Search

SUMMARYRapid and efficient gene transduction via recombinant adeno-associated viruses (rAAVs) is highly desirable across many basic and clinical research domains. Here we report vector co-infusion with doxorubicin, a clinical anti-cancer drug, markedly enhanced rAAV-mediated gene expression in the cerebral cortex across mammalian species (cat, mouse, and macaque), acting throughout the time-period examined and detectable at just three days post-transfection. This enhancement showed serotype generality, being common to rAAV serotypes 2, 8, 9 and PHP.eB tested, and was observed both locally, and at remote locations consistent with doxorubicin undergoing retrograde axonal transport. All these effects were observed at doses matching human blood plasma levels in clinical therapy, and lacked detectable cytotoxicity as assessed by cell morphology, activity, apoptosis and behavioral testing. Altogether, this study identifies an effective means to improve the capability and scope ofin vivorAAV applications, accelerating and augmenting gene transduction at doxorubicin concentrations paralleling medical practice.HighlightsAnti-cancer drug doxorubicin doubles the rate of rAAV-mediated transgene expressionDoxorubicin enhancement generalizes across rAAV serotypes and animal speciesThe effect is observed in both locally and retrogradely infected cortical neuronsThe effective dosage is free from appreciable cytotoxicity and matches clinical settings

Unidirectional connections from the cortex to the matrix of the corpus striatum initiate the cortico-basal ganglia (BG)-thalamocortical loop, thought to be important in momentary action selection and in longer-term fine tuning of behavioural repertoire; a discrete set of striatal compartments, striosomes, has the complementary role of registering or anticipating reward that shapes corticostriatal plasticity. Re-entrant signals traversing the cortico-BG loop impact predominantly frontal cortices, conveyed through topographically ordered output channels; by contrast, striatal input signals originate from a far broader span of cortex, and are far more divergent in their termination. The term ‘disclosed loop’ is introduced to describe this organisation: a closed circuit that is open to outside influence at the initial stage of cortical input. The closed circuit component of corticostriatal afferents is newly dubbed ‘operative’, as it is proposed to establish the bid for action selection on the part of an incipient cortical action plan; the broader set of converging corticostriatal afferents is described as contextual. A corollary of this proposal is that every unit of the striatal volume, including the long, C-shaped tail of the caudate nucleus, should receive a mandatory component of operative input, and hence include at least one area of BG-recipient cortex amongst the sources of its corticostriatal afferents. Individual operative afferents contact twin classes of GABAergic striatal projection neuron (SPN), distinguished by their neurochemical character, and onward circuitry. This is the basis of the classic direct and indirect pathway model of the cortico-BG loop. Each pathway utilises a serial chain of inhibition, with two such links, or three, providing positive and negative feedback, respectively. Operative co-activation of direct and indirect SPNs is, therefore, pictured to simultaneously promote action, and to restrain it. The balance of this rival activity is determined by the contextual inputs, which summarise the external and internal sensory environment, and the state of ongoing behavioural priorities. Notably, the distributed sources of contextual convergence upon a striatal locus mirror the transcortical network harnessed by the origin of the operative input to that locus, thereby capturing a similar set of contingencies relevant to determining action. The disclosed loop formulation of corticostriatal and subsequent BG loop circuitry, as advanced here, refines the operating rationale of the classic model and allows the integration of more recent anatomical and physiological data, some of which can appear at variance with the classic model. Equally, it provides a lucid functional context for continuing cellular studies of SPN biophysics and mechanisms of synaptic plasticity.

Highlights ► All subjects showed a significant bilateral field advantage in a visual search task. ► The group mean scanning speed is 20% faster for bilateral vs. unilateral displays. ► Bilateral field advantage (BFA) is absent for the target-absent condition, implying. ► BFA reflects intrahemispheric competition in a 1st, parallel stage of guided search. ► Interhemispheric competition in the 2nd, serial stage of guided search., The search task of Luck, Hillyard, Mangun and Gazzaniga (1989) was optimised to test for the presence of a bilateral field advantage in the visual search capabilities of normal subjects. The modified design used geometrically regular arrays of 2, 4 or 8 items restricted to hemifields delineated by the vertical or horizontal meridian; the target, if present, appeared at one of two fixed positions per quadrant at an eccentricity of 11 deg. Group and individual performance data were analysed in terms of the slope of response time against display-size functions (‘RT slope’). Averaging performance across all conditions save display mode (bilateral vs. unilateral) revealed a significant bilateral advantage in the form of a 21% increase in apparent item scanning speed for target detection; in the absence of a target, bilateral displays gave a 5% increase in speed that was not significant. Factor analysis by ANOVA confirmed this main effect of display mode, and also revealed several higher order interactions with display geometry, indicating that the bilateral advantage was masked at certain target positions by a crowding-like effect. In a numerical model of search efficiency (i.e. RT slope), bilateral advantage was parameterised by an interhemispheric ‘transfer factor’ (T) that governs the strength of the ipsilateral representation of distractors, and modifies the level of intrahemispheric competition with the target. The factor T was found to be higher in superior field than inferior field; this result held for the modelled data of each individual subject, as well as the group, representing a uniform tendency for the bilateral advantage to be more prominent in inferior field. In fact statistical analysis and modelling of search efficiency showed that the geometrical display factors (target polar and quadrantic location, and associated crowding effects) were all remarkably consistent across subjects. Greater variability was inferred within a fixed, decisional component of response time, with individual subjects capable of opposite hemifield biases. The results are interpretable by a guided search model of spatial attention – a first, parallel stage guiding selection by a second, serial stage – with the proviso that the first stage is relatively insular within each hemisphere. The bilateral advantage in search efficiency can then be attributed to a relative gain in target weight within the initial parallel stage, owing to a reduction in distractor competition mediated specifically by intrahemispheric circuitry. In the absence of a target there is no effective guidance, and hence no basis for a bilateral advantage to enhance search efficiency; the equivalence of scanning speed for the two display modes (bilateral and unilateral) implies a unitary second-stage process mediated via efficient interhemispheric integration.

