Richard B. Darlington

Web-based method for translating neurodevelopment from laboratory species to humans

Biomedical researchers and medical professionals are regularly required to compare a vast quantity of neurodevelopmental literature obtained from an assortment of mammals whose brains grow at diverse rates, including fast developing experimental rodent species and slower developing humans. In this article, we introduce a database-driven website, which was created to address this problem using statistical-based algorithms to integrate hundreds of empirically derived developing neural events in 10 mammalian species (http://translatingtime.net/). The site, based on a statistical model that has evolved over the past decade, currently incorporates 102 different neurodevelopmental events obtained from 10 species: hamsters, mice, rats, rabbits, spiny mice, guinea pigs, ferrets, cats, rhesus monkeys, and humans. Data are arranged in a Structured Query Language database, which allows comparative brain development measured in postconception days to be converted and accessed in real time, using Hypertext Preprocessor language. Algorithms applied to the database also allow predictions for dates of specific neurodevelopmental events where empirical data are not available, including for the human embryo and fetus. By designing a web-based portal, we seek to make these comparative data readily available to all those who need to efficiently estimate the timing of neurodevelopmental events in the human fetus, laboratory species, or across several different species. In an effort to further refine and expand the applicability of this database, we include a mechanism to submit additional data.

Canonical Variate Analysis and Related Techniques

This paper discusses statistical methods for studying relations between two sets of variables, when each set contains more than one variable. The number of methods discussed is about 20 or 25, depending on how one counts. About a third of the methods are old methods criticized here, another third are old methods mentioned favorably, and the rest are new methods published here for the first time. It has not been adequately recognized that problems involving two sets of variables arise frequently in almost every area of the behavioral sciences, as the following list of examples will attest:

Preschool Programs and Later School Competence of Children from Low-Income Families

At follow-up in 1976, low-income children who had attended infant and preschool programs in the 1960s had significantly higher rates of meeting school requirements than did controls, as measured by lower frequency of placement in special education classes and of being retained in grade (held back).

Is Kurtosis Really “Peakedness?”

Abstract Kurtosis is best described not as a measure of peakedness versus flatness, as in most texts, but as a measure of unimodality versus bimodality.

The Limbic System in Mammalian Brain Evolution

Previous accounts of mammalian brain allometry have relied largely on data from primates, insectivores and bats. Here we examine scaling of brain structures in carnivores, ungulates, xenarthrans and sirenians, taxa chosen to maximize potential olfactory and limbic system variability. The data were compared to known scaling of the same structures in bats, insectivores and primates. Fundamental patterns in brain scaling were similar across all taxa. Marine mammals with reduced olfactory bulbs also had reduced limbic systems overall, particularly in those structures receiving direct olfactory input. In all species, a limbic factor with olfactory and non-olfactory components was observed. Primates, insectivores, ungulate and marine mammals collectively demonstrate an inverse relationship between isocortex and limbic volumes, but terrestrial carnivores have high relative volumes of both, and bats low relative volumes of both. We discuss developmental processes that may provide the mechanistic bases for understanding these findings.

A conserved pattern of brain scaling from sharks to primates

Several patterns of brain allometry previously observed in mammals have been found to hold for sharks and related taxa (chondrichthyans) as well. In each clade, the relative size of brain parts, with the notable exception of the olfactory bulbs, is highly predictable from the total brain size. Compared with total brain mass, each part scales with a characteristic slope, which is highest for the telencephalon and cerebellum. In addition, cerebellar foliation reflects both absolute and relative cerebellar size, in a manner analogous to mammalian cortical gyrification. This conserved pattern of brain scaling suggests that the fundamental brain plan that evolved in early vertebrates permits appropriate scaling in response to a range of factors, including phylogeny and ecology, where neural mass may be added and subtracted without compromising basic function.

