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In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-specific brain development, there have been no attempts to formally compare human and mouse neuroanatomical sex differences to ascertain how well they translate. Addressing this question would shed critical light on the use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use structural magnetic resonance imaging to conduct the first comparative neuroimaging study of sex-specific neuroanatomy of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous regions (r=0.30). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-specific brain development in mice to brain regions that best echo sex-specific brain development in humans.

Humans are driven by an intrinsic motivation to learn, but the developmental origins of curiosity-driven exploration remain unclear. We investigated the computational principles guiding 4-year-old children's exploration during a touchscreen game (N = 102, F = 49, M = 53, primarily white and middle-class, data collected in the Netherlands from 2021-2023). Children guessed the location of characters that were hiding following predictable (yet noisy) patterns. Children could freely switch characters, which allowed us to quantify "when" they decided to explore something different and "what" they chose to explore. Bayesian modeling of their responses revealed that children selected activities that were more novel and offered greater learning progress (LP). Moreover, children's interest in making LP correlated with better learning performance. These findings highlight the importance of novelty and LP in guiding children's exploration.

The ever-increasing use of mouse models in preclinical neuroscience research calls for an improvement in the methods used to translate findings between mouse and human brains. Previously, we showed that the brains of primates can be compared in a direct quantitative manner using a common reference space built from white matter tractography data (Mars et al., 2018b). Here, we extend the common space approach to evaluate the similarity of mouse and human brain regions using openly accessible brain-wide transcriptomic data sets. We show that mouse-human homologous genes capture broad patterns of neuroanatomical organization, but the resolution of cross-species correspondences can be improved using a novel supervised machine learning approach. Using this method, we demonstrate that sensorimotor subdivisions of the neocortex exhibit greater similarity between species, compared with supramodal subdivisions, and mouse isocortical regions separate into sensorimotor and supramodal clusters based on their similarity to human cortical regions. We also find that mouse and human striatal regions are strongly conserved, with the mouse caudoputamen exhibiting an equal degree of similarity to both the human caudate and putamen.

Post-mortem magnetic resonance imaging (MRI) provides the opportunity to acquire high-resolution datasets to investigate neuroanatomy and validate the origins of image contrast through microscopy comparisons. We introduce the Digital Brain Bank (open.win.ox.ac.uk/DigitalBrainBank), a data release platform providing open access to curated, multimodal post-mortem neuroimaging datasets. Datasets span three themes—Digital Neuroanatomist: datasets for detailed neuroanatomical investigations; Digital Brain Zoo: datasets for comparative neuroanatomy; and Digital Pathologist: datasets for neuropathology investigations. The first Digital Brain Bank data release includes 21 distinctive whole-brain diffusion MRI datasets for structural connectivity investigations, alongside microscopy and complementary MRI modalities. This includes one of the highest-resolution whole-brain human diffusion MRI datasets ever acquired, whole-brain diffusion MRI in fourteen nonhuman primate species, and one of the largest post-mortem whole-brain cohort imaging studies in neurodegeneration. The Digital Brain Bank is the culmination of our lab’s investment into post-mortem MRI methodology and MRI-microscopy analysis techniques. This manuscript provides a detailed overview of our work with post-mortem imaging to date, including the development of diffusion MRI methods to image large post-mortem samples, including whole, human brains. Taken together, the Digital Brain Bank provides cross-scale, cross-species datasets facilitating the incorporation of post-mortem data into neuroimaging studies.

Chimpanzees (Pan troglodytes) are, along with bonobos, humans' closest living relatives. The advent of diffusion MRI tractography in recent years has allowed a resurgence of comparative neuroanatomical studies in humans and other primate species. Here we offer, in comparative perspective, the first chimpanzee white matter atlas, constructed from in vivo chimpanzee diffusion-weighted scans. Comparative white matter atlases provide a useful tool for identifying neuroanatomical differences and similarities between humans and other primate species. Until now, comprehensive fascicular atlases have been created for humans (Homo sapiens), rhesus macaques (Macaca mulatta), and several other nonhuman primate species, but never in a nonhuman ape. Information on chimpanzee neuroanatomy is essential for understanding the anatomical specializations of white matter organization that are unique to the human lineage.

