Behavioral flexibility is associated with changes in structure and function distributed across a frontal cortical network in macaques.

One of the most influential accounts of central orbitofrontal cortex-that it mediates behavioral flexibility-has been challenged by the finding that discrimination reversal in macaques, the classic test of behavioral flexibility, is unaffected when lesions are made by excitotoxin injection rather than aspiration. This suggests that the critical brain circuit mediating behavioral flexibility in reversal tasks lies beyond the central orbitofrontal cortex. To determine its identity, a group of nine macaques were taught discrimination reversal learning tasks, and its impact on gray matter was measured. Magnetic resonance imaging scans were taken before and after learning and compared with scans from two control groups, each comprising 10 animals. One control group learned discrimination tasks that were similar but lacked any reversal component, and the other control group engaged in no learning. Gray matter changes were prominent in posterior orbitofrontal cortex/anterior insula but were also found in three other frontal cortical regions: lateral orbitofrontal cortex (orbital part of area 12 [12o]), cingulate cortex, and lateral prefrontal cortex. In a second analysis, neural activity in posterior orbitofrontal cortex/anterior insula was measured at rest, and its pattern of coupling with the other frontal cortical regions was assessed. Activity coupling increased significantly in the reversal learning group in comparison with controls. In a final set of experiments, we used similar structural imaging procedures and analyses to demonstrate that aspiration lesion of central orbitofrontal cortex, of the type known to affect discrimination learning, affected structure and activity in the same frontal cortical circuit. The results identify a distributed frontal cortical circuit associated with behavioral flexibility.

Developmental trajectory of social influence integration into perceptual decisions in children.

The opinions of others have a profound influence on decision making in adults. The impact of social influence appears to change during childhood, but the underlying mechanisms and their development remain unclear. We tested 125 neurotypical children between the ages of 6 and 14 years on a perceptual decision task about 3D-motion figures under informational social influence. In these children, a systematic bias in favor of the response of another person emerged at around 12 years of age, regardless of whether the other person was an age-matched peer or an adult. Drift diffusion modeling indicated that this social influence effect in neurotypical children was due to changes in the integration of sensory information, rather than solely a change in decision behavior. When we tested a smaller cohort of 30 age- and IQ-matched autistic children on the same task, we found some early decision bias to social influence, but no evidence for the development of systematic integration of social influence into sensory processing for any age group. Our results suggest that by the early teens, typical neurodevelopment allows social influence to systematically bias perceptual processes in a visual task previously linked to the dorsal visual stream. That the same bias did not appear to emerge in autistic adolescents in this study may explain some of their difficulties in social interactions.

Differences in Frontal Network Anatomy Across Primate Species.

The frontal lobe is central to distinctive aspects of human cognition and behavior. Some comparative studies link this to a larger frontal cortex and even larger frontal white matter in humans compared with other primates, yet others dispute these findings. The discrepancies between studies could be explained by limitations of the methods used to quantify volume differences across species, especially when applied to white matter connections. In this study, we used a novel tractography approach to demonstrate that frontal lobe networks, extending within and beyond the frontal lobes, occupy 66% of total brain white matter in humans and 48% in three monkey species: vervets (Chlorocebus aethiops), rhesus macaque (Macaca mulatta) and cynomolgus macaque (Macaca fascicularis), all male. The simian-human differences in proportional frontal tract volume were significant for projection, commissural, and both intralobar and interlobar association tracts. Among the long association tracts, the greatest difference was found for tracts involved in motor planning, auditory memory, top-down control of sensory information, and visuospatial attention, with no significant differences in frontal limbic tracts important for emotional processing and social behaviour. In addition, we found that a nonfrontal tract, the anterior commissure, had a smaller volume fraction in humans, suggesting that the disproportionally large volume of human frontal lobe connections is accompanied by a reduction in the proportion of some nonfrontal connections. These findings support a hypothesis of an overall rearrangement of brain connections during human evolution.SIGNIFICANCE STATEMENT Tractography is a unique tool to map white matter connections in the brains of different species, including humans. This study shows that humans have a greater proportion of frontal lobe connections compared with monkeys, when normalized by total brain white matter volume. In particular, tracts associated with language and higher cognitive functions are disproportionally larger in humans compared with monkeys, whereas other tracts associated with emotional processing are either the same or disproportionally smaller. This supports the hypothesis that the emergence of higher cognitive functions in humans is associated with increased extended frontal connectivity, allowing human brains more efficient cross talk between frontal and other high-order associative areas of the temporal, parietal, and occipital lobes.

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.