Spatial attention modulates signal processing within visual nuclei of the thalamus—but do other nuclei govern the locus of attention in top-down mode? We examined functional MRI (fMRI) data from three subjects performing a task requiring covert attention to 1 of 16 positions in a circular array. Target position was cued after stimulus offset, requiring subjects to perform target detection from iconic visual memory. We found positionally specific responses at multiple thalamic sites, with individual voxels activating at more than one direction of attentional shift. Voxel clusters at anatomically equivalent sites across subjects revealed a broad range of directional tuning at each site, with little sign of contralateral bias. By reference to a thalamic atlas, we identified the nuclear correspondence of the four most reliably activated sites across subjects: mediodorsal/central-intralaminar (oculomotor thalamus), caudal intralaminar/parafascicular, suprageniculate/limitans, and medial pulvinar/lateral posterior. Hence, the cortical network generating a top-down control signal for relocating attention acts in concert with a spatially selective thalamic apparatus—the set of active nuclei mirroring the thalamic territory of cortical “eye-field” areas, thus supporting theories which propose the visuomotor origins of covert attentional selection.

The complexities of cortical circuitry are nothing short of fiendish, and the problem of integrating genetic, morphological and physiological details from diverse cortical areas and across diverse species is a worthy challenge to the burgeoning science of neuroinformatics. Though inconsistencies abound, the fact that some trans-areal, trans-specific generalisations are possible, and justified, is a quite remarkable observation. Following the strategy of ‘know thine enemy’, it appears that the cortical fiend has some interesting habits, which we can usefully begin to tag with some shorthand, functional labels.

This paper considers neuronal architectures from a computational perspective and asks what aspects of neuroanatomy and neurophysiology can be disclosed by the nature of neuronal computations? In particular, we extend current formulations of the brain as an organ of inference--based upon hierarchical predictive coding--and consider how these inferences are orchestrated. In other words, what would the brain require to dynamically coordinate and contextualize its message passing to optimize its computational goals? The answer that emerges rests on the delicate (modulatory) gain control of neuronal populations that select and coordinate (prediction error) signals that ascend cortical hierarchies. This is important because it speaks to a hierarchical anatomy of extrinsic (between region) connections that form two distinct classes, namely a class of driving (first-order) connections that are concerned with encoding the content of neuronal representations and a class of modulatory (second-order) connections that establish context-in the form of the salience or precision ascribed to content. We explore the implications of this distinction from a formal perspective (using simulations of feature-ground segregation) and consider the neurobiological substrates of the ensuing precision-engineered dynamics, with a special focus on the pulvinar and attention.

The pulvinar is an ‘associative’ thalamic nucleus, meaning that most of its input and output relationships are formed with the cerebral cortex. The function of this circuitry is little understood and its anatomy, though much investigated, is notably recondite. This is because pulvinar connection patterns disrespect the architectural subunits (anterior, medial, lateral and inferior pulvinar nuclei) that have been the traditional reference system. This article presents a simplified, global model of the organization of cortico–pulvinar connections so as to pursue their structure–function relationships. Connections between the cortex and pulvinar are topographically organized, and as a result the pulvinar contains a ‘map’ of the cortical sheet. However, the topography is very blurred. Hence the pulvinar connection zones of nearby cortical areas overlap, allowing indirect transcortical communication via the pulvinar. A general observation is that indirect cortico–pulvino–cortical circuits tend to mimic direct cortico–cortical pathways: this is termed ‘the replication principle’. It is equally apt for certain pairs (or groups) of nearby cortical areas that happen not to connect with each other. The ‘replication’ of this non–connection is achieved by discontinuities and dislocations of the cortical topography within the pulvinar, such that the associated pair of connection zones do not overlap. Certain of these deformations can be used to divide the global cortical topography into specific sub–domains, which form the natural units of a connectional subdivision of the pulvinar. A substantial part of the pulvinar also expresses visual topography, reflecting visual maps in occipital cortex. There are just two well–ordered visual maps in the pulvinar, that both receive projections from area V1, and several other occipital areas; the resulting duplication of cortical topography means that each visual map also acts as a separate connection domain. In summary, the model identifies four topographically ordered connection domains, and reconciles the coexistence of visual and cortical maps in two of them. The replication principle operates at and below the level of domain structure. It is argued that cortico–pulvinar circuitry replicates the pattern of cortical circuitry but not its function, playing a more regulatory role instead. Thalamic neurons differ from cortical neurons in their inherent rhythmicity, and the pattern of cortico–thalamic connections must govern the formation of specific resonant circuits. The broad implication is that the pulvinar acts to coordinate cortical information processing by facilitating and sustaining the formation of synchronized trans–areal assemblies; a more pointed suggestion is that, owing to the considerable blurring of cortical topography in the pulvinar, rival cortical assemblies may be in competition to recruit thalamic elements in order to outlast each other in activity.

