Benjamin H. Landing's research while affiliated with University of California, Los Angeles and other places

The renal lesion of congenital hepatic fibrosis (CHF = Blyth and Ockenden's juvenile polycystic disease of liver and kidneys) was analyzed from 6 specimens from patients aged 3 3/12 to 19 3/12 years and compared with that of 5 patients with infantile polycystic disease (IPCD) aged 6 months to 14 4/12 years. Pathologic, microdissection, injection, and morphometric studies show that the predominantly medullary cystic lesion of CHF shows different distribution in medullary, cortico-medullary, and cortical zones of kidney from the lesion of IPCD, and shows a different time course, from early life to renal insufficiency, from that of IPCD. The renal cysts in CHF affect deep or central collecting tubules, in contrast to the involvement of more peripheral orders of collecting tubules in IPCD. Papillary pore counts, performed for 1 patient, gave significantly low values, in contrast to normal values reported for IPCD. The findings support the previously published conclusion, based on differences in the hepatic lesions of the two conditions, that CHF and IPCD are difference diseases, rather than different permissible manifestations of a single disease.

This study subjects the Coppoletta-Wolbach data of normal organ weights of children from birth to 12 years of age to statistical analysis, producing a set of curves that show the linear regression of organ weight versus age for each set of weights plus, for each organ, the 75%, 80%, 90%, 95%, and 99% confidence bands for single new values.

Cockayne syndrome is an autosomal recessive disease, which includes as major features motor and mental retardation (beginning in the second year), microcephaly, ataxia, retinal degeneration and pigmentation, cataracts, progeroid features, intracranial calcification, hypogonadism, and growth retardation. Many other diseases have some of these features, so that diagnosis of Cockayne syndrome can be difficult, especially in younger children. Eccrine sweat glands were microdissected from autopsy or biopsy specimens from patients with Cockayne syndrome, and mean values for duct length, secretory coil volume, ratio of coil volume to duct length, and axis ratio of the secretory coil were determined. In comparison with values for eccrine glands of patients with no known genetic or chromosomal disease, eccrine glands in Cockayne syndrome are abnormally small for age. Whether other diseases with various similarities to Cockayne syndrome produce similar growth abnormality of eccrine sweat glands is not known, but determination of sweat gland size may provide data suggesting or supporting the diagnosis of Cockayne syndrome.

The thickness of a cortical layer is a composite measure of neuronal, axonal, dendritic, synaptic, and glial numbers and sizes that may relate to thefunction of a cortical area. 35 age-specific behaviors with defined cortical localization whose onset lies between birth and 72 months were selected. Each behavior's function localized to one or more of 12 cytoarchitectonic areas (Brodmann areas 4, with homuncular subdivisions for leg, trunk, face, and hand, plus 17, 18, 19, 20, 21, 24, 36, and 37). Data on cortical thickness for each layer of 41 cytoarchitectonic areas (including the 12 above) of the postnatal human cerebral cortex from birth of 72 months were analyzed for general patterns of change. For the 12 cortical areas functionally related to theage-specific behaviors, we searched for layer thickness changes that co-related to when the behaviors began. Without exception, all layers of the 41 cortical areas of the postnatal human cerebral cortex studied develop through a series of repeated thinning and thickening in a wave-like fashion. With regard to the co-relation of behavioral onset and changes in cortical layer thickness, from birth to 15 months, only layer II has agreater than expected frequency of being the layer with the greatest relative change in thickness (relative to its previous value). From 15 to 72 months, only layer IlI has a greater than expected frequency of being the layer with the greatest absolute change in thickness (81% involved a change in its direction of growth (thinning <--> thickening)). The co-occurrence of directional growth change and having the greatest layer thickness change were only statistically significant for layer III when an age-specific behavior began and was not seen for the 41 cortical areas overall (p = 0.014). Cortical laminar development exhibits aprocess that is mathematically consistent with a random walk with drift and with boundaries so that uncontrolled proliferation and pruning are prevented. The directional changes in layer growth could be controlled by feedback coupled with growth promoting and growth inhibiting factors. Layer II, with its function of establishing local corticocortical connections, appears to be most important in establishing age-specific behaviors of infants from birth to 15 months. Such a process tends to produce relatively simpler behaviors. LayerIII, with its function of establishing longer distance corticocortical connections, appears to be most important in establishing age-specific behaviors of children from 15 to 72 months. This process tends to produce richer, more cross-modal behaviors than those mediated primarily by local corticocortical interactions.

