Cerebral cortex expansion and folding: what have we learned?

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding. Cortical folding takes place during embryonic development and is important to optimize the functional organization and wiring of the brain, as well as to allow fitting a large cortex in a limited cranial volume. Pathological alterations in size or folding of the human cortex lead to severe intellectual disability and intractable epilepsy. Hence, cortical expansion and folding are viewed as key processes in mammalian brain development and evolution, ultimately leading to increased intellectual performance and, eventually, to the emergence of human cognition. Here, we provide an overview and discuss some of the most significant advances in our understanding of cortical expansion and folding over the last decades. These include discoveries in multiple and diverse disciplines, from cellular and molecular mechanisms regulating cortical development and neurogenesis, genetic mechanisms defining the patterns of cortical folds, the biomechanics of cortical growth and buckling, lessons from human disease, and how genetic evolution steered cortical size and folding during mammalian evolution .     

Prefrontal cortex in humans and apes: a comparative study of area 10

Area 10 is one of the cortical areas of the frontal lobe involved in higher cognitive functions such as the undertaking of initiatives and the planning of future actions. It is known to form the frontal pole of the macaque and human brain, but its presence and organization in the great and lesser apes remain unclear. It is here documented that area 10 also forms the frontal pole of chimpanzee, bonobo, orangutan, and gibbon brains. Imaging techniques and stereological tools are used to characterize this area across species and provide preliminary estimates of its absolute and relative size. Area 10 has similar cytoarchitectonic features in the hominoid brain, but aspects of its organization vary slightly across species, including the relative width of its cortical layers and the space available for connections. The cortex forming the frontal pole of the gorilla appears highly specialized, while area 10 in the gibbon occupies only the orbital sector of the frontal pole. Area 10 in the human brain is larger relative to the rest of the brain than it is in the apes, and its supragranular layers have more space available for connections with other higher-order association areas. This suggests that the neural substrates supporting cognitive functions associated with this part of the cortex enlarged and became specialized during hominid evolution.     

Evolution of primary microcephaly genes and the enlargement of primate brains

Brain size, in relation to body size, has varied markedly during the evolution of mammals. In particular, a large cerebral cortex is a feature that distinguishes humans from our fellow primates. Such anatomical changes must have a basis in genetic alterations, but the molecular processes involved have yet to be defined. However, recent advances from the cloning of two human disease genes promise to make inroads in this important area. Microcephalin (MCPH1) and Abnormal spindle-like microcephaly associated (ASPM) are genes mutated in primary microcephaly, a human neurodevelopmental disorder. In this 'atavistic' condition, brain size is reduced in volume to a size comparable with that of early hominids. Hence, it has been proposed that these genes evolved adaptively with increasing primate brain size. Subsequent studies have lent weight to this hypothesis by showing that both genes have undergone positive selection during great ape evolution. Further functional characterisation of their proteins will contribute to an understanding of the molecular and evolutionary processes that have determined human brain size.     

Communicative signaling activates 'Broca's' homolog in chimpanzees

Broca's area, a cerebral cortical area located in the inferior frontal gyrus (IFG) of the human brain, has been identified as one of several critical regions associated with the motor planning and execution of language. Anatomically, Broca's area is most often larger in the left hemisphere, and functional imaging studies in humans indicate significant left-lateralized patterns of activation during language-related tasks. If, and to what extent, nonhuman primates, particularly chimpanzees, possess a homologous region that is involved in the production of their own communicative signals remains unknown. Here, we show that portions of the IFG as well as other cortical and subcortical regions in chimpanzees are active during the production of communicative signals. These findings are the first to provide direct evidence of the neuroanatomical structures associated with the production of communicative behaviors in chimpanzees. Significant activation in the left IFG in conjunction with other cortical and subcortical brain areas during the production of communicative signals in chimpanzees suggests that the neurological substrates underlying language production in the human brain may have been present in the common ancestor of humans and chimpanzees.     