[Abstract] Figure-ground discrimination refers to the perception of an object, the figure, against a nondescript background. Neural mechanisms of figure-ground detection have been associated with feedback interactions between higher centers and primary visual cortex and have been held to index the effect of global analysis on local feature encoding. Here, in recordings from visual thalamus of alert primates, we demonstrate a robust enhancement of neuronal firing when the figure, as opposed to the ground, component of a motion-defined figure-ground stimulus is located over the receptive field. In this paradigm, visual stimulation of the receptive field and its near environs is identical across both conditions, suggesting the response enhancement reflects higher integrative mechanisms. It thus appears that cortical activity generating the higher-order percept of the figure is simultaneously reentered into the lowest level that is anatomically possible (the thalamus), so that the signature of the evolving representation of the figure is imprinted on the input driving it in an iterative process. Biotechnology and Biological Sciences Research Council (United Kingdom); G022305/1 Medical Research Council, (United Kingdom); G0701535

The pulvinar, together with the LGN, makes up the thalamic component of the visual system, and is reciprocally connected to the entire visual cortex. The driving action of retinal input to the LGN is mimicked by a sub-population of cortical layer 5 afferents to the pulvinar, of which area V1 is a rich source. The more numerous afferents from layer 6 are thought to play a modulatory role. The physiological action of the cortico-pulvino-cortical circuitry is unknown. Because, topographically, cortico-pulvino-cortical loops tend to replicate observed patterns of direct cortico-cortical connections, the pulvinar might act as a remote hub for regulating the efficiency of transcortical communication.

The connection zones of cortical areas V3, V4, and V5 (MT) with the thalamic pulvinar nucleus in the macaque monkey were identified. A combination of single- and dual-tracer techniques was used to study their topography and to establish whether these zones occupy separate or overlapping pulvinar territories. In each case, the retinotopic distribution of tracer in the pulvinar was charted by reference to its parallel distribution within the maps of cortical areas V1 and V2. Each of the areas V3, V4, and V5 were found to connect with both the 1° and the 2° maps located within the inferior and lateral pulvinar nuclei and to respect the previously identified topographies of these maps. However, V5 connects to a narrow zone lining the rostrolateral margin of the lateral and inferior pulvinar and V4 to a broader zone within the body of these two nuclei, which is adjacent to but separate from the V5 zone; the V3 zone overlaps both. Focal injections into cortex produce columns of pulvinar label whose trajectory defines a line of isorepresentation. The lines of isorepresentation in the 1° and 2° maps are approximately linear and parallel and adopt a rostrolateral to caudomedial axis; in the 1° map, this axis is roughly perpendicular to the facet of the inferior pulvinar that lies adjacent to the lateral geniculate nucleus. The connections of V5 and V4 can be modelled as successive zones along the axis of isorepresentation, with registered visual topographies. The scheme is extended by existing reports that inferotemporal cortex connects to the caudomedial pole of this axis—reflecting an occipitotemporal cortical gradient, in that V1 and other prestriate areas, e.g., V3, connect to the opposite pole. Thus a simple model of the mapped volume in the pulvinar arises, in which a unidimensional cortical topography is represented orthogonally to retinal topography. Adjoining this volume medially, within the inferior and medial pulvinar, is a second, heavier zone of V5 connectivity, which is poorly topographic. Both the medial and the rostrolateral zones of V5 connectivity may overlap with previously identified regions of tectal input to the pulvinar. J. Comp. Neurol. 439:469‐490, 2001. © 2001 Wiley-Liss, Inc. Indexing terms: thalamus; dual labelling; retinotopic maps; axis of isorepresentation

