Size and shape of the cerebral cortex in mammals. I. The cortical surface

The evolution of the brain in mammals has been accompanied by a progressive enlargement of the cerebral cortex. Allometric analysis of the volume, surface and convolutedness of this cortex shows that among mammals two major groups can be distinguished: (1) species with lissencephalic brains, where surface-volume relationships are determined by linear geometric laws, and (2) species with gyrencephalic brains, where strict geometric similarity no longer applies. Different mathematical models are required to describe the brain morphology in these groups. It has been shown, moreover, that among species with convoluted brains, marine mammals (Cetacea) form a subgroup in that the cerebrocortical surface in these animals is more folded than in terrestrial mammals of similar brain size. Thus it appears that the use of a single allometric relation in studying the effect of size increase on the geometry of the brain - irrespective of convolutedness or ecological strategy - as has been done in previous studies, is unjustified and obscures the differences in the structural organization of mammalian brains. Finally, a dimensionless index of cortical folding is proposed, which indicates that the degree of cortical folding depends not only on the volume of the brain or cortex but on cortical thickness as well.     

Regional White Matter Scaling in the Human Brain

Anatomical organization of the primate cortex varies as a function of total brain size, where possession of a larger brain is accompanied by disproportionate expansion of associative cortices alongside a relative contraction of sensorimotor systems. However, equivalent scaling maps are not yet available for regional white matter anatomy. Here, we use three large-scale neuroimaging datasets to examine how regional white matter volume (WMV) scales with interindividual variation in brain volume among typically developing humans (combined N = 2391: 1247 females, 1144 males). We show that WMV scaling is regionally heterogeneous: larger brains have relatively greater WMV in anterior and posterior regions of cortical white matter, as well as the genu and splenium of the corpus callosum, but relatively less WMV in most subcortical regions. Furthermore, regions of positive WMV scaling tend to connect previously-defined regions of positive gray matter scaling in the cortex, revealing a coordinated coupling of regional gray and white matter organization with naturally occurring variations in human brain size. However, we also show that two commonly studied measures of white matter microstructure, fractional anisotropy (FA) and magnetization transfer (MT), scale negatively with brain size, and do so in a manner that is spatially unlike WMV scaling. Collectively, these findings provide a more complete view of anatomic scaling in the human brain, and offer new contexts for the interpretation of regional white matter variation in health and disease.SIGNIFICANCE STATEMENT Recent work has shown that, in humans, regional cortical and subcortical anatomy show systematic changes as a function of brain size variation. Here, we show that regional white matter structures also show brain-size related changes in humans. Specifically, white matter regions connecting higher-order cortical systems are relatively expanded in larger human brains, while subcortical and cerebellar white matter tracts responsible for unimodal sensory or motor functions are relatively contracted. This regional scaling of white matter volume (WMV) is coordinated with regional scaling of cortical anatomy, but is distinct from scaling of white matter microstructure. These findings provide a more complete view of anatomic scaling of the human brain, with relevance for evolutionary, basic, and clinical neuroscience.     

Age-related brain atrophy with a constant cortical thickness in the normal elderly

A study was performed to determine whether the thickness of the cerebral cortex remains unchanged during agerelated brain atrophy in the normal elderly (physiological brain atrophy of the elderly). Thirty autopsied brains from normal subjects (normal brains; patient age 65–96 years) and two from patients with Alzheimer-type dementia (ATD brains; patient age 90 and 101 years) were analyzed. Volumes of the fresh brain and intracranial cavity were measured at autopsy to estimate the degree of brain atrophy using the ratio of fresh brain volume to intracranial cavity volume (BV/ICV ratio). Each brain was then fixed, and sliced coronally at 1.0 cm intervals. Each cut surface was photographed, and input to a personal computer. Then, the cross-sectional areas of the cortex and the white matter, and the perimeter of the cortex were measured to calculate the volumes of the cortex and the white matter. For normal brains, the cortical thickness was constant (0.27 ± 0.01 cm), regardless of age and the BV/ICV ratio. In addition, the volume ratio of the cortex to the white matter remained unchanged, regardless of the brain volume or BV/ICV ratio. These results show that the cortical thickness remains constant regardless of the degree of brain atrophy or cortical atrophy. In the two ATD brains, the cortical thickness was 0.23 and 0.21 cm, being less than that of any of the normal brains. Thus, the mean cortical thickness remains unchanged in physiological brain atrophy of the elderly, and a decrease in cortical thickness can be a pathological phenomenon.     