Limbic frontal cortex in hominoids: A comparative study of area 13

The limbic frontal cortex forms part of the neural substrate responsible for emotional reactions to social stimuli. Area 13 is one of the cortical areas long known to be part of the posterior orbitofrontal cortex in several monkey species, such as the macaque. Its presence nevertheless in the human brain has been unclear, and the cortex of the frontal lobe of the great and lesser apes remains largely unknown. In this study area 13 was identified in human, chimpanzee, bonobo, gorilla, orangutan, and gibbon brains, and cortical maps were generated on the basis of its cytoarchitecture. Imaging techniques were used to characterize and quantify the microstructural organization of the area, and stereological tools were applied for estimates of the volume of area 13 in all species. Area 13 is conservative in its structure, and features such as size of cortical layers, density of neurons, and space available for connections are similar across hominoids with only subtle differences present. In contrast to the homogeneity found in its organization, variation is present in the relative size of this cortical area (as a percentage of total brain volume). The human and the bonobo include a complex orbitofrontal cortex and a relatively smaller area 13. On the contrary the orangutan stands out by having a shorter orbitofrontal region and a more expanded area 13. Differences in the organization and size of individual cortical areas involved in emotional reactions and social behavior can be related to behavioral specializations of each hominoid and to the evolution of emotions in hominids. Am J Phys Anthropol 106:129–155, 1998. © 1998 Wiley-Liss, Inc.     

Cortical mechanisms in hearing

Current understanding of neural processing in the auditory cortex has been shaped by a variety of experimental approaches in animals and humans. It remains a daunting challenge to reconcile data as diverse as synaptic properties recorded in a rodent brain slice and functional images of auditory cortex in a behaving human. Nevertheless, the gaps are narrowing through a renewed focus on humans and other primates, a continuing interest in evidence for functional pathways, a broader application of modern imaging techniques, a growing awareness of cortical sensitivity to dynamic features of sounds, and an improved understanding of auditory cortical circuitry.     

Human brain evolution: insights from microarrays

Several recent microarray studies have compared gene-expression patterns n humans, chimpanzees and other non-human primates to identify evolutionary changes that contribute to the distinctive cognitive and behavioural characteristics of humans. These studies support the surprising conclusion that the evolution of the human brain involved an upregulation of gene expression relative to non-human primates, a finding that could be relevant to understanding human cerebral physiology and function. These results show how genetic and genomic methods can shed light on the basis of human neural and cognitive specializations, and have important implications for neuroscience, anthropology and medicine.     

Frontal lobe and cognitive development

In phylogeny as in ontogeny, the association cortex of the frontal lobe, also known as the prefrontal cortex, is a late-developing region of the neocortex. It is also one of the cortical regions to undergo the greatest expansion in the course of both evolution and individual maturation. In the human adult, the prefrontal cortex constitutes as much as nearly one-third of the totality of the neocortex. The protracted, relatively large, development of the prefrontal cortex is manifest in gross morphology as well as fine structure. In the developing individual, its late maturation is made most apparent by the late myelination of its axonal connections. This and other indices of morphological development of the prefrontal cortex correlate with the development of cognitive functions that neuropsychological studies in animals and humans have ascribed to this cortex. In broad outline, the ventromedial areas of the prefrontal cortex, which with respect to otherprefrontal areas develop relatively early, are involved in the expression and control of emotional and instinctual behaviors. On the other hand, the late maturing areas of the lateral prefrontal convexity are principally involved in higher executive functions. The most general executive function of the lateral prefrontal cortex is the temporal organization of goal-directed actions in the domains of behavior, cognition, and language. In all three domains, that global function is supported by a fundamental role of the lateral prefrontal cortex in temporal integration, that is, the integration of temporally discontinuous percepts and neural inputs into coherent structures of action. Temporal integration is in turn served by at least three cognitive functions of somewhat different prefrontal topography: working memory, preparatory set, and inhibitory control. These functions engage the prefrontal cortex in interactive cooperation with other neocortical regions. The development of language epitomizes the development of temporal integrative cognitive functions and their underlying neural substrate, notably the lateral prefrontal cortex and other late-developing cortical regions.     

Comparative Analysis of Protocadherin-11 X-Linked Expression among Postnatal Rodents,Non-Human Primates,and Songbirds Suggests Its Possible Involvement in Brain Evolution

Background

Protocadherin-11 is a cell adhesion molecule of the cadherin superfamily. Since, only in humans, its paralog is found on the Y chromosome, it is expected that protocadherin-11X/Y plays some role in human brain evolution or sex differences. Recently, a genetic mutation of protocadherin-11X/Y was reported to be associated with a language development disorder. Here, we compared the expression of protocadherin-11 X-linked in developing postnatal brains of mouse (rodent) and common marmoset (non-human primate) to explore its possible involvement in mammalian brain evolution. We also investigated its expression in the Bengalese finch (songbird) to explore a possible function in animal vocalization and human language faculties.

