interneurons, activated at the same time as excitatory pyramidalneurons, could veto pyramidal neuron connections within eithercircular or stripe-like domains; this could lead to the formationof the pattern of lateral connections observed in this study,and provides a framework for further theoretical studies ofcerebral cortex function.     

The organization and connections of anterior and posterior parietal cortex in titi monkeys: do New World monkeys have an area 2?

We used multiunit electrophysiological recording techniques to examine the topographic organization of somatosensory area 3b and cortex posterior to area 3b, including area 1 and the presumptive area 5, in the New World titi monkey, Callicebus moloch. We also examined the ipsilateral and contralateral connections of these fields, as well as those in a region of cortex that appeared to be similar to both area 7b and the anterior intraparietal area (7b/AIP) described in macaque monkeys. All data were combined with architectonic analysis to generate comprehensive reconstructions. These studies led to several observations. First, area 1 in titi monkeys is not as precisely organized in terms of topographic order and receptive field size as is area 1 in macaque monkeys and a few New World monkeys. Second, cortex caudal to area 1 in titi monkeys is dominated by the representation of the hand and forelimb, and contains neurons that are often responsive to visual stimulation as well as somatic stimulation. This organization is more like area 5 described in macaque monkeys than like area 2. Third, ipsilateral and contralateral cortical connections become more broadly distributed away from area 3b towards the posterior parietal cortex. Specifically, area 3b has a relatively restricted pattern of connectivity with adjacent somatosensory fields 3a, 1, S2 and PV; area 1 has more broadly distributed connections than area 3b; and the presumptive areas 5 and 7b/AIP have highly diverse connections, including connections with motor and premotor cortex, extrastriate visual areas, auditory areas and somatosensory areas of the lateral sulcus. Fourth, the hand representation of the presumptive area 5 has dense callosal connections. Our results, together with previous studies in other primates, suggest that anterior parietal cortex has expanded in some primate lineages, perhaps in relation to manual abilities, and that the region of cortex we term area 5 is involved in integrating somatic inputs with the motor system and across hemispheres. Such connections could form the substrate for intentional reaching, grasping and intermanual transfer of information necessary for bilateral coordination of the hands.     

Cortical connections of the insular and adjacent parieto-temporal fields in the cat

We present a comprehensive analysis of the cortical connections of the insular and adjacent cortical areas in the domestic cat by using microinjections of wheat-germ agglutinin conjugated to horseradish peroxidase. We examined the identity and extent of the cortical fields connected to each area, the relative anatomical weights of the various connections, their laminar origin, and their paths across the cerebral commissures. Our main finding is that despite their relatively small size and close apposition, the connections of the insular and adjacent areas are far more widespread and more specific to each area than previously realized, suggesting that each area is involved in disparate aspects of cortical integration. The granular insular area is linked to a constellation of somatosensory, motor, premotor and prefrontal districts. The dysgranular insular area is chiefly associated with lateral prefrontal and premotor, lateral somatosensory and perirhinal cortices. The dorsal agranular insular area is connected with limbic neocortical fields, while the ventral agranular insular area is associated with an array of olfactory allocortical fields. The anterior sylvian area is associated with visual, auditory and multimodal areas, with the dorsolateral prefrontal cortex, and with perirhinal area 36. The parainsular area is linked to non-tonotopic auditory and ventromedial frontal areas. Trajectories followed by the callosal axons of each of the investigated areas are extremely divergent. As a whole, the picture of the insular region that emerges from this and a parallel study (Clascá et al., J Comp Neurol 384:456-482, 1997) is that of an extreme heterogeneity, both in terms of histological architecture and neural connections. Comparison with earlier published reports on primates suggests that most, but not all, of the areas we investigated in cats may have an direct counterpart within the insula of Old World monkeys.     