This report addresses the connectivity of the cortex occupying middle to dorsal levels of the anterior bank of the parieto-occipital sulcus in the macaque monkey. We have previously referred to this territory, whose perimeter is roughly circumscribed by the distribution of interhemispheric callosal fibres, as area V6, or the 'V6 complex'. Following injections of wheatgerm agglutinin conjugated to horseradish peroxidase (WGA-HRP) into this region, we examined the laminar organization of labelled cells and axonal terminals to attain indications of relative hierarchical status among the network of connected areas. A notable transition in the laminar patterns of the local, intrinsic connections prompted a sub-designation of the V6 complex itself into two separate areas, V6 and V6A, with area V6A lying dorsal, or dorsomedial to V6 proper. V6 receives ascending input from V2 and V3, ranks equal to V3A and V5, and provides an ascending input to V6A at the level above. V6A is not connected to area V2 and in general is less heavily linked to the earliest visual areas; in other respects, the two parts of the V6 complex share similar spheres of connectivity. These include regions of peripheral representation in prestriate areas V3, V3A and V5, parietal visual areas V5A/MST and 7a, other regions of visuo-somatosensory association cortex within the intraparietal sulcus and on the medial surface of the hemisphere, and the premotor cortex. Subcortical connections include the medial and lateral pulvinar, caudate nucleus, claustrum, middle and deep layers of the superior colliculus and pontine nuclei.From this pattern of connections, it is clear that the V6 complex is heavily engaged in sensory-motor integration. The specific somatotopic locations within sensorimotor cortex that receive this input suggest a role in controlling the trunk and limbs, and outward reaching arm movements. There is a secondary contribution to the brain's complex oculomotor circuitry. That the medial region of the cortex is devoted to tightly interconnected representations of the sensory periphery, both visual and somatotopic - which are routinely stimulated in concert - would appear to be an aspect of the global organization of the cortex which must facilitate multimodal integration.

Highlights • Predictive coding explains the recursive hierarchical structure of cortical processes. • Granular layer 4, which relays ascending cortical pathways, is absent from motor cortex. • Perceptual inference results if ascending sensory data modify sensory predictions action, if spinal reflexes enact descending motor and/or proprioceptive predictions. • Motor layer 4 regresses as motor predictions inherently require less modification., The agranular architecture of motor cortex lacks a functional interpretation. Here, we consider a ‘predictive coding’ account of this unique feature based on asymmetries in hierarchical cortical connections. In sensory cortex, layer 4 (the granular layer) is the target of ascending pathways. We theorise that the operation of predictive coding in the motor system (a process termed ‘active inference’) provides a principled rationale for the apparent recession of the ascending pathway in motor cortex. The extension of this theory to interlaminar circuitry also accounts for a sub-class of ‘mirror neuron’ in motor cortex – whose activity is suppressed when observing an action –explaining how predictive coding can gate hierarchical processing to switch between perception and action.

We have used PET (positron emission tomography) to chart the mapping of the retina in human occipital visual cortex and hence to locate the secondary and tertiary visual areas, V2 and V3. A group of four non-selected male volunteers was presented with dynamic stimuli that were aligned with either the vertical or the right horizontal meridians (VM or HM) from 0 degree to 29 degrees eccentricity; the vertical stimuli were restricted to either the inferior or the superior hemifields. PET scans were performed using intravenous infusion of H215O and a Siemens-CTI 953B PET scanner with 3D data acquisition. Subjects received 18 scans, divided equally among the right HM, the superior VM, and the inferior VM. Data were analyzed with SPM software. The group average result confirmed our experimental hypothesis that human occipital visual cortex has retinotopic maps similar to those of the macaque monkey. Thus human areas V2 and V3 can be defined on the basis that the border between them is formed by the HM and that the outer border of V3 is demarcated by a second representation of the VM that runs approximately parallel to the primary representation of the VM at the V1/V2 border. Furthermore, as in many mammals, the extrastriate representation of the HM is "split", such that the superior contralateral quadrant is mapped in lower V2 and V3, occupying the ventral surface of human cortex, and the inferior contralateral quadrant is mapped in upper V2 and V3, which extend over the lateral and medial surfaces of each hemisphere. After stereotaxic normalization, the position of V3 defined by retinal topography was found to correspond to that surmised from our previous PET studies employing moving stimuli.

[Abstract] Many cells in both the central visual system and other sensory systems exhibit a center surround organization in their receptive field, where the response to a centrally placed stimulus is modified when a surrounding area is also stimulated. This can follow from laterally directed connections in the local circuit at the level of the cell in question but could also involve more complex interactions. In the lateral geniculate nucleus (LGN), the cells relaying the retinal input display a concentric, center surround organization that in part follows from the similar organization characterizing the retinal cells providing their input. However, local thalamic inhibitory interneurons also play a role, and as we examine here, feedback from the visual cortex too. Here, we show in the primate (macaque) that spatially organized cortical feedback provides a clear and differential influence serving to enhance both responses to stimulation within the center of the receptive field and the ability of the nonclassical surround mechanism to attenuate this. In short, both center and surround mechanisms are influenced by the feedback. This dynamically sharpens the spatial focus of the receptive field and introduces nonlinearities from the cortical mechanism into the LGN. Medical Research Council (United Kingdom); G0701535

The visual features of an object are processed by multiple, functionally specialized areas of cerebral cortex. When several objects are seen simultaneously, what mechanism preserves the association of features that belong to a single item? We address this question—known as the “binding problem”—by examining combinatorial feature selectivity of neurons in area V2. In recording from anesthetized macaques, we estimate that dual selectivity for chromatic and spatiotemporal attributes is 50% more common (27% vs. 18% sampling frequency) in superficial and deep layer neurons receiving feedback connections from higher areas, compared with layer 4-3 neurons relaying ascending signals. The operation of feedback pathways is thought to mediate attentional modulation of activity that may achieve binding through acting to select one single object for higher representation and filtering out competing objects. We propose that dual-selective neurons perform a “bridging” function, mediating the transfer of feedback-induced bias between feature dimensions. The bias can be propagated through V2 output neurons (of unitary selectivity) to higher levels of specialized processing and so promote selection of the target object's representation among multiple feature maps. The bridging function would thus act to unify the outcome of parallel, object-selective processes taking place along segregated visual pathways.

