Brain growth in modern humans using multiple developmental databases.

OBJECTIVE: Currently, there are several published articles detailing brain growth in modern humans. The contained databases were derived using disparate methodologies. The objective of the present investigation was to determine the level of agreement among several collections of immature modern human brains. MATERIALS AND METHODS: Twenty-one developmental collections of endocranial volume, brain weight, or brain volume were selected for analysis, including one skeletal, six autopsy, and 14 computed tomography/magnetic resonance imaging samples. Step-wise comparisons were determined, using conversion factors for brain specific gravity and size of the subarachnoid space. RESULTS: Derived brain weights are comparable and increase especially during the first year of postnatal life, with a further slight increase (+8-10%) between one and five years, and little change thereafter. The expansion in brain size occurs earlier than body size. Significant sex differences are apparent at all stages of development. Combining all datasets produced a composite database consisting of 3,491 brain weight values, with ages near birth through 18 years. Individual brain weights ranged from 190 to 1,792 g, and mean brain weights ranged from 457 to 1,365 g, with an overall mean and standard deviation of 897 ± 387 g. CONCLUSIONS: The investigation compares modern human collections regarding brain size trajectories from birth through 18 years of age. The 21 datasets are then incorporated into a single composite database. All major age groups and both sexes are well represented. The composite database should prove useful to other investigators interested in developmental aspects of the modern human brain.

Development of the Corpus Callosum: An MRI Study.

The size and shape of the corpus callosum and its major components (genu, body, and splenium) were measured by magnetic resonance imaging (MRI) in 118 normocephalic individuals aged from 1 postnatal week to 18.7 years. Genu, body, splenial, and total corpus callosal areas increased by 40-100% during the first year of life (p < 0.05). The genu expanded to a greater extent than the splenium during the first 6 years, while the splenium expanded to a greater extent between 7 and 18 years. The age-related difference in the maximal expansion of these structures indicated an anterior to posterior wave of corpus callosal enlargement during maturation, probably the consequence of differential axonal myelination. No sex differences existed during these two developmental phases for the genu, splenial, or total corpus callosal areas with or without scaling to the cerebral hemispheric volume. During infancy (0-24 months), however, the mean female splenial ratio (length/height) of 0.79 was greater than the male ratio of 0.65 (p = 0.024). The cerebral hemispheric length/height ratio was also greater in females, indicating that during infancy the female brain (and its component the corpus callosal splenium) is relatively longer than the male brain. This sex difference was confined to the splenium and disappeared with increasing age.

Craniometric ratios of microcephaly and LB1, Homo floresiensis, using MRI and endocasts.

The designation of Homo floresiensis as a new species derived from an ancient population is controversial, because the type specimen, LB1, might represent a pathological microcephalic modern Homo sapiens. Accordingly, two specific craniometric ratios (relative frontal breadth and cerebellar protrusion) were ascertained in 21 microcephalic infants and children by using MRI. Data on 118 age-equivalent control (normocephalic) subjects were collected for comparative purposes. In addition, the same craniometric ratios were determined on the endocasts of 10 microcephalic individuals, 79 normal controls (anatomically modern humans), and 17 Homo erectus specimens. These ratios were then compared with those of two LB1 endocasts. The findings showed that the calculated cerebral/cerebellar ratios of the LB1 endocast [Falk D, et al. (2007) Proc Natl Acad Sci USA 104:2513-2518] fall outside the range of living normocephalic individuals. The ratios derived from two LB1 endocasts also fall largely outside the range of modern normal human and H. erectus endocasts and within the range of microcephalic endocasts. The findings support but do not prove the contention that LB1 represents a pathological microcephalic Homo sapiens rather than a new species, (i.e., H. floresiensis).

Craniometric measures during development using MRI.

