Morphological evolution of language-relevant brain areas.

Human language is supported by a cortical network involving Broca's area, which comprises Brodmann Areas 44 and 45 (BA44 and BA45). While cytoarchitectonic homolog areas have been identified in nonhuman primates, it remains unknown how these regions evolved to support human language. Here, we use histological data and advanced cortical registration methods to precisely compare the morphology of BA44 and BA45 in humans and chimpanzees. We found a general expansion of Broca's areas in humans, with the left BA44 enlarging the most, growing anteriorly into a region known to process syntax. Together with recent functional and receptorarchitectural studies, our findings support the conclusion that BA44 evolved from an action-related region to a bipartite system, with a posterior portion supporting action and an anterior portion supporting syntactic processes. Our findings add novel insights to the longstanding debate on the relationship between language and action, and the evolution of Broca's area.

Hedonic eating, obesity, and addiction result from increased neuropeptide Y in the nucleus accumbens during human brain evolution.

The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in humans and other anthropoid primates in order to determine whether there are differences among these various species that would correspond to behavioral or life history variables. We quantified NPY-immunoreactive axons and neurons in the NAc of 13 primate species, including humans, great apes, and monkeys. Our data show that the human brain is unique among primates in having denser NPY innervation within the NAc, as measured by axon length density to neuron density, even after accounting for brain size. Combined with our previous finding of increased dopaminergic innervation in the same region, our results suggest that the neurochemical profile of the human NAc appears to have rendered our species uniquely susceptible to neurophysiological conditions such as addiction. The increase in NPY specific to the NAc may represent an adaptation that favors fat intake and contributes to an increased vulnerability to eating disorders, obesity, as well as alcohol and drug dependence. Along with our findings for dopamine, these deeply rooted structural attributes of the human brain are likely to have emerged early in the human clade, laying the groundwork for later brain expansion and the development of cognitive and behavioral specializations.

Human and chimpanzee shared and divergent neurobiological systems for general and specific cognitive brain functions.

A long-standing topic of interest in human neurosciences is the understanding of the neurobiology underlying human cognition. Less commonly considered is to what extent such systems may be shared with other species. We examined individual variation in brain connectivity in the context of cognitive abilities in chimpanzees (n = 45) and humans in search of a conserved link between cognition and brain connectivity across the two species. Cognitive scores were assessed on a variety of behavioral tasks using chimpanzee- and human-specific cognitive test batteries, measuring aspects of cognition related to relational reasoning, processing speed, and problem solving in both species. We show that chimpanzees scoring higher on such cognitive skills display relatively strong connectivity among brain networks also associated with comparable cognitive abilities in the human group. We also identified divergence in brain networks that serve specialized functions across humans and chimpanzees, such as stronger language connectivity in humans and relatively more prominent connectivity between regions related to spatial working memory in chimpanzees. Our findings suggest that core neural systems of cognition may have evolved before the divergence of chimpanzees and humans, along with potential differential investments in other brain networks relating to specific functional specializations between the two species.

Phylogenetic differences in the morphology and shape of the central sulcus in great apes and humans: implications for the evolution of motor functions.

The central sulcus divides the primary motor and somatosensory cortices in many anthropoid primate brains. Differences exist in the surface area and depth of the central sulcus along the dorso-ventral plane in great apes and humans compared to other primate species. Within hominid species, there are variations in the depth and aspect of their hand motor area, or knob, within the precentral gyrus. In this study, we used post-image analyses on magnetic resonance images to characterize the central sulcus shape of humans, chimpanzees (Pan troglodytes), gorillas (Gorilla gorilla), and orangutans (Pongo pygmaeus and Pongo abelii). Using these data, we examined the morphological variability of central sulcus in hominids, focusing on the hand region, a significant change in human evolution. We show that the central sulcus shape differs between great ape species, but all show similar variations in the location of their hand knob. However, the prevalence of the knob location along the dorso-ventral plane and lateralization differs between species and the presence of a second ventral motor knob seems to be unique to humans. Humans and orangutans exhibit the most similar and complex central sulcus shapes. However, their similarities may reflect divergent evolutionary processes related to selection for different positional and habitual locomotor functions.