The temporal association cortex is considered a primate specialization and is involved in complex behaviors, with some, such as language, particularly characteristic of humans. The emergence of these behaviors has been linked to major differences in temporal lobe white matter in humans compared with monkeys. It is unknown, however, how the organization of the temporal lobe differs across several anthropoid primates. Therefore, we systematically compared the organization of the major temporal lobe white matter tracts in the human, gorilla, and chimpanzee great apes and in the macaque monkey. We show that humans and great apes, in particular the chimpanzee, exhibit an expanded and more complex occipital-temporal white matter system; additionally, in humans, the invasion of dorsal tracts into the temporal lobe provides a further specialization. We demonstrate the reorganization of different tracts along the primate evolutionary tree, including distinctive connectivity of human temporal gray matter.

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.

With the increasing necessity of animal models in biomedical research, there is a vital need to harmonise findings across species by establishing similarities and differences in rodent and primate neuroanatomy. Using connectivity fingerprint matching, we compared cortico-striatal circuits across humans, non-human primates, and mice using resting-state fMRI data in all species. Our results suggest that the connectivity patterns for the nucleus accumbens and cortico-striatal motor circuits (posterior/lateral putamen) were conserved across species, making them reliable targets for cross-species comparisons. However, a large number of human and macaque striatal voxels were not matched to any mouse cortico-striatal circuit (mouse->human: 85% unassigned; mouse->macaque 69% unassigned; macaque->human; 31% unassigned). These unassigned voxels were localised to the caudate nucleus and anterior putamen, overlapping with executive function and social/language regions of the striatum and connected to prefrontal-projecting cerebellar lobules and anterior prefrontal cortex, forming circuits that seem to be unique for non-human primates and humans.

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.

The interactions of anterior temporal structures, and especially the amygdala, with the prefrontal cortex are pivotal to learning, decision-making, and socio-emotional regulation. A clear anatomical description of the organization and dissociation of fiber bundles linking anterior temporal cortex/amygdala and prefrontal cortex in humans is still lacking. Using diffusion imaging techniques, we reconstructed fiber bundles between these anatomical regions in human and macaque brains. First, by studying macaques, we assessed which aspects of connectivity known from tracer studies could be identified with diffusion imaging. Second, by comparing diffusion imaging results in humans and macaques, we estimated the patterns of fibers coursing between human amygdala and prefrontal cortex and compared them with those in the monkey. In posterior prefrontal cortex, we observed a prominent and well-preserved bifurcation of bundles into primarily two fiber systems—an amygdalofugal path and an uncinate path—in both species. This dissociation fades away in more rostral prefrontal regions.

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.

Habituation and dishabituation are the most prevalent measures of infant cognitive functioning, and they have reliably been shown to predict later cognitive outcomes. Yet, the exact mechanisms underlying infant habituation and dishabituation are still unclear. To investigate them, we tested 106 8-month-old infants on a classic habituation task and a novel visual learning task. We used a hierarchical Bayesian model to identify individual differences in sustained attention, learning performance, processing speed and curiosity from the visual learning task. These factors were then related to habituation and dishabituation. We found that habituation time was related to individual differences in processing speed, while dishabituation was related to curiosity, but only for infants who did not habituate. These results offer novel insights in the mechanisms underlying habituation and serve as proof of concept for hierarchical models as an effective tool to measure individual differences in infant cognitive functioning.

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.

Humans and animals construct internal models of their environment in order to select appropriate courses of action. The representation of uncertainty about the current state of the environment is a key feature of these models that controls the rate of learning as well as directly affecting choice behaviour. To maintain flexibility, given that uncertainty naturally decreases over time, most theoretical inference models include a dedicated mechanism to drive up model uncertainty. Here we probe the long-standing hypothesis that noradrenaline is involved in determining the uncertainty, or entropy, and thus flexibility, of neural models. Pupil diameter, which indexes neuromodulatory state including noradrenaline release, predicted increases (but not decreases) in entropy in a neural state model encoded in human medial orbitofrontal cortex, as measured using multivariate functional MRI. Activity in anterior cingulate cortex predicted pupil diameter. These results provide evidence for top-down, neuromodulatory control of entropy in neural state models.