Developmental changes in brain volume and shape in infants, children, and adolescents were ascertained with MRI, using craniometric (linear brain) measures in 118 individuals, ages 1 postnatal week to 18.7years. Collected clinical data included age, sex, weight, height, body mass index, occipito-frontal circumference (OFC), and diagnosis prompting the MRI scan. Twenty craniometric measures were obtained to allow for the determination of specific ratios as well as sex and age-related changes in brain shape and size. Analysis of the cohort showed that OFC is larger today than 40years ago, likely related to a concomitant increase in body stature. The data indicated a wide variation in the maturational pattern of several specific craniometric ratios, which reflects changes in the volume and configuration of the brain with advancing age. The increases in brain volume and changes in brain shape were most dramatic during infancy, with continued minor escalations in volume and reshaping during childhood and adolescence. Sex differences existed both in brain volume and shape, as well as evidence of sexual dimorphism. Changes in cerebellar volume and shape lagged behind the corresponding changes in the cerebral hemispheres. These collective data in living developing individuals allow for comparisons of clinical or craniometric measures in distant and more recent humans.

Cerebral asymmetry during development using linear measures from MRI.

Asymmetry of the human brain is a well-known phenomenon, but the nature and extent of these differences throughout postnatal development have not been examined. Accordingly, linear measurements of the brains of 121 infants, children, and adolescents were determined to ascertain cerebral hemispheric asymmetries. Using multiple statistical methods, the results showed that: 1) the frontal lobe is wider on the right, while the occipital lobe is wider on the left; 2) there are no side to side differences in cerebral hemispheric length or height; and 3) there are no major sex differences. Especially notable is the lack of any correlation between side to side differences in length, width, or height and increasing age, which was also the case for cerebral hemispheric area or volume with increasing age. Regarding petalias: 1) the right frontal petalia occurs in 61%, the left occipital in 60%, and both petalias in 36% of the cohort; 2) the right frontal and left occipital petalias are of similar lengths; 3) the distances of both petalias increase with advancing age but not when scaled to either cerebral hemispheric area or volume, indicating that petalias are equally prominent early in postnatal life compared to later development; and 4) there are no major sex differences in the frequency or magnitude of either petalia. These findings provide comprehensive new information regarding age and sex related cerebral hemispheric asymmetries during development.

Secondary energy failure after cerebral hypoxia-ischemia in the immature rat.

A delayed or secondary energy failure occurs during recovery from perinatal cerebral hypoxia-ischemia. The question remains as to whether the energy failure causes or accentuates the ultimate brain damage or is a consequence of cell death. To resolve the issue, 7-day postnatal rats underwent unilateral common carotid artery occlusion followed thereafter by systemic hypoxia with 8% oxygen for 2.5 hours. During recovery, the brains were quick frozen and individually processed for histology and the measurements of 1) high-energy phosphate reserves and 2) neuronal (MAP-2, SNAP-25) and glial (GFAP) proteins. Phosphocreatine (PCr) and ATP, initially depleted during hypoxia-ischemia, were partially restored during the first 18 hours of recovery, with secondary depletions at 24 and 48 hours. During the initial recovery phase (6 to 18 hours), there was a significant correlation between PCr and the histology score (0 to 3), but not for ATP. During the late recovery phase, there was a highly significant correlation between all measured metabolites and the damage score. Significant correlation also exhibited between the neuronal protein markers, MAP-2 and SNAP-25, and PCr as well as the sum of PCr and Cr at both phases of recovery. No correlation existed between the high-energy reserves and the glial protein marker, GFAP. The close correspondence of PCr to histologic brain damage and the loss of MAP-2 and SNAP-25 during both the early and late recovery intervals suggest evolving cellular destruction as the primary event, which precedes and leads to the secondary energy failure.

Neuropathology of seizures in the immature rabbit.