Top-down modulation of early sensory cortex

Data from nine previous studies of human visual information processing using positron emission tomography were reanalyzed to contrast blood flow responses during passive viewing and active discriminations of the same stimulus array. The analysis examined whether active visual processing (i) increases blood flow in medial visual regions early in the visual hierarchy and (ii) decreases blood flow in auditory and somatosensory cortex. Significant modulation of medial visual regions was observed in six of nine studies, indicating that top-down processes can affect early visual cortex. Modulations showed several task dependencies, suggesting that in some cases the underlying mechanism was selective (e.g. analysis-or feature-specific) rather than non- selective. Replicable decreases at or near auditory Brodmann area (BA) left 41/42 were observed in two of five studies, but in different locations. Analyses that combined data across studies yielded modest but significant decreases. Replicable decreases were not found in primary somatosensory cortex but were observed in an insular region that may be a somatosensory association area. Decreases were also noted in the parietal operculum (perhaps SII) and BA 40. These results are inconsistent with a model in which the precortical input to task- irrelevant sensory cortical areas is broadly suppressed.      

Areal organization of the posterior parietal cortex of the ferret (Mustela putorius)

On grounds of electrophysiological mapping, cytoarchitecture, myeloarchitecture and callosal and thalamic connectivity, we have identified two cortical areas in the posterior parietal cortex of the ferret: posterior parietal caudal and rostral (PPc and PPr). These areas occupy the lateral and suprasylvian gyri, from the cingulate sulcus (medially) to the suprasylvian sulcus (laterally) and lie between visual areas 18 and 21 (posteriorly) and the somatosensory areas (anteriorly). Within both areas a coarse representation of the visual field was found and within PPr there was also a representation of the body. Each representation mirrors those within neighboring areas. Cytoarchitectonic and myeloarchitectonic fields within this cortical region did not correspond in any simple way to the physiological representations. The architectonic differences correlate to differential callosal connectivity, with predominant connectivity corresponding to the upper hemifield/head representations. PPr and PPc receive thalamic projections from a different, but overlapping, complement of thalamic nuclei. The superimposition of somatic and visual maps in PPr might relate to the probable role of this area in transforming retinal-centered to body-centered spatial coordinates. The organization of the parietal areas in the ferret resembles that of the flying fox and might unveil a common organizational plan from which the primate posterior parietal cortex evolved.     

Serial processing in the human somatosensory system

Although numerous anatomical and electrophysiological findings in animal studies have supported a hierarchical scheme of somatosensory processing, precise activation timings of each cortical area are not known. Therefore we examined the temporal relationship of activities among multiple cortical areas using magnetoencephalography in humans. We found activations in Brodmann's areas 3b, 4, 1, 5 and the secondary somatosensory cortex region in the right hemisphere following transcutaneous electrical stimulation of the dorsum of the left hand. The mean onset latencies of each cortical activity were 14.4, 14.5, 18.0, 22.4 and 21.7 ms, respectively. The differences of onset latencies among these activations indicated the serial mode of processing both through the postcentral gyrus and through the primary and secondary somatosensory cortices.     

The anatomical connections of the macaque monkey orbitofrontal cortex. A review

The orbitofrontal cortex (OfC) is a heterogeneous prefrontal sector selectively connected with a wide constellation of other prefrontal, limbic, sensory and premotor areas. Among the limbic cortical connections, the ones with the hippocampus and parahippocampal cortex are particularly salient. Sensory cortices connected with the OfC include areas involved in olfactory, gustatory, somatosensory, auditory and visual processing. Subcortical structures with prominent OfC connections include the amygdala, numerous thalamic nuclei, the striatum, hypothalamus, periaqueductal gray matter, and biochemically specific cell groups in the basal forebrain and brainstem. Architectonic and connectional evidence supports parcellation of the OfC. The rostrally placed isocortical sector is mainly connected with isocortical areas, including sensory areas of the auditory, somatic and visual modalities, whereas the caudal non-isocortical sector is principally connected with non-isocortical areas, and, in the sensory domain, with olfactory and gustatory areas. The connections of the isocortical and non-isocortical orbital sectors with the amygdala, thalamus, striatum, hypothalamus and periaqueductal gray matter are also specific. The medial sector of the OfC is selectively connected with the hippocampus, posterior parahippocampal cortex, posterior cingulate and retrosplenial areas, and area prostriata, while the lateral orbitofrontal sector is the most heavily connected with sensory areas of the gustatory, somatic and visual modalities, with premotor regions, and with the amygdala.     