Validation of structural brain connectivity networks: The impact of scanning parameters.

Evaluation of the structural connectivity (SC) of the brain based on tractography has mainly focused on the choice of diffusion model, tractography algorithm, and their respective parameter settings. Here, we systematically validate SC derived from a post mortem monkey brain, while varying key acquisition parameters such as the b-value, gradient angular resolution and image resolution. As gold standard we use the connectivity matrix obtained invasively with histological tracers by Markov et al. (2014). As performance metric, we use cross entropy as a measure that enables comparison of the relative tracer labeled neuron counts to the streamline counts from tractography. We find that high angular resolution and high signal-to-noise ratio are important to estimate SC, and that SC derived from low image resolution (1.03 mm3) are in better agreement with the tracer network, than those derived from high image resolution (0.53 mm3) or at an even lower image resolution (2.03 mm3). In contradiction, sensitivity and specificity analyses suggest that if the angular resolution is sufficient, the balanced compromise in which sensitivity and specificity are identical remains 60-64% regardless of the other scanning parameters. Interestingly, the tracer graph is assumed to be the gold standard but by thresholding, the balanced compromise increases to 70-75%. Hence, by using performance metrics based on binarized tracer graphs, one risks losing important information, changing the performance of SC graphs derived by tractography and their dependence of different scanning parameters.

Calretinin interneuron density in the caudate nucleus is lower in autism spectrum disorder.

Autism spectrum disorder is a debilitating condition with possible neurodevelopmental origins but unknown neuroanatomical correlates. Whereas investigators have paid much attention to the cerebral cortex, few studies have detailed the basal ganglia in autism. The caudate nucleus may be involved in the repetitive movements and limbic changes of autism. We used immunohistochemistry for calretinin and neuropeptide Y in 24 age- and gender-matched patients with autism spectrum disorder and control subjects ranging in age from 13 to 69 years. Patients with autism had a 35% lower density of calretinin+ interneurons in the caudate that was driven by loss of small calretinin+ neurons. This was not caused by altered size of the caudate, as its cross-sectional surface areas were similar between diagnostic groups. Controls exhibited an age-dependent increase in the density of medium and large calretinin+ neurons, whereas subjects with autism did not. Diagnostic groups did not differ regarding ionized calcium-binding adapter molecule 1+ immunoreactivity for microglia, suggesting chronic inflammation did not cause the decreased calretinin+ density. There was no statistically significant difference in the density of neuropeptide Y+ neurons between subjects with autism and controls. The decreased calretinin+ density may disrupt the excitation/inhibition balance in the caudate leading to dysfunctional corticostriatal circuits. The description of such changes in autism spectrum disorder may clarify pathomechanisms and thereby help identify targets for drug intervention and novel therapeutic strategies.

Delineating extrastriate visual area MT(V5) using cortical myeloarchitecture.

Visual area MT is a model of choice in primate neurophysiological and human imaging research of visual perception, due to its considerable sensitivity to moving stimuli and the strong direction selectivity of its neurons. While the location of MT(V5) in the non-human primate is easily identifiable based on gross anatomy and appears consistent between animals, this is less the case in human subjects. Functional localisation of human MT+ with moving stimuli can identify a group of motion-sensitive regions, but defining MT proper has proved more challenging. In this review we consider approaches to studying the cyto- and myleoarchitecture of this cortical area that may, in the future, allow identification of human MT in vivo based on anatomy.

Long-range clustered connections within extrastriate visual area V5/MT of the rhesus macaque.

Visual area V5/MT in the rhesus macaque has a distinct functional organization, where neurons with specific preferences for direction of motion and binocular disparity are co-organized in columns or clusters. Here, we analyze the pattern of intrinsic connectivity within cortical area V5/MT in both parasagittal sections of the intact brain and tangential sections from flatmounted cortex using small injections of the retrograde tracer cholera toxin subunit b. Labeled cells were predominantly found in cortical layers 2, 3, and 6. Going along the cortical layers, labeled cells were concentrated in regularly spaced clusters. The clusters nearest to the injection site were approximately 2 mm from its center. In flatmounted cortex, along the dorsoventral axis of V5/MT, we identified further clusters of labeled cells up to 10 mm from the injection site. Quantitative analysis of parasagittal sections estimated average cluster spacing at 2.2 mm; in cortical flatmounts, spacing was 2.3 mm measured radially from the injection site. The results suggest a regular pattern of intrinsic connectivity within V5/MT, which is consistent with connectivity between sites with a common preference for both direction of motion and binocular depth. The long-range connections can potentially account for the large suppressive surrounds of V5/MT neurons.