Acute morphologic changes of brain due to chemically induced seizures are studied in developing rabbits. Accordingly, rabbits of postnatal days 6 and 7 (p6-7) and p10-12 are injected with a single dose of 1-6 mg/kg kainic acid (KA) intraperitoneally (i.p.) or injected with a single dose of 200-300 mg/kg pilocarpine subcutaneously (s.c.). Many animals developed seizures of varying severity and length. Histologic examination of brain 2 days following injection showed that KA-induced seizures did not cause neuronal death. Pilocarpine-induced seizures resulted in neuronal death mainly involving the CA1 region of hippocampus. In the p6-7 group, only a small number of brains were involved, lesions were mild and limited to CA1. In the p10-12 group, majority of the brains were damaged, lesions were relatively severe, and in some brains extended beyond the CA1 region involving the subiculum, CA3, cortex, and amygdala. Measurements of physiologic parameters indicate that these changes were not secondary to hypoxemia during seizures. However, there was hypotension and hyperthermia, both of which may contribute to brain damage during seizures. The findings suggest that pilocarpine-induced seizures during the second postnatal week in rabbits is a useful model to study the morphologic changes of brain due to seizure in the developing animal and also to assess the systemic physiologic alterations during seizures.

Frontal brain expansion during development using MRI and endocasts: relation to microcephaly and Homo floresiensis.

A major hall of hominid brain evolution is an expansion of the frontal lobes. To determine if a similar trajectory occurs during modern human development, the MRI scans of 118 living infants, children, and adolescents were reviewed and three specific measurements obtained: frontal width (FW), maximal cerebral width (MW), and maximal cerebral length (ML). The infantile brain is uniformly wide but relatively short, with near equal FW and MW. The juvenile brain exhibits a wider MW than FW, while FW of the adolescent brain expands to nearly equal MW, concurrent with an increase in ML. The preferential frontal lobe expansion during modern human development parallels that observed during the evolution of Homo. In 17 microcephalic individuals, only 6 (35%) exhibited preferential frontal lobe hypoplasia, presumably a reflection of multiple etiologies that adversely affect differing brain regions. Compared to 79 modern human adult endocasts and 12 modern microcephalic endocasts, LB1 (Homo floresiensis) clustered more consistently with the microcephalic sample than with the normocephalic sample.

Craniometric measures of microcephaly using MRI.

BACKGROUND: Microcephalic brains exhibit varying sizes, shapes, and dimensions when compared to normocephalic counterparts, but the extent of these differences is unresolved. AIMS: To ascertain developmental changes in brain morphology using craniometric (linear brain) measures derived from MRI in microcephalic individuals and in normocephalic controls. STUDY DESIGN: A retrospective, cross-sectional cohort study. SUBJECTS: Twenty-one primary and secondary microcephalic individuals ages 2 postnatal weeks to 8.5 years with occipito-frontal circumference<2nd percentile for age; 83 age-equivalent normocephalic controls. OUTCOME MEASURES: Age, sex, weight, height, body mass index, occipito-frontal circumference, and diagnosis prompting the MRI scan. Sixteen craniometric measures to determine specific ratios and age-related changes in brain shape and size. RESULTS: Microcephalic infants and children not only have abnormally small brains but also proportionately lower weights and heights. The brain volumes of both primary and secondary microcephalics were quite variable, ranging from 266 to 723 cm(3) and 440 to 730 cm(3), respectively (p=0.34). Despite their smaller sizes, the shapes of 15/21 (71%) microcephalic brains were similar to those of age-equivalent controls. Cerebral hemispheric configurations were not consistent among the 6 misshapen brains, which included 2 primary, 3 secondary, and 1 unknown microcephalics. Older microcephalic brains could be distinguished from their normocephalic counterparts by two specific craniometric ratios (frontal cerebellar pole/sagittal cerebral length; axial temporal width/axial cerebellar width), each incorporating cerebral and cerebellar dimensions in either length or width. CONCLUSIONS: The findings should provide useful information for distinguishing the characteristics of both modern and ancient microcephalic from normocephalic brains.

Perinatal hypoxic-ischemic brain damage: evolution of an animal model.