Weak correlations between body height and several brain metrics in healthy elderly subjects

The question whether body height is related to different brain size measures has recently gained renewed interest as some studies have reported that body height correlates with intelligence and several brain size measures. In this study, we re‐evaluated this question by examining the relationship between body height and different brain size measures including intracranial volume, total brain volume, total cortical surface area, total cortical volume, volume of normal‐appearing white matter, white matter hyperintensity, cortical surface area, cortical thickness, subcortical grey matter volume, cerebellar cortex and cerebellar white matter in a relatively large sample (n = 216) of physically and cognitively healthy elderly subjects (mean age 71 years, age range 65–85 years). We identified small correlations (r = .11–.19) between body height and seven out of 10 brain metrics (total brain volume, cortical surface area, cortical volume, subcortical volume, normal‐appearing white matter volume and cerebellar grey as well as white matter volumes) when controlling for sex and age. Based on these small relationships between body height and various brain size measures, we discuss the possible reasons and theoretical problems for these small relationships.     

Brain size and grey matter volume in the healthy human brain

Magnetic resonance imaging was used to evaluate the influence of sex and brain size on compartmental brain volumes (grey matter, white matter, CSF) in a large and well-matched sample of neurologically normal women (n = 50) and men (n = 50). As expected, we found a significant sex difference for the absolute volumes of total brain, grey matter, white matter and CSF, with greater volumes for men. Relating these compartmental volume measures to brain volume resulting in proportional volume measures revealed a higher proportion of grey matter in women. No significant sex differences were found for white matter and CSF proportions. However, when the influence of sex was partialized out by regression analyses, brain volume explained 40-81% of the variance of the absolute grey matter, white matter and CSF volumes. Performing these regression analyses for the proportional volume measures revealed that brain volume explained approximately 16% of the variance in grey matter proportion. Sex or the interaction between sex and brain volume revealed no additional predicitve values. Interestingly, the correlation between brain volume and grey matter proportion was negative, with larger brains exhibiting relatively smaller proportions of grey matter. Thus, sex is not the main variable explaining the variability in grey matter volume. Rather, we suggest that brain size is the main variable determining the proportion of grey matter.     

Effects of very low birthweight on brain structure in adulthood

Very-low-birthweight (VLBW) individuals are at high risk of brain injury in the perinatal period. We wished to determine how such early brain lesions affect brain structure in adulthood. Thirty-two VLBW adults (20 female, 12 male) and 18 term, normal birthweight sibling control individuals (nine female, nine male) underwent structural MRI at a mean age of 23 years 4 months (range 17 to 33 years; SD 3.4). Images were analyzed using an automated tissue segmentation algorithm in order to estimate whole brain tissue class volumes in native space. Images were then warped to a template image in standard space. There was no significant between-group difference in whole brain, grey matter, white matter, or total cerebral spinal fluid (CSF) volumes. However, lateral ventricular volume was significantly increased by 41% in those with VLBW. The ratio of grey to white matter was also significantly increased (by 10%) in those with VLBW. Group comparison maps showed widespread changes in the distribution of grey and white matter, and relative excess of ventricular CSF, in the brains of VLBW individuals. Increased ventricular volume predicted decreased grey matter in subcortical nuclei and limbic cortical structures, and decreased periventricular white matter. We conclude that these diffuse abnormalities of grey and white matter are a consequence of the interaction of perinatal brain injury and ongoing neurodevelopmental processes.     