Genetic determinants of individual variation in the superior temporal sulcus of chimpanzees (Pan troglodytes).

The superior temporal sulcus (STS) is a conserved fold that divides the middle and superior temporal gyri. In humans, there is considerable variation in the shape, folding pattern, lateralization, and depth of the STS that have been reported to be associated with social cognition and linguistic functions. We examined the role that genetic factors play on individual variation in STS morphology in chimpanzees. The surface area and depth of the STS were quantified in sample of 292 captive chimpanzees comprised of two genetically isolated population of individuals. The chimpanzees had been previously genotyped for AVPR1A and KIAA0319, two genes that play a role in social cognition and communication in humans. Single nucleotide polymorphisms in the KIAA0319 and AVPR1A genes were associated with average depth as well as asymmetries in the STS. By contrast, we found no significant effects of these KIA0319 and AVPR1A polymorphism on surface area and depth measures for the central sulcus. The overall findings indicate that genetic factors account for a small to moderate amount of variation in STS morphology in chimpanzees. These findings are discussed in the context of the role of the STS in social cognition and language in humans and their potential evolutionary origins.

Neutrophil to lymphocyte ratio in captive olive baboons (Papio anubis): The effects of age, sex, rearing, stress, and pregnancy.

In apes and humans, neutrophil to lymphocyte ratio (NLR) can be used as a predictive indicator of a variety of clinical conditions, longevity, and physiological stress. In chimpanzees specifically, NLR systematically varies with age, rearing, sex, and premature death, indicating that NLR may be a useful diagnostic tool in assessing primate health. To date, just one very recent study has investigated NLR in old world monkeys and found lower NLR in males and nursery-reared individuals, as well as a negative relationship between NLR and disease outcomes. Given that baboons are increasingly used as research models, we aimed to characterize NLR in baboons by providing descriptive data and examinations of baboon NLR heritability, and of the relationships between NLR, age, rearing, and sex in 387 olive baboons (Papio anubis) between 6 months and 19 years of age. We found that (1) mother-reared baboons had higher NLRs than nursery-reared baboons; (2) females had higher NLRs than males; and (3) there was a quadratic relationship between NLR and age, such that middle-aged individuals had the highest NLR values. We also examined NLR as a function of transport to a new facility using a subset of the data. Baboons exhibited significantly higher transport NLRs compared to routine exam NLRs. More specifically, adult baboons had higher transport NLRs than routine NLRs, whereas juveniles showed no such difference, suggesting that younger animals may experience transport stress differently than older animals. We also found that transport NLR was heritable, whereas routine NLR was not, possibly suggesting that stress responses (as indicated in NLR) have a strong genetic component. Consistent with research in humans and chimpanzees, these findings suggest that NLR varies with important biological and life history variables and that NLR may be a useful health biomarker in baboons.

Comparative analysis reveals distinctive epigenetic features of the human cerebellum.

Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution.

In vivo mapping of the deep and superficial white matter connectivity in the chimpanzee brain.

Mapping the chimpanzee brain connectome and comparing it to that of humans is key to our understanding of similarities and differences in primate evolution that occurred after the split from their common ancestor around 6 million years ago. In contrast to studies on macaque species' brains, fewer studies have specifically addressed the structural connectivity of the chimpanzee brain and its comparison with the human brain. Most comparative studies in the literature focus on the anatomy of the cortex and deep nuclei to evaluate how their morphology and asymmetry differ from that of the human brain, and some studies have emerged concerning the study of brain connectivity among humans, monkeys, and apes. In this work, we established a new white matter atlas of the deep and superficial white matter structural connectivity in chimpanzees. In vivo anatomical and diffusion-weighted magnetic resonance imaging (MRI) data were collected on a 3-Tesla MRI system from 39 chimpanzees. These datasets were subsequently processed using a novel fiber clustering pipeline adapted to the chimpanzee brain, enabling us to create two novel deep and superficial white matter connectivity atlases representative of the chimpanzee brain. These atlases provide the scientific community with an important and novel set of reference data for understanding the commonalities and differences in structural connectivity between the human and chimpanzee brains. We believe this study to be innovative both in its novel approach and in mapping the superficial white matter bundles in the chimpanzee brain, which will contribute to a better understanding of hominin brain evolution.