Neurons in dorsal visual area V5/MT signal relative disparity.

Judgments of visual depth rely crucially on the relative binocular disparity between two visual features. While areas of ventral visual cortex contain neurons that signal the relative disparity between spatially adjacent visual features, the same tests in dorsal visual areas yield little evidence for relative disparity selectivity. We investigated the sensitivity of neurons in dorsal visual area V5/MT of macaque monkeys to relative disparity, using two superimposed, transparent planes composed of dots moving in opposite directions. The separation of the planes in depth specifies their relative disparity, while absolute disparity can be altered independently by changing the binocular depth of the two planes with respect to the monkey's fixation point. Many V5/MT neurons were tuned to relative disparity, independent of the absolute disparities of the individual planes. For the two plane stimulus, neuronal responses were often linearly related to responses to the absolute disparity of each component plane presented individually, but some aspects of relative disparity tuning were not explained by linear combination. Selectivity for relative disparity could not predict whether neuronal firing was related to the monkeys' perceptual reports of the rotation direction of structure-from-motion figures centered on the plane of fixation. In sum, V5/MT neurons are not just selective for absolute disparity, but also code for relative disparity between visual features. This selectivity may be important for segmentation and depth order of moving visual features, particularly the processing of three-dimensional information in scenes viewed by an actively moving observer.

Coding Perceptual Decisions: From Single Units to Emergent Signaling Properties in Cortical Circuits.

Spiking activity in single neurons of the primate visual cortex has been tightly linked to perceptual decisions. Any mechanism that reads out these perceptual signals to support behavior must respect the underlying neuroanatomy that shapes the functional properties of sensory neurons. Spatial distribution and timing of inputs to the next processing levels are critical, as conjoint activity of precursor neurons increases the spiking rate of downstream neurons and ultimately drives behavior. I set out how correlated activity might coalesce into a micropool of task-sensitive neurons signaling a particular percept to determine perceptual decision signals locally and for flexible interarea transmission depending on the task context. As data from more and more neurons and their complex interactions are analyzed, the space of computational mechanisms must be constrained based on what is plausible within neurobiological limits. This review outlines experiments to test the new perspectives offered by these extended methods.

Cross-species cortical alignment identifies different types of anatomical reorganization in the primate temporal lobe.

Evolutionary adaptations of temporo-parietal cortex are considered to be a critical specialization of the human brain. Cortical adaptations, however, can affect different aspects of brain architecture, including local expansion of the cortical sheet or changes in connectivity between cortical areas. We distinguish different types of changes in brain architecture using a computational neuroanatomy approach. We investigate the extent to which between-species alignment, based on cortical myelin, can predict changes in connectivity patterns across macaque, chimpanzee, and human. We show that expansion and relocation of brain areas can predict terminations of several white matter tracts in temporo-parietal cortex, including the middle and superior longitudinal fasciculus, but not the arcuate fasciculus. This demonstrates that the arcuate fasciculus underwent additional evolutionary modifications affecting the temporal lobe connectivity pattern. This approach can flexibly be extended to include other features of cortical organization and other species, allowing direct tests of comparative hypotheses of brain organization.

How did language evolve? Since the human lineage diverged from that of the other great apes millions of years ago, changes in the brain have given rise to behaviors that are unique to humans, such as language. Some of these changes involved alterations in the size and relative positions of brain areas, while others required changes in the connections between those regions. But did these changes occur independently, or can the changes observed in one actually explain the changes we see in the other? One way to answer this question is to use neuroimaging to compare the brains of related species, using different techniques to examine different aspects of brain structure. Imaging a fatty substance called myelin, for example, can produce maps showing the size and position of brain areas. Measuring how easily water molecules diffuse through brain tissue, by contrast, provides information about connections between areas. Eichert et al. performed both types of imaging in macaques and healthy human volunteers, and compared the results to existing data from chimpanzees. Computer simulations were used to manipulate the myelin-based images so that equivalent brain areas in each species occupied the same positions. In most cases, the distortions ­ or 'warping' ­ needed to superimpose brain regions on top of one another also predicted the differences between species in the connections between those regions. This suggests that movement of brain regions over the course of evolution explain the differences previously observed in brain connectivity. But there was one notable exception, namely a bundle of fibers with a key role in language called the arcuate fasciculus. This structure follows a slightly different route through the brain in humans compared to chimpanzees and macaques. Eichert et al. show that this difference cannot be explained solely by changes in the positions of brain regions. Instead, the arcuate fasciculus underwent additional changes in its course, which may have contributed to the evolution of language. The framework developed by Eichert et al. can be used to study evolution in many different species. Interspecies comparisons can provide clues to how brain structure and activity relate to each other and to behavior, and this knowledge could ultimately help to understand and treat brain disorders.