Early research in the Vannucci laboratory prior to 1981 focused largely on brain energy metabolism in the developing rat. At that time, there was no experimental model to study the effects of perinatal hypoxia-ischemia in the rodent, despite the tremendous need to investigate the pathophysiology of perinatal asphyxial brain damage in infants. Accordingly, we developed such a model in the postnatal day 7 rat, using a modification of the Levine preparation in the adult rat. Rat pups underwent unilateral common carotid artery ligation followed by exposure to systemic hypoxia (8% oxygen) at a constant temperature of 37 degrees C. Brain damage, seen histologically, was generally confined to the cerebral hemisphere ipsilateral to the arterial occlusion, and consisted of selective neuronal death or infarction, depending on the duration of the systemic hypoxia. Tissue injury was observed in the cerebral cortex, hippocampus, striatum, and thalamus. Subcortical and periventricular white matter injury was also observed. This model was originally described in the Annals of Neurology in 1981, and during the more than 20 years since that publication numerous investigations utilizing the model have been conducted in our laboratories as well as laboratories around the world. Cerebral blood flow and metabolic correlates have been fully characterized. Physiologic and pharmacologic manipulations have been applied to the model in search of neuroprotective strategies. More recently, molecular biologic alterations during and following the hypoxic-ischemic stress have been ascertained and the model has been adapted to the immature mouse for specific use in genetically altered animals. As predicted in the original article, the model has proven useful for the study of the short- and long-term effects of hypoxic-ischemic brain damage on motor activity, behavior, seizure incidence, and the process of maturation in the brain and other organ systems.

Glycolysis and perinatal hypoxic-ischemic brain damage.

To ascertain the regulation of glycolysis during perinatal hypoxia-ischemia, 7-day postnatal rats were subjected to unilateral common carotid artery ligation followed by hypoxia with 8% oxygen for up to 90 min. Brain concentrations of glucose, lactate, and key glycolytic intermediates were determined at specific intervals of hypoxia. During hypoxia-ischemia, anaerobic glycolysis increased to approximately 62% of its maximal capacity, which equates to a 135% stimulation of the glycolytic flux. The key regulatory enzymes, hexokinase, phosphofructokinase and pyruvate kinase, were all stimulated during hypoxia-ischemia, and there were no enzymatic rate limitations. The major rate-limiting step for glycolysis was the transport of glucose across the blood-brain barrier into the brain.

Hypoxic preconditioning increases brain glycogen and delays energy depletion from hypoxia-ischemia in the immature rat.

Recent studies have shown a protection from cerebral hypoxic-ischemic (HI) brain damage in the immature rat following a prior systemic hypoxic exposure when compared with those not exposed previously. To investigate the mechanism(s) of hypoxic preconditioning, brain glycogen and high-energy phosphate reserves were measured in naïve and preconditioned rat pups subjected to HI. Groups in this study included untouched (naïve) controls, preconditioned controls (i.e., hypoxia only), preconditioned with HI insult, and naïve pups with HI insult. Hypoxic preconditioning was achieved in postnatal-day-6 rats subjected to 8% systemic hypoxia for 2.5 h at 37 degrees C. Twenty-four hours later, they were subjected to unilateral common carotid artery ligation and systemic hypoxia with 8% oxygen at 37 degrees C for 90 min. Animals were allowed to recover from HI for up to 24 h. At specific intervals, animals in each group were frozen in liquid nitrogen for determination of cerebral metabolites. Preconditioned animals showed a significant increase in brain glycogen 24 h following the initial hypoxic exposure, corresponding to the beginning of the HI insult. Measurement at the end of 90 min of HI showed a depletion of high-energy phosphates, ATP and phosphocreatine, in all animals although ATP remained significantly higher in the preconditioned animals. Thus, the energy from increased glycogen following preconditioning slowed high-energy phosphate depletion during HI, thereby allowing for long-term protection.