The association of astrogliosis and microglial activation with aging and Alzheimer's disease pathology in the chimpanzee brain.

Aging and neurodegenerative disorders, such as Alzheimer's disease (AD), trigger an immune response known as glial activation in the brain. Recent evidence indicates species differences in inflammatory responses to AD pathology, highlighting the need for additional comparative studies to further understand human-specific neuropathologies. In the present study, we report on the occurrence of astrogliosis, microglial activation, and their relationship with age and AD-like pathology in a cohort of male and female chimpanzees (Pan troglodytes). Chimpanzees with severe astrogliosis exhibited widespread upregulation of hypertrophic astrocytes immunoreactive for glial fibrillary acidic protein (GFAP) throughout all layers of the dorsolateral prefrontal cortex and a loss of the interlaminar palisade. In addition, extreme astrogliosis was associated with increased astrocyte density in the absence of significant microglial activation and AD lesions. A shift from decreased resting to increased phagocytotic microglia occurred with aging, although proliferation was absent and no changes in astrogliosis was observed. Vascular amyloid correlated with decreased astrocyte and microglia densities, while tau lesions were associated with morphological changes in microglia and greater total glia density and glia: neuron ratio. These results further our understanding of inflammatory processes within the chimpanzee brain and provide comparative data to improve our understanding of human aging and neuropathological processes.

Cognitive control of orofacial motor and vocal responses in the ventrolateral and dorsomedial human frontal cortex.

In the primate brain, a set of areas in the ventrolateral frontal (VLF) cortex and the dorsomedial frontal (DMF) cortex appear to control vocalizations. The basic role of this network in the human brain and how it may have evolved to enable complex speech remain unknown. In the present functional neuroimaging study of the human brain, a multidomain protocol was utilized to investigate the roles of the various areas that comprise the VLF-DMF network in learning rule-based cognitive selections between different types of motor actions: manual, orofacial, nonspeech vocal, and speech vocal actions. Ventrolateral area 44 (a key component of the Broca's language production region in the human brain) is involved in the cognitive selection of orofacial, as well as, speech and nonspeech vocal responses; and the midcingulate cortex is involved in the analysis of speech and nonspeech vocal feedback driving adaptation of these responses. By contrast, the cognitive selection of speech vocal information requires this former network and the additional recruitment of area 45 and the presupplementary motor area. We propose that the basic function expressed by the VLF-DMF network is to exert cognitive control of orofacial and vocal acts and, in the language dominant hemisphere of the human brain, has been adapted to serve higher speech function. These results pave the way to understand the potential changes that could have occurred in this network across primate evolution to enable speech production.

The effects of early rearing experiences on mutual eye gaze among captive olive baboons (Papio anubis).

Among human and nonhuman primates, mutual eye gaze (MEG) and gaze following are believed to be important for social cognition and communicative signaling. The goals of this study were to examine how early rearing experiences contribute to individual variation in MEG and to examine the potential role of genetic factors underlying this variation. Subjects included 93 female and 23 male baboons (Papio anubis) ranging from 3 to 20 years of age. Within the sample, there were 55 mother-reared (MR) and 61 nursery-reared (NR) baboons. MEG was assessed in four 60-s test sessions. For each session, the duration, frequency, and bout length were recorded. Mean values were then calculated for each individual from the four sessions. A multivariate analysis of covariance revealed an overall significant main effect for rearing. Subsequent univariate analyses revealed significant rearing effects on mean bout length, but not mean duration or mean frequency, with MR baboons having longer bout lengths compared to NR baboons. Furthermore, mean bout length was found to be significantly heritable. These results indicate that rearing experiences, and to a small extent, genetic factors, affect patterns of mutual eye gaze - in particular, bout length. These results differ from previous findings in MR and NR chimpanzees, further suggesting that rearing may impact MEG in a species-specific manner that reflects the function of gaze in different primate species.