Preserved extrastriate visual network in a monkey with substantial, naturally occurring damage to primary visual cortex.

Lesions of primary visual cortex (V1) lead to loss of conscious visual perception with significant impact on human patients. Understanding the neural consequences of such damage may aid the development of rehabilitation methods. In this rare case of a Rhesus macaque (monkey S), likely born without V1, the animal's in-group behaviour was unremarkable, but visual task training was impaired. With multi-modal magnetic resonance imaging, visual structures outside of the lesion appeared normal. Visual stimulation under anaesthesia with checkerboards activated lateral geniculate nucleus of monkey S, while full-field moving dots activated pulvinar. Visual cortical activation was sparse but included face patches. Consistently across lesion and control monkeys, functional connectivity analysis revealed an intact network of bilateral dorsal visual areas temporally correlated with V5/MT activation, even without V1. Despite robust subcortical responses to visual stimulation, we found little evidence for strengthened subcortical input to V5/MT supporting residual visual function or blindsight-like phenomena.

Offline impact of transcranial focused ultrasound on cortical activation in primates.

To understand brain circuits it is necessary both to record and manipulate their activity. Transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique. To date, investigations report short-lived neuromodulatory effects, but to deliver on its full potential for research and therapy, ultrasound protocols are required that induce longer-lasting 'offline' changes. Here, we present a TUS protocol that modulates brain activation in macaques for more than one hour after 40 s of stimulation, while circumventing auditory confounds. Normally activity in brain areas reflects activity in interconnected regions but TUS caused stimulated areas to interact more selectively with the rest of the brain. In a within-subject design, we observe regionally specific TUS effects for two medial frontal brain regions - supplementary motor area and frontal polar cortex. Independently of these site-specific effects, TUS also induced signal changes in the meningeal compartment. TUS effects were temporary and not associated with microstructural changes.

Perceptual switch rates with ambiguous structure-from-motion figures in bipolar disorder.

Slowing of the rate at which a rivalrous percept switches from one configuration to another has been suggested as a potential trait marker for bipolar disorder. We measured perceptual alternations for a bistable, rotating, structure-from-motion cylinder in bipolar and control participants. In a control task, binocular depth rendered the direction of cylinder rotation unambiguous to monitor participants' performance and attention during the experimental task. A particular direction of rotation was perceptually stable, on average, for 33.5s in participants without psychiatric diagnosis. Euthymic, bipolar participants showed a slightly slower rate of switching between the two percepts (percept duration 42.3s). Under a parametric analysis of the best-fitting model for individual participants, this difference was statistically significant. However, the variability within groups was high, so this difference in average switch rates was not big enough to serve as a trait marker for bipolar disorder. We also found that low-level visual capacities, such as stereo threshold, influence perceptual switch rates. We suggest that there is no single brain location responsible for perceptual switching in all different ambiguous figures and that perceptual switching is generated by the actions of local cortical circuitry.

Short parietal lobe connections of the human and monkey brain.

The parietal lobe has a unique place in the human brain. Anatomically, it is at the crossroad between the frontal, occipital, and temporal lobes, thus providing a middle ground for multimodal sensory integration. Functionally, it supports higher cognitive functions that are characteristic of the human species, such as mathematical cognition, semantic and pragmatic aspects of language, and abstract thinking. Despite its importance, a comprehensive comparison of human and simian intraparietal networks is missing. In this study, we used diffusion imaging tractography to reconstruct the major intralobar parietal tracts in twenty-one datasets acquired in vivo from healthy human subjects and eleven ex vivo datasets from five vervet and six macaque monkeys. Three regions of interest (postcentral gyrus, superior parietal lobule and inferior parietal lobule) were used to identify the tracts. Surface projections were reconstructed for both species and results compared to identify similarities or differences in tract anatomy (i.e., trajectories and cortical projections). In addition, post-mortem dissections were performed in a human brain. The largest tract identified in both human and monkey brains is a vertical pathway between the superior and inferior parietal lobules. This tract can be divided into an anterior (supramarginal gyrus) and a posterior (angular gyrus) component in both humans and monkey brains. The second prominent intraparietal tract connects the postcentral gyrus to both supramarginal and angular gyri of the inferior parietal lobule in humans but only to the supramarginal gyrus in the monkey brain. The third tract connects the postcentral gyrus to the anterior region of the superior parietal lobule and is more prominent in monkeys compared to humans. Finally, short U-shaped fibres in the medial and lateral aspects of the parietal lobe were identified in both species. A tract connecting the medial parietal cortex to the lateral inferior parietal cortex was observed in the monkey brain only. Our findings suggest a consistent pattern of intralobar parietal connections between humans and monkeys with some differences for those areas that have cytoarchitectonically distinct features in humans. The overall pattern of intraparietal connectivity supports the special role of the inferior parietal lobule in cognitive functions characteristic of humans.