Methodology/Principal Findings

Protocadherin-11 X-linked was strongly expressed in the cerebral cortex, hippocampus, amygdala and brainstem. Comparative analysis between mice and marmosets revealed that in certain areas of marmoset brain, the expression was clearly enriched. In Bengalese finches, protocadherin-11 X-linked was expressed not only in nuclei of regions of the vocal production pathway and the tracheosyringeal hypoglossal nucleus, but also in areas homologous to the mammalian amygdala and hippocampus. In both marmosets and Bengalese finches, its expression in pallial vocal control areas was developmentally regulated, and no clear expression was seen in the dorsal striatum, indicating a similarity between songbirds and non-human primates.

Conclusions/Significance

Our results suggest that the enriched expression of protocadherin-11 X-linked is involved in primate brain evolution and that some similarity exists between songbirds and primates regarding the neural basis for vocalization.     

Did brain-specific genes evolve faster in humans than in chimpanzees?

One of the most distinctive characteristics of humans among primates is the size, organization and function of the brain. A recent study has proposed that there was widespread accelerated sequence evolution of genes functioning in the nervous system during human origins. Here we test this hypothesis by a genome-wide analysis of genes that are expressed predominantly or specifically in brain tissues and genes that have important roles in the brain, identified on the basis of five different definitions of brain specificity. Although there is little overlap among the five sets of brain-specific genes, none of them supports human acceleration. On the contrary, some datasets show significantly fewer nonsynonymous substitutions in humans than in chimpanzees for brain-specific genes relative to other genes in the genome. Our results suggest that the unique features of the human brain did not arise by a large number of adaptive amino acid changes in many proteins.     

Lateral prefrontal cortex: architectonic and functional organization

A comparison of the architecture of the human prefrontal cortex with that of the macaque monkey showed a very similar architectonic organization in these two primate species. There is no doubt that the prefrontal cortical areas of the human brain have undergone considerable development, but it is equally clear that the basic architectonic organization is the same in the two species. Thus, a comparative approach to the study of the functional organization of the primate prefrontal cortex is more likely to reveal the essential aspects of the various complex control processes that are the domain of frontal function. The lateral frontal cortex appears to be functionally organized along both a rostral-caudal axis and a dorsal-ventral axis. The most caudal frontal region, the motor region on the precentral gyrus, is involved in fine motor control and direct sensorimotor mappings, whereas the caudal lateral prefrontal region is involved in higher order control processes that regulate the selection among multiple competing responses and stimuli based on conditional operations. Further rostrally, the mid-lateral prefrontal region plays an even more abstract role in cognitive control. The mid-lateral prefrontal region is itself organized along a dorsal-ventral axis of organization, with the mid-dorsolateral prefrontal cortex being involved in the monitoring of information in working memory and the mid-ventrolateral prefrontal region being involved in active judgments on information held in posterior cortical association regions that are necessary for active retrieval and encoding of information.     

Evolution of ASPM coding variation in apes and associations with brain structure in chimpanzees

Studying genetic mechanisms underlying primate brain morphology can provide insight into the evolution of human brain structure and cognition. In humans, loss‐of‐function mutations in the gene coding for ASPM (Abnormal Spindle Microtubule Assembly) have been associated with primary microcephaly, which is defined by a significantly reduced brain volume, intellectual disability and delayed development. However, less is known about the effects of common ASPM variation in humans and other primates. In this study, we characterized the degree of coding variation at ASPM in a large sample of chimpanzees (N = 241), and examined potential associations between genotype and various measures of brain morphology. We identified and genotyped five non‐synonymous polymorphisms in exons 3 (V588G), 18 (Q2772K, K2796E, C2811Y) and 27 (I3427V). Using T1‐weighted magnetic resonance imaging of brains, we measured total brain volume, cerebral gray and white matter volume, cerebral ventricular volume, and cortical surface area in the same chimpanzees. We found a potential association between ASPM V588G genotype and cerebral ventricular volume but not with the other measures. Additionally, we found that chimpanzee, bonobo, and human lineages each independently show a signature of accelerated ASPM protein evolution. Overall, our results suggest the potential effects of ASPM variation on cerebral cortical development, and emphasize the need for further functional studies. These results are the first evidence suggesting ASPM variation might play a role in shaping natural variation in brain structure in nonhuman primates.     