Redefining varicose projection astrocytes in primates.

Varicose projection astrocytes (VP-As) are found in the cerebral cortex and have been described to be specific to humans and chimpanzees. To further examine the phylogenetic distribution of this cell type, we analyzed cortical tissue from several primates ranging from primitive primates to primates evolutionary closer to human such as apes. We specifically analyzed tissue from four strepsirrhine species, one tarsier, six species of platyrrhine monkeys, ten species of cercopithecoid monkeys, two hylobatid ape species, four to six cases each of chimpanzee, bonobo, gorilla, and orangutan, and thirteen human. We found that VP-As were present only in human and other apes (hominoids) and were absent in all other species. We showed that VP-As are localized to layer VI and the superficial white matter of the cortex. The presence of VP-As co-occured with interlaminar astrocytes that also had varicosities in their processes. Due to their location, their long tangential processes, and their irregular presence within species, we propose that VP-As are astrocytes that develop varicosities under specific conditions and that are not a distinct astrocyte type.

Sulcal Morphology in Cingulate Cortex is Associated with Voluntary Oro-Facial Motor Control and Gestural Communication in Chimpanzees (Pan troglodytes).

Individual differences in sulcal variation within the anterior and mid-cingulate cortex of the human brain, particularly the presence or absence of a paracingulate sulcus (PCGS), are associated with various motor and cognitive processes. Recently, it has been reported that chimpanzees possess a PCGS, previously thought to be a unique feature of the human brain. Here, we examined whether individual variation in the presence or absence of a PCGS as well as the variability in the intralimbic sulcus (ILS) are associated with oro-facial motor control, handedness for manual gestures, and sex in a sample of MRI scans obtained in 225 chimpanzees. Additionally, we quantified the depth of the cingulate sulcus (CGS) along the anterior-posterior axis and tested for association with oro-facial motor control, handedness, and sex. Chimpanzees with better oro-facial motor control were more likely to have a PCGS, particularly in the left hemisphere compared to those with poorer control. Male chimpanzees with better oro-facial motor control showed increased leftward asymmetries in the depth of the anterior CGS, whereas female chimpanzees showed the opposite pattern. Significantly, more chimpanzees had an ILS in the left compared to the right hemisphere, but variability in this fold was not associated with sex, handedness, or oro-facial motor control. Finally, significant population-level leftward asymmetries were found in the anterior portion of the CGS, whereas significant rightward biases were evident in the posterior regions. The collective results suggest that the emergence of a PCGS and enhanced gyrification within the anterior and mid-cingulate gyrus may have directly or indirectly evolved in response to selection for increasing oro-facial motor control in primates.

Cortical Interlaminar Astrocytes Are Generated Prenatally, Mature Postnatally, and Express Unique Markers in Human and Nonhuman Primates.

Interlaminar astrocytes (ILAs) are a subset of cortical astrocytes that reside in layer I, express GFAP, have a soma contacting the pia, and contain long interlaminar processes that extend through several cortical layers. We studied the prenatal and postnatal development of ILAs in three species of primates (rhesus macaque, chimpanzee, and human). We found that ILAs are generated prenatally likely from radial glial (RG) cells, that ILAs proliferate locally during gestation, and that ILAs extend interlaminar processes during postnatal stages of development. We showed that the density and morphological complexity of ILAs increase with age, and that ILAs express multiple markers that are expressed by RG cells (Pax6, Sox2, and Nestin), specific to inner and outer RG cells (Cryab and Hopx), and astrocyte markers (S100ß, Aqp4, and GLAST) in prenatal stages and in adult. Finally, we demonstrated that rudimentary ILAs in mouse also express the RG markers Pax6, Sox2, and Nestin, but do not express S100ß, Cryab, or Hopx, and that the density and morphological complexity of ILAs differ between primate species and mouse. Together these findings contribute new information on astrogenesis of this unique class of cells and suggest a lineal relationship between RG cells and ILAs.