Neurophysiological architecture of functional magnetic resonance images of human brain

We investigated large-scale systems organization of the whole human brain using functional magnetic resonance imaging (fMRI) data acquired from healthy volunteers in a no-task or 'resting' state. Images were parcellated using a prior anatomical template, yielding regional mean time series for each of 90 regions (major cortical gyri and subcortical nuclei) in each subject. Significant pairwise functional connections, defined by the group mean inter-regional partial correlation matrix, were mostly either local and intrahemispheric or symmetrically interhemispheric. Low-frequency components in the time series subtended stronger inter-regional correlations than high-frequency components. Intrahemispheric connectivity was generally related to anatomical distance by an inverse square law; many symmetrical interhemispheric connections were stronger than predicted by the anatomical distance between bilaterally homologous regions. Strong interhemispheric connectivity was notably absent in data acquired from a single patient, minimally conscious following a brainstem lesion. Multivariate analysis by hierarchical clustering and multidimensional scaling consistently defined six major systems in healthy volunteers-- corresponding approximately to four neocortical lobes, medial temporal lobe and subcortical nuclei- - that could be further decomposed into anatomically and functionally plausible subsystems, e.g. dorsal and ventral divisions of occipital cortex. An undirected graph derived by thresholding the healthy group mean partial correlation matrix demonstrated local clustering or cliquishness of connectivity and short mean path length compatible with prior data on small world characteristics of non-human cortical anatomy. Functional MRI demonstrates a neurophysiological architecture of the normal human brain that is anatomically sensible, strongly symmetrical, disrupted by acute brain injury, subtended predominantly by low frequencies and consistent with a small world network topology.     

Cortical connections of functional zones in posterior parietal cortex and frontal cortex motor regions in new world monkeys

We examined the connections of posterior parietal cortex (PPC) with motor/premotor cortex (M1/PM) and other cortical areas. Electrical stimulation (500 ms trains) delivered to microelectrode sites evoked movements of reach, defense, and grasp, from distinct zones in M1/PM and PPC, in squirrel and owl monkeys. Tracer injections into M1/PM reach, defense, and grasp zones showed dense connections with M1/PM hand/forelimb representations. The densest inputs outside of frontal cortex were from PPC zones. M1 zones were additionally connected with somatosensory hand/forelimb representations in areas 3a, 3b, and 1 and the somatosensory areas of the upper bank of the lateral sulcus (S2/PV). Injections into PPC zones showed primarily local connections and the densest inputs outside of PPC originated from M1/PM zones. The PPC reach zone also received dense inputs from cortex caudal to PPC, which likely relayed visual information. In contrast, the PPC grasp zone was densely connected with the hand/forelimb representations of areas 3a, 3b, 1, and S2/PV. Thus, the dorsal parietal-frontal network involved in reaching was preferentially connected to visual cortex, whereas the more ventral network involved in grasping received somatosensory inputs. Additional weak interlinks between dissimilar zones (e.g., PPC reach and PPC grasp) were apparent and may coordinate actions.     

Evidence for cross-modal plasticity in adult mouse visual cortex following monocular enucleation

The goal of this study was to assess cortical reorganization in the visual system of adult mice in detail. A combination of deprivation of one eye and stimulation of the remaining eye previously led to the identification of input-specific subdivisions in mouse visual cortex. Using this information as a reference map, we established to what extent each of these functional subdivisions take part in cortical reactivation and reorganization upon unilateral enucleation. A recovery experiment revealed a differential laminar and temporal reactivation profile. Initiation of infragranular recovery of molecular activity near the border with nonvisual cortex and simultaneous hyperactivation of this adjacent cortex implied a partial nonvisual contribution to this plasticity. The strong effect of somatosensory deprivation as well as stimulation on infragranular visual cortex activation in long-term enucleated animals support this view. Furthermore, targeted tracer injections in visual cortex of control and enucleated animals revealed preexisting connections between the visual and somatosensory cortices of adult mice as possible mediators. In conclusion, this study supports an important cross-modal component in reorganization of adult mouse visual cortex upon monocular enucleation.     