Neuronal migration disorders in cerebral palsy

We retrospectively analyzed 58 autopsy cases of cerebral palsy which were clinically diagnosed at the Aichi Prefecture Colony Hospital. Most of the cases of cerebral palsy had brainweights that were 60–70% of the normal brainweight for their ages. However, approximately 20% of the brains were not small, especially in cases over 20 years of age. The brains of cerebral palsy cases showed wide morphological variation, and were classified into thinned cerebral mantle type (10 cases), hydrocephalus type (three cases) and microgyria-pachygyria type (45 cases). Macroscopic morphometric analysis was performed in the brains of the microgyria-pachygyria type using the coronal whole brain sections through the mammillary bodies stained with Klüver-Barerra (KB) stain, and compared with the brains of four cases of the Fukuyama type congenital muscular dystrophy (FCMD), two cases of lissencephaly, and nine cases of non-neural diseases as controls. The morphometric values of the coronal sections in the cerebral palsy cases showed diminished white matter with more dilatated ventricles compared with the control brains. This tendency was stronger in the brains of spastic cerebral palsy cases than in the brain of athetotic cerebral palsy cases. Cerebral palsy, in terms of the morphological complexity of the cerebrum as determined by the morphometric analysis, was situated between FCMD and lissencephaly. Although microscopic analysis of cerebral palsy brains was limited to 19 cases, there were four brains with heterotopic gray matter, three brains with cortical folding, a sign of cortical dysplasia, and three brains with neuronal cytomegaly. In addition, more than half of the brains showed disorganization of lamination in the cortex with disorientation of neurons. These findings suggest that some cases of cerebral palsy may result from disrupted neuronal migration during cortical development.     

Morphological regionalization using fetal magnetic resonance images of normal developing brains

Regional differences in human brain development during infancy have been studied for many years, but little is known about how regionalization of the brain proceeds during intrauterine life. We investigated the regionalization of cerebral volume and cortical convolutions based on the volumetric magnetic resonance images (MRIs) of 43 fetuses, ranging from 21 to 37 weeks of gestation. Two plausible parcellations of MRI are proposed, and curvature index together with gyrification index are used to quantify the regional cortical convolutions. Our results elucidate that the cortical foldings among different brain regions develop at comparable rates, suggesting a similar uniformity of changes in size of the cortical sheet in these regions over time. On the contrary, the growth of the cerebral volume presents regional difference, with the frontal and parieto-temporal regions growing significantly faster than other regions due to the contribution from expansion of basal ganglia. This quantitative regional information suggests that cerebral volume is not a relevant parameter to measure in relation to gyrification, and that the size of the cortical sheet is more likely to be directly related to cortical folding. The availability of quantitative regional information on normal fetal brains in utero will allow clinical application of this information when probing neurodevelopmental disorders in the future.     

Neuroanatomical effects of neonatal transection of the corpus callosum in hamsters

Newborn hamsters were subjected to surgical transection of their corpora callosa under hypothermic anesthesia. After completion of their development, one group of animals had their brains prepared for cyto- and myeloarchitectonic analysis. Another group had a small pellet of polyacrylamide gel containing horseradish peroxidase (HRP) implanted in different cortical loci. All were perfused with fixatives and had their brains cut into serial sections. The operated brains showed the following anatomical features: (1) The corpus callosum was partially or totally absent; (2) an abnormal longitudinal bundle was present bilaterally underneath the white matter; and (3) except for the physical displacement of some medial structures, the general architecture of the brain appeared unchanged. Analysis of HRP material revealed that (1) the longitudinal bundle contains cortical fibers, of which at least some are commissural; (2) these cortical fibers display a topographic arrangement within the bundle. Results suggest that brain anatomy of "surgical" acallosal hamsters compares closely with that observed in mice with congenital defects of the corpus callosum, a spontaneous condition which also occurs in humans.     

Morphometric analysis of the human infant brain: effects of intraventricular hemorrhage and periventricular leukomalacia

Absolute and relative growth of cerebral structures was assessed morphometrically in 34 neurologically normal live-born infants surviving up to 1 year of age, 20 infants with fatal intraventricular hemorrhage, and 4 with periventricular leukomalacia. In the normal brain, cerebral cortex grew 25% faster than white matter throughout infancy. Thus, to achieve the normal adult size and 1:1 ratio of cortex to white matter, white matter must continue to grow for several years after cessation of cortical growth. Brains with intraventricular hemorrhage or periventricular leukomalacia manifested accelerated growth of gray-matter structures compared with controls. In addition, brains with periventricular leukomalacia had markedly depressed rates of white-matter growth compared with controls of similar age, whereas brains with intraventricular hemorrhage had disproportionate hydrocephalus. The findings suggest that (1) gray-matter growth is accelerated in premature infants with intraventricular hemorrhage or periventricular leukomalacia, perhaps reflecting perinatal stress; (2) periventricular leukomalacia is associated with impaired growth of white matter during a critical period; and (3) sequential quantitative assessment of ventricular size following intraventricular hemorrhage may assist in early recognition of progressive posthemorrhagic hydrocephalus.     