We introduce a database of the microscopic, laminar development of ∼73% of postnatal human cerebral cortical areas from 0 to 72 months. These data have yielded important findings, such as overturning the dogma of no postnatal neurogenesis in humans. To facilitate their use in computational models, the data are being interfaced with GENESIS.

From 1939 to 1967, J.L. Conel quantitatively studied the microscopic features of the developing human cerebral cortex and published the findings in eight volumes. We have constructed a database using his neuroanatomical measurements (neuronal packing density, myelinated large fiber density, large proximal dendrite density, somal breadth and height, and total cortical and cortical layer thickness) at the eight age periods (0 [term birth], 1, 3, 6, 15, 24, 48, and 72 postnatal months) he studied. In this report, we examine changes in neuron numbers over the eight age-points for 35 von Economo areas for which Conel gave appropriate data. From birth to 3 months postnatal age, total cortical neuron number increases 23-30%, then falls to within 3.5% of the birth value at 24 months, supporting our previous work showing that the observed decrease in the number of neurons per column of cortex under a 1-mm2 cortical surface from birth to 15 months is almost entirely due to cortical surface expansion. The present study also shows a 60-78% increase in total cortical neuron number above the birth value from postnatal ages 24 to 72 months. The generalization, to humans at least, of the finding of no postnatal neurogenesis in rhesus macaques, a species belonging to a superfamily that diverged from that of Homo sapiens more than 25 million years ago, is not warranted until explicitly proven for humans. The data of the present study support the existence of substantial postnatal neurogenesis in humans for the 35 cortical areas studied.

This study examines JL Conel's data on neuron numbers in 35 human cortical areas for eight age points from 0 (birth) to 72 months, to analyze cortical columns, the presumed functional units of the cortex. For each cortical area at each age point, cortical surface divided by the square root of the area's neuron number gives cross-sectional areas with radii ranging from 180 microns at birth to 250 microns at 72 months. For the prefrontal cortex at birth and 48 months, these radii are approximately 2.10 and 1.19 times the longest radial basal dendrites, suggesting similar dimensions between these two measures of column radius. The logarithm of neuron number per cortical area and age point was examined in relation to the Weber-Fechner law governing the relationship between stimulus intensity and perception. A mechanism for this law consistent with the cortical model of Douglas et al. illustrates the importance of local circuit neurons. The cross-sectional areas of hexagonal columns for prefrontal cortex, using as radius, the longest radial extent of layer 5 pyramidal neuron basal dendrites, ranging from 0.013 mm2 at birth to 0.064 mm2 at 48 months, suggests that functional cortical columns increase cross-sectional area during development. These cross-sectional areas are 55-100-fold larger at birth, and 229-277-fold larger at 48 months, than those computed from somal width in prefrontal, layer 5 pyramidal neurons. Comparison of radial extent of pyramidal basal dendrites to their soma-to-soma distances shows that layer 3 pyramidal basal dendrites reach 1.5 and 4.0 other pyramidal neurons at 15 and 60 months, respectively, while layer 5, extra-large pyramidal basal dendrites reach 1.14 and 1.72 other such neurons at birth and 48 months, respectively. If such a relationship holds for other cortical areas, then the Conel data can be used to estimate basal dendrite extent, for which there currently is a paucity of data.