The pulvinar, together with the lateral geniculate nucleus (LGN), makes up the thalamic component of the visual system and is reciprocally connected to the entire visual cortex. The driving action of retinal input to the LGN is mimicked by a subpopulation of cortical layer 5 afferents to the pulvinar, of which area V1 is a rich source. The more numerous afferents from layer 6 are thought to play a modulatory role. The physiological action of the corticopulvinocortical circuitry is unknown. Because topographically corticopulvinocortical loops tend to replicate observed patterns of direct corticocortical connections, the pulvinar might act as a remote hub for regulating the efficiency of transcortical communication.

SummaryThe primate retina serves up three channels for visual entertainment, of which just one is used for the primary analysis of motion. A prominent, unique class of neuron has a dominant role in transmission from cortical area V1.

The agranular cortex is an important landmark—anatomically, as the architectural flag of mammalian motor cortex, and historically, as a spur to the development of theories of localization of function. But why, exactly, do agranularity and motor function go together? To address this question, it should be noted that not only does motor cortex lack granular layer four, it also has a relatively thinner layer three. Therefore, it is the two layers which principally constitute the ascending pathways through the sensory (granular) cortex that have regressed in motor cortex: simply stated, motor cortex does not engage in serial reprocessing of incoming sensory data. But why should a granular architecture not be demanded by the downstream relay of motor instructions through the motor cortex? The scant anatomical evidence available regarding laminar patterns suggests that the pathways from frontal and premotor areas to the primary motor cortex actually bear a greater resemblance to the descending, or feedback connections of sensory cortex that avoid the granular layer. The action of feedback connections is generally described as ‘modulatory’ at a cellular level, or ‘selective’ in terms of systems analysis. By contrast, ascending connections may be labelled ‘driving’ or ‘instructive’. Where the motor cortex uses driving inputs, they are most readily identified as sensory signals instructing the visual location of targets and the kinaesthetic state of the body. Visual signals may activate motor concepts, e.g. ‘mirror neurons’, and the motor plan must select the appropriate muscles and forces to put the plan into action, if the decision to move is taken. This, perhaps, is why ‘driving’ motor signals might be inappropriate—the optimal selection and its execution are conditional upon both kinaesthetic and motivational factors. The argument, summarized above, is constructed in honour of Korbinian Brodmann's centenary, and follows two of the fundamental principles of his school of thought: that uniformities in cortical structure, and development imply global conservation of some aspects of function, whereas regional variations in architecture can be used to chart the ‘organs’ of the cortex, and perhaps to understand their functional differences.

From an operational perspective, attention is a matter of organizing multiple brain centres to act in concert on the task at hand. Taking focal visual attention as an example, recent anatomical findings suggest that the pulvinar might act as a remote hub for coordinating spatial activity within multiple cortical visual maps. The pulvinar can, in turn, be influenced by signals originating in the frontal and parietal eye fields, using common visuomotor neural circuitry, with the superior colliculus acting as an important link. By identifying a complex, real neural architecture ('RNA') model for attention, it is possible to integrate several different modes of operation - such as parallel or serial, bottom-up or top-down, preattentive or attentive - that characterize conflicting cognitive models of attention in visual search paradigms.

We have compared physiological data recorded from three alert macaque monkeys with separate observations of local connectivity, to locate and characterize the functional border between two related but distinct visual areas on the caudal face of the superior parietal gyrus. We refer to these areas as V6 and V6A. The occupy almost the entire extent of the anterior bank of the parieto-occipital sulcus, V6A being the more dorsal. These two areas are strongly interconnected. Anatomically, we have defined the border as the point at which labelled axon terminals first adopt a recognizably 'descending' pattern in their laminar characteristics, after injections of wheatgerm agglutinin-horseradish peroxidase into the dorsal half of the gyrus (in presumptive V6A). A similar principle was used to recognize the same border by the pattern of input from area V5, except that in this case the relevant transition in laminar characteristics is that between an 'intermediate' pattern (in V6) and an 'ascending' pattern (in V6A). V6A was found to be distinct from V6 in a number of its physiological properties. Unlike V6, it contains visually unresponsive cells as well as units with craniotopic receptive fields ('real-position' cells), units tuned to very slow stimulus speeds, units with complex visual selectivities and units with activity related to attention. V6A was also found to have a larger mean receptive field size and scatter than V6. By contrast, response properties related to the basic orientation and direction of moving bar stimuli were indistinguishable between V6 and V6A, as was the influence of gaze direction on cell activity in the two areas. Two-dimensional maps of the recording sites allowed reconstruction of the V6/V6A border. For comparison, the anatomical results were rendered on two-dimensional maps of identical format to those used to summarize the physiological data. After normalizing for relative size, the physiological and connectional estimates of the border between V6 and V6A were found to coincide, at least within the range of individual variation between hemispheres. An architectonic map in the same format was also made from a hemisphere stained for myelin and Nissl substance. Area PO, defined by its general density of myelination was not distinct in this material, but several architectural features were traceable and one of these was also found to approximate the V6/V6A border. The particular criteria that distinguish V6 from V6A differ from a recent description of areas PO and POd in the Cebus monkey; we believe it most likely that PO and POd together may correspond to V6.