Gender effects on cortical thickness and the influence of scaling

Using magnetic resonance imaging and well-validated computational cortical pattern matching methods in a large and well-matched sample of healthy subjects (n = 60), we analyzed the regional specificity of gender-related cortical thickness differences across the lateral and medial cortices at submillimeter resolution. To establish the influences of brain size correction on gender effects, comparisons were performed with and without applying affine transformations to scale each image volume to a template. We revealed significantly greater cortical thickness in women compared to men, after correcting for individual differences in brain size, while no significant regional thickness increases were observed in males. The pattern and direction of the results were similar without brain size correction, although effects were less pronounced and a small cortical region in the lateral temporal lobes showed greater thickness in males. Our gender-specific findings support a dimorphic organization in male and female brains that appears to involve the architecture of the cortical mantle and that manifests as increased thickness in female brains. This sexual dimorphism favoring women, even without correcting for brain size, may have functional significance and possibly account for gender-specific abilities and/or behavioral differences between sexes.     

Brain size and social complexity: a computed tomography study in Hyaenidae

The social brain hypothesis posits that the demands of living in complex social groups require increased neural processing, and that this underlies the expansion of brain areas involved in mediation of complex social behavior. However, much of the support for the social brain hypothesis is derived from comparative studies in primates. If large brains evolved as a result of selection pressures imposed by life within complex societies, as the social brain hypothesis predicts, then gregarious nonprimate species should possess large brains and exhibit comparable expansion of brain areas mediating social behavior. Our purpose here was to test a prediction of the social brain hypothesis-- that increased brain size is related to social complexity --by examining species in the carnivore family Hyaenidae. Hyaenidae contains 4 extant species that span a spectrum of social complexity: the aardwolf (Proteles cristata) is solitary during the nonbreeding season, and forms monogamous pairs during the breeding season; the striped hyena (Hyaena hyaena) lives solitarily or in small groups; the brown hyena (Parahyaena brunnea) lives in groups of up to 14 individuals; and the spotted hyena (Crocuta crocuta) lives in complex hierarchically organized groups containing up to 90 animals. Computed tomography was used to create three-dimensional endocasts based on serial analysis of coronal sections of the adult endocranium. The largest brain volume, relative to body size, is found in the spotted hyena. We found no significant variation in relative brain volume among striped hyenas, brown hyenas, and aardwolves. The spotted hyena also possesses a larger anterior cerebrum volume relative to total brain volume than is found in the other hyena species; this region is composed primarily of frontal cortex. These data are consistent with the idea that expansion of the frontal cortex is driven by the demands of processing cognitive information associated with complex social lives, but other factors may drive the evolution of large brains in hyaenids.     

Is the ferret a suitable species for studying perinatal brain injury?

Complications of prematurity often disrupt normal brain development and/or cause direct damage to the developing brain, resulting in poor neurodevelopmental outcomes. Physiologically relevant animal models of perinatal brain injury can advance our understanding of these influences and thereby provide opportunities to develop therapies and improve long-term outcomes. While there are advantages to currently available small animal models, there are also significant drawbacks that have limited translation of research findings to humans. Large animal models such as newborn pig, sheep and nonhuman primates have complex brain development more similar to humans, but these animals are expensive, and developmental testing of sheep and piglets is limited. Ferrets (Mustela putorius furo) are born lissencephalic and undergo postnatal cortical folding to form complex gyrencephalic brains. This review examines whether ferrets might provide a novel intermediate animal model of neonatal brain disease that has the benefit of a gyrified, altricial brain in a small animal. It summarizes attributes of ferret brain growth and development that make it an appealing animal in which to model perinatal brain injury. We postulate that because of their innate characteristics, ferrets have great potential in neonatal neurodevelopmental studies.     

Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study

The purpose of the present study was to describe in greater anatomical detail the changes in brain structure that occur during maturation between childhood and adolescence. High-resolution MRI, tissue classification, and anatomical segmentation of cortical and subcortical regions were used in a sample of 35 normally developing children and adolescents between 7 and 16 years of age (mean age 11 years; 20 males, 15 females). Each cortical and subcortical measure was examined for age and sex effects on raw volumes and on the measures as proportions of total supratentorial cranial volume. Results indicate age-related increases in total supratentorial cranial volume and raw and proportional increases in total cerebral white matter. Gray-matter volume reductions were only observed once variance in total brain size was proportionally controlled. The change in total cerebral white-matter proportion was significantly greater than the change in total cerebral gray-matter proportion over this age range, suggesting that the relative gray-matter reduction is probably due to significant increases in white matter. Total raw cerebral CSF volume increases were also observed. Within the cerebrum, regional patterns varied depending on the tissue (or CSF) assessed. Only frontal and parietal cortices showed changes in gray matter, white matter, and CSF measures. Once the approximately 7% larger brain volume in males was controlled, only mesial temporal cortex, caudate, thalamus, and basomesial diencephalic structures showed sex effects with the females having greater relative volumes in these regions than the males. Overall, these results are consistent with earlier reports and describe in greater detail the regional pattern of age-related differences in gray and white matter in normally developing children and adolescents.     

Quantitative analysis of neocortical gyrencephaly in African elephants (Loxodonta africana) and six species of cetaceans: comparison with other mammals

This study provides quantitative data on the extent of gyrencephaly in the large-brained African elephant and several species of cetaceans (from smaller to larger brained) in comparison with other mammals. Across three mammalian orders (primates, carnivores, and artiodactyls), the species with the larger brains are more gyrencephalic with each order, exhibiting a specific negative allometry. The African elephant, with a 5-kg brain, has a gyrencephalic index (GI) of 3.89, which, though highly gyrencephalic, is not more so than would be predicted for a mammal with a 5-kg brain. The cetaceans had an average GI of 5.43, are the most gyrencephalic mammals studied to date, and are more gyrencephalic than one would predict based on comparison with other mammals. No relationship between brain mass and GI was evident in the cetaceans as seen in other mammals, with all cetaceans showing similar GIs irrespective of brain mass (range of GI 5.23-5.70, range of brain mass 577-5617 g). This is yet another parameter indicating cetaceans to be neuroanatomical outliers. Two species of pinnipeds studied had GIs that were well above those seen for terrestrial carnivores, and the aquatic manatee was close to lissencephalic. Thus, all three groups of marine mammals showed unusual extents of cortical gyrencephaly, indicating a morphological alteration of the telencephalon associated with the return to the marine environment. The analysis suggests that cortical thickness and neuronal density are important factors in determining the extent of gyrencephaly across mammalian species.     

Smaller frontal gray matter volume in postmortem schizophrenic brains

OBJECTIVE: The prefrontal cortex exhibits prominent functional, biochemical, and anatomic abnormalities in schizophrenic patients. However, smaller than normal volume of the frontal lobe has not been found in previous postmortem studies of schizophrenic subjects, and magnetic resonance imaging (MRI) scans of schizophrenic subjects have not consistently revealed frontal volumetric deficits. The variability in MRI findings may be related partly to difficulty in defining the posterior border of the frontal lobe. In this study, precise measurements of frontal lobe volume from postmortem brains were derived by defining the posterior border according to the brain atlas of Talairach and Tournoux and by applying stereologic methods to estimate gray and white matter volumes. METHOD: Whole, or nearly whole, formalin-fixed left hemispheres from 14 schizophrenic and 19 normal comparison subjects were analyzed. Total cortical gray and white matter volumes, as well as frontal cortical gray and white matter volumes, were measured by using the Cavalieri method. RESULTS: Only frontal gray matter volume was significantly smaller in the schizophrenic subjects than in the comparison subjects (12% difference). The differences between groups in total gray and white matter volumes and frontal white matter volume (6%-8% smaller in the schizophrenic subjects than in the comparison subjects) did not reach statistical significance. CONCLUSIONS: The smaller frontal gray matter volume observed in schizophrenic brains suggests that pathology of the frontal lobe may be more severe than that of the three posterior lobes and may account for the prominence of prefrontal dysfunction associated with schizophrenia.     