The brain displays a remarkable ability to adapt following injury by altering its connections through neural plasticity. Many of the biological mechanisms that underlie plasticity are known, but there is little knowledge as to when, or where in the brain plasticity will occur following injury. This knowledge could guide plasticity-promoting interventions and create a more accurate roadmap of the recovery process following injury. We causally investigated the time-course of plasticity after hippocampal lesions using multi-modal MRI in monkeys. We show that post-injury plasticity is highly dynamic, but also largely predictable on the basis of the functional connectivity of the lesioned region, gradients of cell densities across the cortex and the pre-lesion network structure of the brain. The ability to predict which brain areas will plastically adapt their functional connectivity following injury may allow us to decipher why some brain lesions lead to permanent loss of cognitive function, while others do not.

Comparing the brains of related species faces the challenges of establishing homologies whilst accommodating evolutionary specializations. Here we propose a general framework for understanding similarities and differences between the brains of primates. The approach uses white matter blueprints of the whole cortex based on a set of white matter tracts that can be anatomically matched across species. The blueprints provide a common reference space that allows us to navigate between brains of different species, identify homologous cortical areas, or to transform whole cortical maps from one species to the other. Specializations are cast within this framework as deviations between the species’ blueprints. We illustrate how this approach can be used to compare human and macaque brains.

Correlations in brain activity between two areas (functional connectivity) have been shown to relate to their underlying structural connections. We examine the possibility that functional connectivity also reflects short-term changes in synaptic efficacy. We demonstrate that paired transcranial magnetic stimulation (TMS) near ventral premotor cortex (PMv) and primary motor cortex (M1) with a short 8-ms inter-pulse interval evoking synchronous pre- and post-synaptic activity and which strengthens interregional connectivity between the two areas in a pattern consistent with Hebbian plasticity, leads to increased functional connectivity between PMv and M1 as measured with functional magnetic resonance imaging (fMRI). Moreover, we show that strengthening connectivity between these nodes has effects on a wider network of areas, such as decreasing coupling in a parallel motor programming stream. A control experiment revealed that identical TMS pulses at identical frequencies caused no change in fMRI-measured functional connectivity when the inter-pulse-interval was too long for Hebbian-like plasticity.

Primate comparative anatomy is an established field that has made rich and substantial contributions to neuroscience. However, the labor-intensive techniques employed mean that most comparisons are often based on a small number of species, which limits the conclusions that can be drawn. In this review we explore how new developments in magnetic resonance imaging have the potential to apply comparative neuroscience to a much wider range of species, allowing it to realize an even greater potential. We discuss (1) new advances in the type of data that can be acquired, (2) novel methods for extracting meaningful measures from such data that can be compared between species, and (3) methods to analyse these measures within a phylogenetic framework. Taken together, these developments will allow researchers to characterize the relationship between different brains, the ecological niche they occupy, and the behavior they produce in more detail than ever before.

Despite widespread interest in social dominance, little is known of its neural correlates in primates. We hypothesized that social status in primates might be related to individual variation in subcortical brain regions implicated in other aspects of social and emotional behavior in other mammals. To examine this possibility we used magnetic resonance imaging (MRI), which affords the taking of quantitative measurements noninvasively, both of brain structure and of brain function, across many regions simultaneously. We carried out a series of tests of structural and functional MRI (fMRI) data in 25 group-living macaques. First, a deformation-based morphometric (DBM) approach was used to show that gray matter in the amygdala, brainstem in the vicinity of the raphe nucleus, and reticular formation, hypothalamus, and septum/striatum of the left hemisphere was correlated with social status. Second, similar correlations were found in the same areas in the other hemisphere. Third, similar correlations were found in a second data set acquired several months later from a subset of the same animals. Fourth, the strength of coupling between fMRI-measured activity in the same areas was correlated with social status. The network of subcortical areas, however, had no relationship with the sizes of individuals' social networks, suggesting the areas had a simple and direct relationship with social status. By contrast a second circuit in cortex, comprising the midsuperior temporal sulcus and anterior and dorsal prefrontal cortex, covaried with both individuals' social statuses and the social network sizes they experienced. This cortical circuit may be linked to the social cognitive processes that are taxed by life in more complex social networks and that must also be used if an animal is to achieve a high social status.