Areal differences in diameter and length of corticofugal projections

Cortical areas differ in the size and distribution of neuronal cell bodies, density, and distribution of myelinated axons, connections, and functional properties. We find that they also differ in the diameter of long corticofugal axons, with the thickest axons originating from primary motor, somatosensory, and visual areas and the thinnest ones from prefrontal and temporal areas. Since diameter is proportional to axonal conduction velocity, it can be inferred that action potentials issued from the different areas will be relayed to their targets at different speed. Conduction delays also depend on conduction distance. By computing conduction velocity and conduction distances, we found the longest conduction delays for the primary visual and temporal areas and the shortest for the premotor, primary motor, and somatosensory areas, compatible with the available electrophysiological data. These findings seem to establish a new principle in cortical organization relevant to the pathophysiology of neurological or psychiatric illnesses as well as to the speed of information processing in cortical circuits.     

Cortical connections of the inferior parietal cortical convexity of the macaque monkey

We traced the cortical connections of the 4 cytoarchitectonic fields--Opt, PG, PFG, PF--forming the cortical convexity of the macaque inferior parietal lobule (IPL). Each of these fields displayed markedly distinct sets of connections. Although Opt and PG are both targets of dorsal visual stream and temporal visual areas, PG is also target of somatosensory and auditory areas. Primary parietal and frontal connections of Opt include area PGm and eye-related areas. In contrast, major parietal and frontal connections of PG include IPL, caudal superior parietal lobule (SPL), and agranular frontal arm-related areas. PFG is target of somatosensory areas and also of the medial superior temporal area (MST) and temporal visual areas and is connected with IPL, rostral SPL, and ventral premotor arm- and face-related areas. Finally, PF is primarily connected with somatosensory areas and with parietal and frontal face- and arm-related areas. The present data challenge the bipartite subdivision of the IPL convexity into a caudal and a rostral area (7a and 7b, respectively) and provide a new anatomical frame of reference of the macaque IPL convexity that advances our present knowledge on the functional organization of this cortical sector, giving new insight into its possible role in space perception and motor control.     

The representation of the visual field in three extrastriate areas of the ferret (Mustela putorius) and the relationship of retinotopy and field boundaries to callosal connectivity

We describe representations of the visual field in areas 18, 19 and 21 of the ferret using standard microelectrode mapping techniques. In all areas the azimuths are represented as islands of peripheral visual field surrounded by central visual field representation. The zero meridian was found at the 17/18 and 19/21 borders; at the 18/19 and anterior border of 21 the relative periphery of the visual field was found. In areas 18 and 19, elevations are represented in a smooth medio-lateral progression from lower to upper visual field. In several cases the elevations in area 21 evidenced a similar medio-lateral progression; however, in others the elevations exhibited a split representation of the horizontal meridian. Anatomically determined callosal connections coincided with the representation of azimuths near the zero meridian. Medio-lateral bands of callosal connectivity that straddle the 17/18 and 19/21 borders are connected by bridges of callosally projecting cells. Acallosal cortical islands corresponded to the peripheral visual field and were found straddling the 18/19 border and the anterior border of area 21. The results are discussed in relation to callosal connectivity and retinotopy in extrastriate visual cortex and to proposed homologies of carnivore and primate visual cortex.     

Revealing modular architecture of human brain structural networks by using cortical thickness from MRI

Modularity, presumably shaped by evolutionary constraints, underlies the functionality of most complex networks ranged from social to biological networks. However, it remains largely unknown in human cortical networks. In a previous study, we demonstrated a network of correlations of cortical thickness among specific cortical areas and speculated that these correlations reflected an underlying structural connectivity among those brain regions. Here, we further investigated the intrinsic modular architecture of the human brain network derived from cortical thickness measurement. Modules were defined as groups of cortical regions that are connected morphologically to achieve the maximum network modularity. We show that the human cortical network is organized into 6 topological modules that closely overlap known functional domains such as auditory/language, strategic/executive, sensorimotor, visual, and mnemonic processing. The identified structure-based modular architecture may provide new insights into the functionality of cortical regions and connections between structural brain modules. This study provides the first report of modular architecture of the structural network in the human brain using cortical thickness measurements.