Stereological studies of capillary length density in the frontal cortex of schizophrenics

The presence of microvasculature abnormalities in the prefrontal cortex of schizophrenics was proposed in a recent study of molecular signatures of schizophrenia [Prabakaran et al (2004) Mol Psychiat 9:684–697]. To assess this possibility further, we investigated capillary length densities in prefrontal cortex area 9 and anterior cingulate cortex area 24 in postmortem brains from 13 schizophrenics and 13 age- and sex-matched controls. To check that our sample of brains shared cardinal neuropathological features of schizophrenia with previously reported case studies, we also measured cortical gray matter volumes and cortical thickness in areas 9 and 24. The mean cortical gray matter volume was significantly reduced in brains from schizophrenics compared to controls. Mean cortical thickness was significantly reduced in area 24, but not in area 9, in schizophrenics. There were no differences in mean capillary length densities in either area 9 or 24 between the two groups. Thus, alterations in capillary length density in the prefrontal cortex cannot be considered a general feature of schizophrenia. Compromised brain metabolism and occurrence of oxidative stress in the brain of schizophrenics are likely caused by other mechanisms.     

GROWTH AND DEVELOPMENT OF THE BRAIN IN NORMAL AND HEAT-RETARDED GUINEA-PIGS

Guinea-pigs were exposed to a temperature of 41.5–42.5°C for 1h daily on days 20–23 of gestation. Fetuses from control and from heated mothers were studied at 30, 35, 41, 48, 55 and 62 days gestation and post-natal offspring at 69, 76, 83, 90, 104, 118, 132, 146 and 160 days after conception. Body weights, whole and regional brain weights, and the dry matter, DNA (an index of cellularity) and cholesterol (an index of myelination) contents of these brain regions were measured. There was frequently a small but variable deficit in the body weight of heated offspring. A significant reduction of whole brain weight was found in the heated groups. The deficit in brain weight was detected 7 days after the heat-stress and remained at about the same relative level until maturity. The DNA and cholesterol concentrations were the same in control and heated brains, but the absolute amounts were less in the latter which resembled proportional, normally shaped miniatures of the control brains. Hyperthermia is known to disrupt cellular proliferations, and since it was given during neurogenesis it is concluded that the size which might be attained by the brain is largely determined by the extent of early neuronal proliferation.     

An MRI study of increased cortical thickness in autism

OBJECTIVE: The purpose of this study was to examine cortical thickness in autism in light of the postmortem evidence of cortical abnormalities of the disorder. METHOD: Magnetic resonance imaging (MRI) scans were acquired from 17 children with autism and 14 healthy comparison subjects, and sulcal and gyral thickness were measured for the total brain and for all lobes. RESULTS: Increases in total cerebral sulcal and gyral thickness were observed in children with autism relative to comparison subjects. Similar findings were noted in the temporal and parietal lobes but not in the frontal and occipital lobes. CONCLUSIONS: These preliminary findings indicate that increased cortical thickness may contribute to the increased gray matter volume and total brain size that have been observed in autism and may also be related to anomalies in cortical connectivity.     

Brain gyrification in wild and domestic canids: Has domestication changed the gyrification index in domestic dogs?

Over the last 15 years, research on canid cognition has revealed that domestic dogs possess a surprising array of complex sociocognitive skills pointing to the possibility that the domestication process might have uniquely altered their brains; however, we know very little about how evolutionary processes (natural or artificial) might have modified underlying neural structure to support species-specific behaviors. Evaluating the degree of cortical folding (i.e., gyrification) within canids may prove useful, as this parameter is linked to functional variation of the cerebral cortex. Using quantitative magnetic resonance imaging to investigate the impact of domestication on the canine cortical surface, we compared the gyrification index (GI) in 19 carnivore species, including six wild canid and 13 domestic dog individuals. We also explored correlations between global and local GI with brain mass, cortical thickness, white and gray matter volume and surface area. Our results indicated that GI values for domestic dogs are largely consistent with what would be expected for a canid of their given brain mass, although more variable than that observed in wild canids. We also found that GI in canids is positively correlated with cortical surface area, cortical thickness and total cortical gray matter volumes. While we found no evidence of global differences in GI between domestic and wild canids, certain regional differences in gyrification were observed.