Two distinct pathways in the visual cortex shadow each other from start to finish. Why?

We have used the technique of PET to chart the areas of human cerebral cortex specifically responsive to an optical flow stimulus simulating forward motion in depth over a flat horizontal surface. The optical flow display contained about 2000 dots accelerating in radial directions away from the focus of expansion, which subjects fixated at the centre of the display monitor: Dots remained of constant size, but their density decreased from the horizon, lying across the middle of the screen, to the foreground at the lower screen margin; the top half of the display was void. For the control stimulus the dot motions were randomized, removing any sensation of motion in depth and diminishing the impression of a flat terrain. Comparison of the regional cerebral blood flow (rCBF) elicited by the optical flow and control stimuli was thus intended to reveal any area selectively responsive to the radial velocity field that is characteristic of optical flow in its simplest natural form. Six subjects were scanned, and analysed as a group. Four subjects were analysed as individuals, their PET data being co-registered with MRIs of the cerebrum to localize rCBF changes to individual gyri and sulci. There were three main areas of activation associated with optical flow: the dorsal cuneus (area V3) and the latero-posterior precuneus (or superior parietal lobe) in the right hemisphere, and the occipito-temporal ventral surface, in the region of the fusiform gyrus, in both hemispheres. There was no significant activation of V1/V2, nor of V5. These results show that higher stages of motion take place in both the ‘dorsal’ and ‘ventral’ visual pathways, as these are commonly conceived, and that both may be fed by area V3. The information potentially derivable from optical flow concerns the direction of heading, and the layout of the visual environment, a form of three-dimensional structure-from-motion. The perceptual division of labour between the various activated areas cannot be directly inferred, though it is a reasonable supposition that the parietal activation reflects the utility of optic flow for guiding self-motion.

The lateral suprasylvian (LS) area (or Clare-Bishop area) is a region of visual cortex in the cat which has been defined as an isolated projection zone of area 17 (VI or striate cortex) within the suprasylvian sulcus. We have studied the overall topography and detailed pattern of connection between these two visual areas following injections of WGA-HRP into one or the other.The projection from area 17 to LS is formed largely (-90%) from supragranular layer neurons that are distributed, in the coronal plane, in multiple regularly spaced patches. These patches are especially prominent in regions of area 17 representing central vision along and around the horizontal meridian. In reconstructions of serial coronal sections, and in flatmounts of the same region, the patches are seen to align so that in the plane tangential to the cortical surface they appear as a system of parallel bands whose main axis of elongation is rostro-ventral to caudo-dorsal, or near parallel to the area 17/18 border. The mean periodicity of the bands is about 1.0 mm.The projection from area 17 terminates mainly in layers 4, 3, and 2 of area LS, and also appears patchy in the coronal plane. Reconstruction of the cortical surface view again reveals a system of rostrocaudal bands, but with a mean periodicity of 2 mm. The back projection is less periodically organized, arising predominantly (-80%) from a continuous sheet of infragranular neurons in area LS and terminating mainly in layer 1 of area 17, across the underlying patch and interpatch zones of the supragranular projection cells. However, neurons in layers 2 and upper 3 of area LS, which form the minority origin of the back projection, are mostly located in columnar registration with the patches of area 17 terminals.The bands of supragranular layer neurons projecting to area LS are aligned obliquely to the iso-orientation domains of area 17, indicating a further component to its organization. It is suggested that this may correspond to a segregation of the X and Y channels in area 17, with outputs to area LS selectively arising from the Y pathway, in accordance with previous reports.