Psychopathy is often linked to disturbed reinforcement-guided adaptation of behaviour in both clinical and non-clinical populations. Recent work suggests that these disturbances might be due to a deficit in actively using information to guide changes in behaviour. However, how much information is actually used to guide behaviour is difficult to observe directly. Therefore, we used a computational model to estimate the use of information during learning. Thirty-six female subjects were recruited based on their total scores on the Psychopathic Personality Inventory (PPI), a self-report psychopathy list, and performed a task involving simultaneous learning of reward-based and social information. A Bayesian reinforcement-learning model was used to parameterize the use of each source of information during learning. Subsequently, we used the subscales of the PPI to assess psychopathy-related traits, and the traits that were more strongly related to the model’s parameters were isolated through a formal variable selection procedure. Finally, we assessed how these covaried with model parameters. We succeeded in isolating key personality traits believed to be relevant for psychopathy that can be related to model-based descriptions of subject behaviour. Use of reward-history information was negatively related to levels of trait anxiety and fearlessness, whereas use of social advice decreased as the perceived ability to manipulate others and lack of anxiety increased. These results corroborate previous findings suggesting that sub-optimal use of different types of information might be implicated in psychopathy. They also further highlight the importance of considering the potential of computational modelling to understand the role of latent variables, such as the weight people give to various sources of information during goal-directed behaviour, when conducting research on psychopathy-related traits and in the field of forensic psychiatry.

The functional role of the right inferior frontal cortex (rIFC) in mediating human behavior is the subject of ongoing debate. Activation of the rIFC has been associated with both response inhibition and with signaling action adaptation demands resulting from unpredicted events. The goal of this study is to investigate the role of rIFC by combining a go/no-go paradigm with paired-pulse transcranial magnetic stimulation (ppTMS) over rIFC and the primary motor cortex (M1) to probe the functional connectivity between these brain areas. Participants performed a go/no-go task with 20% or 80% of the trials requiring response inhibition (no-go trials) in a classic and a reversed version of the task, respectively. Responses were slower to infrequent compared to frequent go trials, while commission errors were more prevalent to infrequent compared to frequent no-go trials. We hypothesized that if rIFC is involved primarily in response inhibition, then rIFC should exert an inhibitory influence over M1 on no-go (inhibition) trials regardless of no-go probability. If, by contrast, rIFC has a role on unexpected trials other than just response inhibition then rIFC should influence M1 on infrequent trials regardless of response demands. We observed that rIFC suppressed M1 excitability during frequent no-go trials, but not during infrequent no-go trials, suggesting that the role of rIFC in response inhibition is context dependent rather than generic. Importantly, rIFC was found to facilitate M1 excitability on all low frequent trials, irrespective of whether the infrequent event involved response inhibition, a finding more in line with a predictive coding framework of cognitive control.

The default mode network (DMN) of the brain consists of areas that are typically more active during rest than during active task performance. Recently however, this network has been shown to be activated by certain types of tasks. Social cognition, particularly higher-order tasks such as attributing mental states to others, has been suggested to activate a network of areas at least partly overlapping with the DMN. Here, we explore this claim, drawing on evidence from meta-analyses of functional MRI data and studies investigating the structural and functional connectivity of the social brain. Finally, we discuss recent evidence for the existence of a DMN in non-human primates and evidence for its involvement in mediating social abilities. We end by discussing some of the implications of these observations.