In this study, we searched for patterns in selected, quantitative microscopic features of the developing postnatal human cortex for 35 cytoarchitectural areas at eight age points from birth to 72 months. These data come from the largest extant survey of the microscopic features of the developing postnatal human cerebral cortex (JL Conel, 1939-67). In contrast to Jacobson's proposal that cortical surface area increases in proportion to brain weight, Conel's data show that surface area increases as brain weight2/3, with the maximal rate of increase in both brain weight and cortical surface area occurring from 1 to 3 months. We computed the numbers of cortical neurons per cortical layer under 1 mm2 of cortical surface (neurons/layer per mm2 column) and divided these values by the total neuron number/mm2 column. For all areas, these data show plateaux in most of the layers for periods of months to years, often preceded and followed by changes in their neuron number in a sinusoidal fashion. The age points of the maxima and minima of such laminar values differ across the 35 cortical areas, indicating that their sinusoids are phase-shifted with respect to each other. Ranking the six layers in each area at each age point by their neuron number/layer per mm2 column shows that, by 72 months, the first areas to receive thalamic auditory or visual input (primary sensory and unimodal association cortices) have the most neurons in layer 4 and in either layer 3 or 6. In contrast, by 72 months, other areas have the most neurons in layers 3 and 6, with the primary motor cortex reaching this ranking earlier than any other area. For temporal and parietal association areas, layers 2 (short cortico-cortical connections) and 4 (thalamo-cortical connections) have the most neurons from birth to 6 months, whereas layers 3 (long cortico-cortical connections) and 6 (cortico-thalamic connections) have the most neurons by 72 months. The quantitative, statistically non-random patterns demonstrated by our analyses suggest that hierarchical correlations between such structural changes and age-specific behavioral acquisitions exist during the first 72 months of postnatal development.

The generalization of the finding of no postnatal neurogenesis in non-human primates to humans may be incorrect because: (1) rhesus macaques belong to a superfamily that diverged more than 25 million years ago from the superfamily including the genus Homo; (2) the pulse thymidine labeling method, which demonstrates DNA synthesis rather than mitosis per se, is less reliable than some have assumed. This study examines changes in the number of neurons in a column underneath a cortical surface area of 1 mm2, extending through all cortical layers (mm2-column) for 35 gyri (representing about 73% of the human cerebral cortex) based on the data of J.L. Conel (1939 to 1967). We corrected these data, derived from his measures of cortical neuronal packing density, somal breadth and height, and cortical layer thickness at postnatal ages 0, 1, 3, 6, 15, 24, 48, and 72 months, for shrinkage and stereological errors. In all 35 gyri, neuron number/mm2-column: (1) initially declines (mu = 46% decline, sigma = 8%), 95% of which is due to surface area expansion (mean age of nadir value = 15.8 months); (2) then increases to age 72 months by 70% (mu = 1.7-fold increase, (mu rate = 1.1% per month). Because of a a concomitant 1.3-fold increase in cortical surface from 15 to 72 months, total cortical neuron number increases 2.2-fold. The close agreement between neuron number/mm2-column for Conel's age 72-month data to the corresponding values reported by others for adult human and primate cortex using more modern methods suggests the finding is not an artifact. Neuronal proliferative fate-determining factors provide at least four mechanisms for increasing cortical neuron number postnatally, with or without DNA synthesis.

This paper uses correspondence analysis to examine the developmental patterns in the cytoarchitecture of the human cerebral cortex from birth to 72 months. The study is based on data collected by the late J. L. Conel, which consist of over 4 million individual measurements of six microscopic neuroanatomic features for each of six cortical layers in 46 cytoarchitecturally distinct regions. We analyze 1,727 profiles of development over eight age-points (term birth, 1, 3, 6, 15, 24, 48, and 72 postnatal months) resulting from the combinations of neuroanatomic feature, cortical layer, and brain cytoarchitectural region in the Conel data. The profiles for any given combination of feature and layer are found to be remarkably similar in all regions of the brain, and therefore the developmental patterns of different cytoarchitectural regions are not distinguishable from one another. Developmental change is most rapid at the earlier stages; of the total change in profile patterns observed, more than one-third occurs between birth and 6 months, about one-third occurs between 6 and 15 months, and less than one-third occurs between 15 and 72 months. The majority of the variance in developmental profiles is accounted for by the six microscopic, neuroanatomic features. Correspondence analysis shows that Conel's data are highly consistent and reliable.