We have explored the visuotopic organization of the territory surrounding the middle suprasylvian sulcus (MSS) of cat cerebral cortex by electrophysiological mapping, and by tracing the topography of its cortical and subcortical connections using wheatgerm-agglutinin horseradish peroxidase (WGA-HRP). Observations from the two approaches were concordant, and confirmed the presence of two separate visual areas in the MSS that approximate, but do not exactly correspond, to the location and internal organization of the posterior medial and posterior lateral lateral suprasylvian (PMLS, PLLS) areas of Palmer et al. (1978).We define as part of the lateral suprasylvian (LS) area the territory on the medial bank and caudal end of the lateral bank of the MSS that receives a topographically organized projection from the region of area 17 representing the lower visual quadrant. This territory is connected with other structures that are themselves striate-recipient (cortical areas 18 and 19, and the lateral division of the lateral posterior (LPI) nucleus), and with a variety of nuclei that receive direct retinal input, such as the C-laminae of the LGd, the medial interlaminar nucleus (MIN), and the superficial layers of the superior colliculus (SC). Its connections with the LP1, LGd, MIN, and SC correspond topographically with the input from area 17. Revised maps of area LS were produced from the physiological and connectional data: its rostral border is formed by a representation of lower visual elevations with the horizontal meridian represented caudally, and its lateral border is formed by the vertical meridian; area LS shares a representation of the center of gaze with the visual area of the lateral bank at its caudal end.The adjacent lateral bank area has larger receptive fields than area LS, and very different connectivity. It receives no input from area 17 and little input from striate-recipient structures, including area LS, but instead is connected to more remote extrastriate visual areas, such as the anterior ectosylvian visual (AEV) area in insular cortex, and to zones of the thalamus in receipt of tectal input (LPm and the lateromedial-suprageniculate nuclear complex). According to both mapping approaches, the lateral bank area contains representations of both the upper and lower visual quadrants but a rather limited degree of visuotopic order. We refer to it as the posterior ectosylvian visual (PEV) area, because it appears to be functionally and connectionally dissociated from area LS, but is possibly a functional antecedent of area AEV.

Area V5 or MT of primate extrastriate visual cortex is specialized for involvement in the analysis of motion and receives input from two layers, 4B and 6, of the striate cortex or V1. Injections of horseradish peroxidase - wheatgerm agglutinin into V5 reveal a patchy distribution of labelled cells and axonal terminals in layer 4B, suggesting the presence of a segregated and functionally specialized subsystem within the layer. The patches are similar in size and frequency to the cytochrome oxidase blobs of layers 2 and 3, but bear little systematic relationship to them. V5-efferent cells in layer 6, however, tend to avoid the cores of the blobs. The back projection from V5 is continuously distributed in layers 6 and 1, though it is absent inside representations of the central 10 degrees in the latter; it is also diffusely distributed between the patches in layer 4B and over a territory wider than that occupied by labelled cells. It is thus inferred that the back projection probably influences (a) V5-efferent cells other than those projecting to the injected site in V5, and (b) cells projecting to locations other than V5. There are no major changes in the cortical frequency of V5-efferent cells with eccentricity in the visual field representation. The V5-efferent cells of layer 6 are tenfold less frequent than those of layer 4B and as a population may therefore be involved with only a limited sector of directions of movement. Furthermore, their topographic distribution does not always coincide exactly with that of the layer 4B population, as if a site in V5 receives information about slightly non-corresponding regions of the visual field from the two layers.

We have studied the connections between two visual areas of macaque monkey cortex, V2 and V4, by injecting wheat-germ agglutinin horseradish peroxidase (HRP-WGA) into V4 and examining the distribution of labelled cells and terminals in V2, in relation to its characteristically striped cytochrome oxidase architecture. The cells projecting from V2 to V4 are arranged in bands and the number of bands per cycle of cytochrome oxidase stripes varies (one cycle consists of a thin stripe, a thick stripe and two interstripes). In the Type 1 connectivity pattern, there is just one band per cycle, centred over the thin stripes but normally spreading into the neighbouring interstripes. In the Type 2 connectivity pattern there are two bands per cycle, generally rather narrower and centred over the interstripes. Thick stripes are mostly free of labelled cells. The return projection from V4 to V2, whilst being concentrated in the vicinity of the labelled cells, is more diffusely distributed and invades the territory of all the stripes.

The descending projections from motor cortex share many features with top-down or backward connections in visual cortex; for example, corticospinal projections originate in infragranular layers, are highly divergent and (along with descending cortico-cortical projections) target cells expressing NMDA receptors. This is somewhat paradoxical because backward modulatory characteristics would not be expected of driving motor command signals. We resolve this apparent paradox using a functional characterisation of the motor system based on Helmholtz’s ideas about perception; namely, that perception is inference on the causes of visual sensations. We explain behaviour in terms of inference on the causes of proprioceptive sensations. This explanation appeals to active inference, in which higher cortical levels send descending proprioceptive predictions, rather than motor commands. This process mirrors perceptual inference in sensory cortex, where descending connections convey predictions, while ascending connections convey prediction errors. The anatomical substrate of this recurrent message passing is a hierarchical system consisting of functionally asymmetric driving (ascending) and modulatory (descending) connections: an arrangement that we show is almost exactly recapitulated in the motor system, in terms of its laminar, topographic and physiological characteristics. This perspective casts classical motor reflexes as minimising prediction errors and may provide a principled explanation for why motor cortex is agranular.