Tractography of the Spider Monkey (Ateles geoffroyi) Corpus Callosum Using Diffusion Tensor Magnetic Resonance Imaging

The objective of this research was to describe the organization, connectivity and microstructure of the corpus callosum of the spider monkey (Ateles geoffroyi). Non-invasive magnetic resonance imaging and diffusion-tensor imaging were obtained from three subjects using a 3T Philips scanner. We hypothesized that the arrangement of fibers in spider monkeys would be similar to that observed in other non-human primates. A repeated measure (n = 3) of fractional anisotropy values was obtained of each subject and for each callosal subdivision. Measurements of the diffusion properties of corpus callosum fibers exhibited a similar pattern to those reported in the literature for humans and chimpanzees. No statistical difference was reached when comparing this parameter between the different CC regions (p = 0.066). The highest fractional anisotropy values corresponded to regions projecting from the corpus callosum to the posterior cortical association areas, premotor and supplementary motor cortices. The lowest fractional anisotropy corresponded to projections to motor and sensory cortical areas. Analyses indicated that approximately 57% of the fibers projects to the frontal cortex and 43% to the post-central cortex. While this study had a small sample size, the results provided important information concerning the organization of the corpus callosum in spider monkeys.     

Accelerated evolution of nervous system genes in the origin of Homo sapiens

Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, we examined the evolution of genes involved in diverse aspects of nervous system biology. We found that these genes display significantly higher rates of protein evolution in primates than in rodents. Importantly, this trend is most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution is most prominent in the lineage leading from ancestral primates to humans. Thus, the remarkable phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. In addition to uncovering broad evolutionary trends, our study also identified many candidate genes--most of which are implicated in regulating brain size and behavior--that might have played important roles in the evolution of the human brain.     

Topography of the chimpanzee corpus callosum

The corpus callosum (CC) is the largest commissural white matter tract in mammalian brains, connecting homotopic and heterotopic regions of the cerebral cortex. Knowledge of the distribution of callosal fibers projecting into specific cortical regions has important implications for understanding the evolution of lateralized structures and functions of the cerebral cortex. No comparisons of CC topography in humans and great apes have yet been conducted. We investigated the topography of the CC in 21 chimpanzees using high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Tractography was conducted based on fiber assignment by continuous tracking (FACT) algorithm. We expected chimpanzees to display topographical organization similar to humans, especially concerning projections into the frontal cortical regions. Similar to recent studies in humans, tractography identified five clusters of CC fibers projecting into defined cortical regions: prefrontal; premotor and supplementary motor; motor; sensory; parietal, temporal and occipital. Significant differences in fractional anisotropy (FA) were found in callosal regions, with highest FA values in regions projecting to higher-association areas of posterior cortical (including parietal, temporal and occipital cortices) and prefrontal cortical regions (p<0.001). The lowest FA values were seen in regions projecting into motor and sensory cortical areas. Our results indicate chimpanzees display similar topography of the CC as humans, in terms of distribution of callosal projections and microstructure of fibers as determined by anisotropy measures.     

Accelerated Evolution of the ASPM Gene Controlling Brain Size Begins Prior to Human Brain Expansion

Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by global reduction in cerebral cortical volume. The microcephalic brain has a volume comparable to that of early hominids, raising the possibility that some MCPH genes may have been evolutionary targets in the expansion of the cerebral cortex in mammals and especially primates. Mutations in ASPM, which encodes the human homologue of a fly protein essential for spindle function, are the most common known cause of MCPH. Here we have isolated large genomic clones containing the complete ASPM gene, including promoter regions and introns, from chimpanzee, gorilla, orangutan, and rhesus macaque by transformation-associated recombination cloning in yeast. We have sequenced these clones and show that whereas much of the sequence of ASPM is substantially conserved among primates, specific segments are subject to high Ka/Ks ratios (nonsynonymous/synonymous DNA changes) consistent with strong positive selection for evolutionary change. The ASPM gene sequence shows accelerated evolution in the African hominoid clade, and this precedes hominid brain expansion by several million years. Gorilla and human lineages show particularly accelerated evolution in the IQ domain of ASPM. Moreover, ASPM regions under positive selection in primates are also the most highly diverged regions between primates and nonprimate mammals. We report the first direct application of TAR cloning technology to the study of human evolution. Our data suggest that evolutionary selection of specific segments of the ASPM sequence strongly relates to differences in cerebral cortical size.     

Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion

Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by global reduction in cerebral cortical volume. The microcephalic brain has a volume comparable to that of early hominids, raising the possibility that some MCPH genes may have been evolutionary targets in the expansion of the cerebral cortex in mammals and especially primates. Mutations in ASPM, which encodes the human homologue of a fly protein essential for spindle function, are the most common known cause of MCPH. Here we have isolated large genomic clones containing the complete ASPM gene, including promoter regions and introns, from chimpanzee, gorilla, orangutan, and rhesus macaque by transformation-associated recombination cloning in yeast. We have sequenced these clones and show that whereas much of the sequence of ASPM is substantially conserved among primates, specific segments are subject to high Ka/Ks ratios (nonsynonymous/synonymous DNA changes) consistent with strong positive selection for evolutionary change. The ASPM gene sequence shows accelerated evolution in the African hominoid clade, and this precedes hominid brain expansion by several million years. Gorilla and human lineages show particularly accelerated evolution in the IQ domain of ASPM. Moreover, ASPM regions under positive selection in primates are also the most highly diverged regions between primates and nonprimate mammals. We report the first direct application of TAR cloning technology to the study of human evolution. Our data suggest that evolutionary selection of specific segments of the ASPM sequence strongly relates to differences in cerebral cortical size.     

Evolution of Brain Active Gene Promoters in Human Lineage Towards the Increased Plasticity of Gene Regulation

Adaptability to a variety of environmental conditions is a prominent feature of Homo sapiens. We hypothesize that this feature can be explained by evolutionary changes in gene promoters active in the brain prefrontal cortex leading to a more flexible gene regulation network. The genotype-dependent range of gene expression can be broader in humans than in other higher primates. Thus, we searched for specific signatures of evolutionary changes in promoter architectures of multiple hominid genes, including the genes active in human cortical neurons that may indicate an increase of variability of gene expression rather than just changes in the level of expression, such as downregulation or upregulation of the genes. We performed a whole-genome search for genetic-based alterations that may impact gene regulation “flexibility” in a process of hominids evolution, such as (i) CpG dinucleotide content, (ii) predicted nucleosome-DNA dissociation constant, and (iii) predicted affinities for TATA-binding protein (TBP) in gene promoters. We tested all putative promoter regions across the human genome and especially gene promoters in active chromatin state in neurons of prefrontal cortex, the brain region critical for abstract thinking and social and behavioral adaptation. Our data imply that the origin of modern man has been associated with an increase of flexibility of promoter-driven gene regulation in brain. In contrast, after splitting from the ancestral lineages of H. sapiens, the evolution of ape species is characterized by reduced flexibility of gene promoter functioning, underlying reduced variability of the gene expression.     

Brain reorganization,not relative brain size,primarily characterizes anthropoid brain evolution

Comparative analyses of primate brain evolution have highlighted changes in size and internal organization as key factors underlying species diversity. It remains, however, unclear (i) how much variation in mosaic brain reorganization versus variation in relative brain size contributes to explaining the structural neural diversity observed across species, (ii) which mosaic changes contribute most to explaining diversity, and (iii) what the temporal origin, rates and processes are that underlie evolutionary shifts in mosaic reorganization for individual branches of the primate tree of life. We address these questions by combining novel comparative methods that allow assessing the temporal origin, rate and process of evolutionary changes on individual branches of the tree of life, with newly available data on volumes of key brain structures (prefrontal cortex, frontal motor areas and cerebrocerebellum) for a sample of 17 species (including humans). We identify patterns of mosaic change in brain evolution that mirror brain systems previously identified by electrophysiological and anatomical tract-tracing studies in non-human primates and functional connectivity MRI studies in humans. Across more than 40 Myr of anthropoid primate evolution, mosaic changes contribute more to explaining neural diversity than changes in relative brain size, and different mosaic patterns are differentially selected for when brains increase or decrease in size. We identify lineage-specific evolutionary specializations for all branches of the tree of life covered by our sample and demonstrate deep evolutionary roots for mosaic patterns associated with motor control and learning.