Evidence for independent brain and neurocranial reorganization during hominin evolution.

Throughout hominin evolution, the brain of our ancestors underwent a 3-fold increase in size and substantial structural reorganization. However, inferring brain reorganization from fossil hominin neurocrania (=braincases) remains a challenge, above all because comparative data relating brain to neurocranial structures in living humans and great apes are still scarce. Here we use MRI and same-subject spatially aligned computed tomography (CT) and MRI data of humans and chimpanzees to quantify the spatial relationships between these structures, both within and across species. Results indicate that evolutionary changes in brain and neurocranial structures are largely independent of each other. The brains of humans compared to chimpanzees exhibit a characteristic posterior shift of the inferior pre- and postcentral gyri, indicative of reorganization of the frontal opercular region. Changes in human neurocranial structure do not reflect cortical reorganization. Rather, they reflect constraints related to increased encephalization and obligate bipedalism, resulting in relative enlargement of the parietal bones and anterior displacement of the cerebellar fossa. This implies that the relative position and size of neurocranial bones, as well as overall endocranial shape (e.g., globularity), should not be used to make inferences about evolutionary changes in the relative size or reorganization of adjacent cortical regions of fossil hominins.

Predicting their past: Machine language learning can discriminate the brains of chimpanzees with different early-life social rearing experiences.

Early life experiences, including separation from caregivers, can result in substantial, persistent effects on neural, behavioral, and physiological systems as is evidenced in a long-standing literature and consistent findings across species, populations, and experimental models. In humans and other animals, differential rearing conditions can affect brain structure and function. We tested for whole brain patterns of morphological difference between 108 chimpanzees reared typically with their mothers (MR; N = 54) and those reared decades ago in a nursery with peers, human caregivers, and environmental enrichment (NR; N = 54). We applied support vector machine (SVM) learning to archival MRI images of chimpanzee brains to test whether we could, with any degree of significant probability, retrospectively classify subjects as MR and NR based on variation in gray matter within the entire brain. We could accurately discriminate MR and NR chimpanzee brains with nearly 70% accuracy. The combined brain regions discriminating the two rearing groups were widespread throughout the cortex. We believe this is the first report using machine language learning as an analytic method for discriminating nonhuman primate brains based on early rearing experiences. In this sense, the approach and findings are novel, and we hope they stimulate application of the technique to studies on neural outcomes associated with early experiences. The findings underscore the potential for infant separation from caregivers to leave a long-term mark on the developing brain.

Comparison of Surface Area and Cortical Thickness Asymmetry in the Human and Chimpanzee Brain.

Comparative study of the structural asymmetry of the human and chimpanzee brain may shed light on the evolution of language and other cognitive abilities in humans. Here we report the results of vertex-wise and ROI-based analyses that compared surface area (SA) and cortical thickness (CT) asymmetries in 3D MR images obtained for 91 humans and 77 chimpanzees. The human brain is substantially more asymmetric than the chimpanzee brain. In particular, the human brain has 1) larger total SA in the right compared with the left cerebral hemisphere, 2) a global torque-like asymmetry pattern of widespread thicker cortex in the left compared with the right frontal and the right compared with the left temporo-parieto-occipital lobe, and 3) local asymmetries, most notably in medial occipital cortex and superior temporal gyrus, where rightward asymmetry is observed for both SA and CT. There is also 4) a prominent asymmetry specific to the chimpanzee brain, namely, rightward CT asymmetry of precentral cortex. These findings provide evidence of there being substantial differences in asymmetry between the human and chimpanzee brain. The unique asymmetries of the human brain are potential neural substrates for cognitive specializations, and the presence of significant CT asymmetry of precentral gyrus in the chimpanzee brain should be further investigated.

The Paracingulate Sulcus Is a Unique Feature of the Medial Frontal Cortex Shared by Great Apes and Humans.