Area V2 of the cerebral cortex of higher primates has a complex cytochrome oxidase architecture whose most characteristic element is a set of stripes running orthogonal to its long axis. These stripes can be related to the segregation between the various pathways in which V2 participates. In the macaque monkey the more metabolically active stripes are alternately thick and thin and only one set, the thick stripes, is found to possess clusters of labelled cells following injections of horseradish peroxidase — wheatgerm agglutinin into area V5. Some of these clusters, but not all, coincide with substructures inside the thick stripes. V2 of the owl monkey has a similar organization except that the diversification into thick and thin stripes is less prominent, both in terms of their appearance and in that more than every alternate stripe is connected to area MT, the likely homologue of V5. The return projection from V5 to V2 is more widespread than the origin of the forward projection. It extends not only between the clusters of V5‐efferent cells within the thick stripes but also across the intervening thin stripes and less active interstripes. Because the latter subserve functions different from those of the thick stripes it would seem that their receipt of a back projection from an area to which they do not project, V5, may be relevant to the process of intergration of signals relating to different attributes of vision. Copyright © 1989, Wiley Blackwell. All rights reserved

V5 and V4 are areas of macaque monkey prestriate visual cortex that are specialized for involvement in different aspects of visual perception, namely motion for V5 (refs 1-4) and colour vision, with other possible functions, for V4 (refs 2, 5-9). Thus, it is unlikely that they should be fed the same information for further processing, yet both receive a strong input from patches of the upper layers of V2 (refs 10, 11), the area immediately adjoining the primary visual cortex, V1. V2, however, seems to comprise functionally distinct subregions, which can be revealed by staining the tissue for the mitochondrial enzyme cytochrome oxidase. Here we report that V4 and V5 are connected with separate cytochrome oxidase-defined subregions of V2, suggesting that cortical pathways dealing with motion and colour perception are segregated in their passage through V2, and reinforcing evidence for functional specialization in the visual cortex.

Patterns of anatomical connections in the visual cortex form the structural basis for segregating features of the visual image into separate cortical areas and for communication between these areas at all levels to produce a coherent percept. Such multi-stage integration may be a common strategy throughout the cortex for producing complex behaviour.

In pursuing our work on the organization of human visual cortex, we wanted to specify more accurately the position of the visual motion area (area V5) in relation to the sulcal and gyral pattern of the cerebral cortex. We also wanted to determine the intersubject variation of area V5 in terms of position and extent of blood flow change in it, in response to the same task. We therefore used positron emission tomography (PET) to determine the foci of relative cerebral blood flow increases produced when subjects viewed a moving checkerboard pattern, compared to viewing the same pattern when it was stationary. We coregistered the PET images from each subject with images of the same brain obtained by magnetic resonance imaging, thus relating the position of V5 in all 24 hemispheres examined to the individual gyral configuration of the same brains. This approach also enabled us to examine the extent to which results obtained by pooling the PET data from a small group of individuals (e.g., six), chosen at random, would be representative of a much larger sample in determining the mean location of V5 after transformation into Talairach coordinates. After stereotaxic transformation of each individual brain, we found that the position of area V5 can vary by as much as 27 mm in the left hemisphere and 18 mm in the right for the pixel with the highest significance for blood flow change. There is also an intersubject variability in blood flow change within it in response to the same visual task. V5 nevertheless bears a consistent relationship, within each brain, to the sulcal pattern of the occipital lobe. It is situated ventrolaterally, just posterior to the meeting point of the ascending limb of the inferior temporal sulcus and the lateral occipital sulcus. In position it corresponds almost precisely with Flechsig's Feld 16, one of the areas that he found to be myelinated at birth. © 1993 Oxford University Press.

We have used the technique of PET to chart the cortical areas activated by visual motion in the brain of a patient with a severe impairment in the ability to recognize the motion of objects (akinetopsia), following bilateral lesions which have so far been presumed to include area V5. High resolution MRI of her brain showed that the zone occupied by area V5 had indeed been destroyed bilaterally. Positron emission tomography activation images, co-registered to the MRIs, showed three principal regions of the cortex activated by motion. These were located (i) bilaterally in the precuneus of superior parietal cortex (area 7 of Brodmann); (ii) bilaterally in the cuneus (a region considered to represent upper V3); (iii) in the left lingual and fusiform gyri (possibly lower V3 and adjacent areas). In contrast to normal subjects, there was no significant activation of area V1 or V2. The stimuli used for scanning were chosen by prior testing of the patient's visual capacities. The control stimulus was a static random distribution of light squares on a dark background. In the moving stimulus these squares moved coherently, the direction of motion changing periodically between the cardinal directions (left, right, up and down). It was ascertained that the patient could correctly identify these directions. We also found (i) that her occasional errors were always in the direction opposite to the motion presented, so that her identification of axis of motion (i.e. vertical or horizontal) was 100% correct; (ii) that when a few static squares were added to the moving the display her identification of direction fell to chance but her identification of the axis of motion remained 100%; (iii) that when a few squares moving opposite and orthogonal to the predominant direction of motion were incorporated, her performance on both direction and axis fell to chance; (iv) that she was unable to identify motion in oblique directions between the horizontal or vertical axes, always guessing one of the cardinal directions. In accounting for her residual vision in terms of cortex, which remains active, we hypothesize; (i) that the bilateral loss of V5 has affected direction sensitive mechanisms at other sites in the cortex which are interconnected with V5 and (ii) that in consequence her performance on our tests reflects the properties of dynamic orientation selective mechanisms that were also differentially activated by the stimuli used during scanning.