Patterns of Vertebrate Neurogenesis and the Paths of Vertebrate Evolution

Any substantial change in brain size requires a change in the number of neurons and their supporting elements in the brain, which in turn requires an alteration in either the rate, or the duration of neurogenesis. The schedule of neurogenesis is surprisingly stable in mammalian brains, and increases in the duration of neurogenesis have predictable outcomes: late-generated structures become disproportionately large. The olfactory bulb and associated limbic structures may deviate in some species from this general brain enlargement: in the rhesus monkey, reduction of limbic system size appears to be produced by an advance in the onset of terminal neurogenesis in limbic system structures. Not only neurogenesis but also many other features of neural maturation such as process extension and retraction, follow the same schedule with the same predictability. Although the underlying order of event onset remains the same for all of the mammals we have yet studied, changes in overall rate of neural maturation distinguish related subclasses, such as marsupial and placental mammals, and changes in duration of neurodevelopment distinguish species within subclasses. A substantial part of the regularity of event sequence in neurogenesis can be related directly to the two dimensions of the neuraxis in a recently proposed prosomeric segmentation of the forebrain [Rubenstein et al., Science, 266: 578, 1994]. Both the spatial and temporal organization of development have been highly conserved in mammalian brain evolution, showing strong constraint on the types of brain adaptations possible. The neural mechanisms for integrative behaviors may become localized to those locations that have enough plasticity in neuron number to support them.

Neural development in metatherian and eutherian mammals: variation and constraint.

A model for predicting the timing of neurogenesis in mammals (Finlay and Darlington [1995] Science 268:1578–1584) is here extended to an additional five metatherian species and to a variety of other events in neural development. The timing of both the outgrowth of axonal processes and the establishment and segregation of connections proves to be as highly predictable as neurogenesis. Expressed on a logarithmic scale, late developmental events are as predictable as early ones. The fundamental order of events is the same in eutherian and metatherian animals, but there is a curvilinear relation between the event scales of the two; for metatherians, later events are slowed relative to earlier events. Furthermore, in metatherians, the timing of developmental events is more variable than in eutherians. The slowing of late developmental events in metatherians is associated with their considerably longer time to weaning compared with eutherians. J. Comp. Neurol. 411:359–368, 1999.

Peripheral variability and central constancy in mammalian visual system evolution

Neural systems are necessarily the adaptive products of natural selection, but a neural system, dedicated to any particular function in a complex brain, may be composed of components that covary with functionally unrelated systems, owing to constraints beyond immediate functional requirements. Some studies support a modular or mosaic organization of the brain, whereas others emphasize coordination and covariation. To contrast these views, we have analysed the retina, striate cortex (V1) and extrastriate cortex (V2, V3, MT, etc.) in 30 mammals, examining the area of the neocortex and individual neocortical areas and the relative numbers of rods and cones. Controlling for brain size and species relatedness, the sizes of visual cortical areas (striate, extrastriate) within the brains of nocturnal and diurnal mammals are not statistically different from one another. The relative sizes of all cortical areas, visual, somatosensory and auditory, are best predicted by the total size of the neocortex. In the sensory periphery, the retina is clearly specialized for niche. New data on rod and cone numbers in various New World primates confirm that rod and cone complements of the retina vary substantially between nocturnal and diurnal species. Although peripheral specializations or receptor surfaces may be highly susceptible to niche-specific selection pressures, the areal divisions of the cerebral cortex are considerably more conservative.

The course of human events: predicting the timing of primate neural development

A recent model of the timing in which neural developmental events occur in a variety of mammals has shown high predictability of the order and duration of these events across species when appropriately computed. The model, originally derived to study the developmental mechanisms of evolutionary change in the nervous system, is adapted in this paper to predict the course of those events in the developing human, a sequence that has been difficult to determine using non-invasive neuroanatomical techniques. Using a modified version of our original regression model, we generate predicted times of occurrence for a large number of developmental events in the human embryo and fetus, and include a chart of comparable events for macaque monkeys. We discuss a bidirectional variability in the original model which allowed us to identify limbic and cortical primate neural events that are significantly deviant from the general mammalian norm, but which also proved predictable following modification. We test the modified model against empirically derived values for neural events not included in the original model, as well as through comparisons with human developmental sequences inferred by other methods. In view of the remarkable stability in the course of development across species, knowledge of the timing of human neural events need not be entirely restricted to the limited existent embryonic and infant data. Although the primate neural development sequence is somewhat more complex than that for other mammals, primate data continue to support a theory of developmental conservation across evolution.