Primate brains display a wide range of variation in size and cerebral gyrification, leading to the appearance of novel sulci in particular groups of species. We investigated sulcal organization in the medial frontal cortex of great apes, with a particular focus on the paracingulate sulcus (PCGS). Until recently, the presence of the PCGS was thought to be a structural feature unique to the human brain. However, upon closer examination, the PCGS has been observed as a variable feature that also may appear in chimpanzee brains. To understand the evolutionary origins of the sulcal anatomy in the medial frontal cortex of apes, we examined high-resolution MRI scans for the presence or absence of the PCGS and, when present, measured its length in a sample of ape brains (chimpanzees, bonobos, gorillas, orangutans, gibbons, and siamangs). We found that the PCGS is variable in its appearance among these species, being present in 23 to 50% of great ape individuals depending on the species, but not present in gibbons or siamangs. We did not find population level hemispheric lateralization patterns or sex differences in PCGS presence across species, and we did not detect a relationship between cerebral volume and PCGS occurrence or length. Our data suggest that the PCGS is a common sulcal variant present in great apes and humans due to a shared evolutionary ancestry.

Age- and cognition-related differences in the gray matter volume of the chimpanzee brain (Pan troglodytes): A voxel-based morphometry and conjunction analysis.

Several primate species have been shown to exhibit age-related changes in cognition, brain, and behavior. However, severe neurodegenerative illnesses, such as Alzheimer's disease (AD), were once thought to be uniquely human. Recently, some chimpanzees naturally were documented to develop both neurofibrillary tangles and amyloid plaques, the main characteristics of AD pathology. In addition, like humans and other primates, chimpanzees show similar declines in cognition and motor function with age. Here, we used voxel-based morphometry to examine the relationships among gray matter volume, age, and cognition using magnetic resonance imaging scans previously acquired from chimpanzees (N = 216). We first determined the relationship between age and gray matter volume, identifying the regions that declined with age. With a subset of our sample (N = 103), we also determined differences in gray matter volume between older chimpanzees with higher cognition scores than expected for their age, and older chimpanzees with lower than expected scores. Finally, we ran a conjunction analysis to determine any overlap in brain regions between these two analyses. We found that as chimpanzees age, they lose gray matter in regions associated with cognition. In addition, cognitively healthy older chimpanzees (those performing better for their age) have greater gray matter volume in many brain regions compared with chimpanzees who underperform for their age. Finally, the conjunction analysis revealed that regions of age-related decline overlap with the regions that differ between cognitively healthy chimpanzees and those who underperform. This study provides further evidence that chimpanzees are an important model for research on the neurobiology of aging. Future studies should investigate the effects of cognitive stimulation on both cognitive performance and brain structure in aging nonhuman primates.

Age-related changes in chimpanzee (Pan troglodytes) cognition: Cross-sectional and longitudinal analyses.

Chimpanzees are the species most closely related to humans, yet age-related changes in brain and cognition remain poorly understood. The lack of studies on age-related changes in cognition in chimpanzees is particularly unfortunate in light of the recent evidence demonstrating that this species naturally develops Alzheimer's disease (AD) neuropathology. Here, we tested 213 young, middle-aged, and elderly captive chimpanzees on the primate cognitive test battery (PCTB), a set of 13 tasks that assess physical and social cognition in nonhuman primates. A subset of these chimpanzees (n = 146) was tested a second time on a portion of the PCTB tasks as a means of evaluating longitudinal changes in cognition. Cross-sectional analyses revealed a significant quadratic association between age and cognition with younger and older chimpanzees performing more poorly than middle-aged individuals. Longitudinal analyses showed that the oldest chimpanzees at the time of the first test showed the greatest decline in cognition, although the effect was mild. The collective data show that chimpanzees, like other nonhuman primates, show age-related decline in cognition. Further investigations into whether the observed cognitive decline is associated with AD pathologies in chimpanzees would be invaluable in understanding the comparative biology of aging and neuropathology in primates.