Neuronal mechanisms for the perception of ambiguous stimuli.

Ambiguous figures that may take on the appearance of two or more distinct forms have fascinated philosophers and psychologists for generations. Recently, several laboratories have studied the neuronal basis of perceptual appearance at the level of single neurons in the cerebral cortex. Experiments that integrate neuronal recording with analyses based on sensory detection theory reveal a remarkable degree of specificity in these neuronal responses. The new challenges are to understand how cognitive processes, such as attention and memory, interact with perception to generate these neuronal signals.

Defining the V5/MT neuronal pool for perceptual decisions in a visual stereo-motion task.

In the primate visual cortex, neurons signal differences in the appearance of objects with high precision. However, not all activated neurons contribute directly to perception. We defined the perceptual pool in extrastriate visual area V5/MT for a stereo-motion task, based on trial-by-trial co-variation between perceptual decisions and neuronal firing (choice probability (CP)). Macaque monkeys were trained to discriminate the direction of rotation of a cylinder, using the binocular depth between the moving dots that form its front and rear surfaces. We manipulated the activity of single neurons trial-to-trial by introducing task-irrelevant stimulus changes: dot motion in cylinders was aligned with neuronal preference on only half the trials, so that neurons were strongly activated with high firing rates on some trials and considerably less activated on others. We show that single neurons maintain high neurometric sensitivity for binocular depth in the face of substantial changes in firing rate. CP was correlated with neurometric sensitivity, not level of activation. In contrast, for individual neurons, the correlation between perceptual choice and neuronal activity may be fundamentally different when responding to different stimulus versions. Therefore, neuronal pools supporting sensory discrimination must be structured flexibly and independently for each stimulus configuration to be discriminated.This article is part of the themed issue 'Vision in our three-dimensional world'.

Neural architectures for stereo vision.

Stereoscopic vision delivers a sense of depth based on binocular information but additionally acts as a mechanism for achieving correspondence between patterns arriving at the left and right eyes. We analyse quantitatively the cortical architecture for stereoscopic vision in two areas of macaque visual cortex. For primary visual cortex V1, the result is consistent with a module that is isotropic in cortical space with a diameter of at least 3 mm in surface extent. This implies that the module for stereo is larger than the repeat distance between ocular dominance columns in V1. By contrast, in the extrastriate cortical area V5/MT, which has a specialized architecture for stereo depth, the module for representation of stereo is about 1 mm in surface extent, so the representation of stereo in V5/MT is more compressed than V1 in terms of neural wiring of the neocortex. The surface extent estimated for stereo in V5/MT is consistent with measurements of its specialized domains for binocular disparity. Within V1, we suggest that long-range horizontal, anatomical connections form functional modules that serve both binocular and monocular pattern recognition: this common function may explain the distortion and disruption of monocular pattern vision observed in amblyopia.This article is part of the themed issue 'Vision in our three-dimensional world'.

Playing the electric light orchestra--how electrical stimulation of visual cortex elucidates the neural basis of perception.

Vision research has the potential to reveal fundamental mechanisms underlying sensory experience. Causal experimental approaches, such as electrical microstimulation, provide a unique opportunity to test the direct contributions of visual cortical neurons to perception and behaviour. But in spite of their importance, causal methods constitute a minority of the experiments used to investigate the visual cortex to date. We reconsider the function and organization of visual cortex according to results obtained from stimulation techniques, with a special emphasis on electrical stimulation of small groups of cells in awake subjects who can report their visual experience. We compare findings from humans and monkeys, striate and extrastriate cortex, and superficial versus deep cortical layers, and identify a number of revealing gaps in the 'causal map' of visual cortex. Integrating results from different methods and species, we provide a critical overview of the ways in which causal approaches have been used to further our understanding of circuitry, plasticity and information integration in visual cortex. Electrical stimulation not only elucidates the contributions of different visual areas to perception, but also contributes to our understanding of neuronal mechanisms underlying memory, attention and decision-making.