by Arnold B. Scheibel, MD
In the following article, Dr. Scheibel tells the fascinating story of how the brain develops in human beings from conception to birth. He makes clear that this complex, rapidly developing process is affected continually by the environment in which it is taking place. What mothers eat, drink, and feel-- the environments which they themselves experience-- affect daily the neural development of their unborn child.
Nowhere are the beauty and power of life processes better expressed than in the development of the human nervous system. The adult human brain is believed to consist of at least one hundred billion neurons (nerve cells) and probably five to ten times as many neuroglial (functional support) cells. Together these elements make up a three pound mass of protoplasm which is unique on our world and in our solar system and, so far as we now know, in our galaxy.
During the intrauterine period of life, a great excess of neurons is produced-- perhaps twice as many as necessary, but these are winnowed out in the final month or so of pregnancy and in the months just after birth. So great is the profusion of primitive neurons that at least fifty thousand cells are produced during each second of most of intrauterine life to provide the necessary number. So complex are the challenges involved in developing a brain that at least one half of our entire genome (the full catalogue of human genes on all the chromosomes) is devoted to producing this organ that will constitute only two percent of our body weight. It should be realized at this point that for the nine months of intrauterine life and for a short but indeterminate postnatal period, brain growth and development will be largely genetically determined. However, environmental (epigenetic) factors will also be involved almost from the beginning of embryonic life, and will assume an increasingly important role. It is, in fact, the complex intertwining of genetic and epigenetic factors which guarantee the uniqueness of each individual.
The human embryo develops from the union of a single sperm with an egg. In the nine months of pregnancy that follow, the developing organism undergoes a rapid sequence of transformations in which it recapitulates on an extremely compressed time scale the developmental progression of the entire vertebrate lineage. For example, the very early human fetus has gill arches like a fish. These are converted into other structures such as the muscles of the face, larynx and pharynx. Similarly, at a slightly later stage in development, the human embryo has a tail which is rapidly reabsorbed (at about the fortieth day after conception) with further development. The drama of fertilization and development is so intricate and yet so repeatable (only a few percent of embryos fail to develop normally) that it is worth our while to follow the major steps in the process.
The number of potential germinal cells in the human female is limited to about four hundred thousand in both ovaries. Of these, only about three hundred to three hundred fifty will go on to maturity. One will be released, usually one every 28-29 days, approximately half way between menstrual periods. Thus the egg is, biologically speaking, a very rare and valuable entity, and the monthly ceremony of ovulation a celebration of biological immortality.
The female germ cell (oocyte) is released from a small, fluid-filled mound, the ovarian follicle, on the surface of the ovary. Finger-like appendages of the ovarian (Fallopian) tube continuously sweep over the ovarian surface during this period and are usually successful in guiding the oocyte into the open end of the tube. Once in the tube, the oocyte is slowly carried along in the direction of the uterus by two different mechanisms working together. The wall of the tube is made up of continuous coils of smooth (involuntary) muscle which undergo waves of contraction, very much like the peristaltic contraction of the muscles in the intestinal wall. Additionally, the Fallopian tube itself is lined by millions of fine hairs called cilia. These beat in waves which pass along the inner surface of the tube, tending also to move the egg toward the uterus.
The male germinal cell, the sperm, in contradistinction to the egg, is produced in enormous numbers. Two hundred to three hundred million sperm are usually released in a single ejaculation. Each sperm is little more than a package with one complete set of paternal genes and a powerful tail that must propel the sperm cell through several centimeters of cervix, uterus and Fallopian tube. Once the sperm reaches the uterine end of the Fallopian tube, two familiar mechanisms take over to facilitate its journey. Contractile waves of musculature in the tubal walls and synchronized beating of the lining cilia help the sperm to move outward along the tube in the general direction of the oocyte. Notice here that the tubal musculature and cilia are working in a direction opposite to those in the more peripheral part of the tube which are working on the oocyte. We can almost think of the Fallopian tube as a kind of biological marriage broker, doing its best to bring male and female components together.
When a sperm makes contact with an oocyte (a target approximately one millimeter in diameter) a series of biochemical mechanisms are triggered that result in entry of the sperm head into the egg. With the junction of sperm and egg, a process known as fertilization, a new entity comes into being. This fertilized egg (or ovum) now has a complete (diploid) set of genes, one half from the father and one half from the mother. The maternal donation includes not only the genetic material in the nucleus of the oocyte, but a small extra amount that comes with highly specialized structures from the cytoplasm of the cell. These microscopic structures called mitochondria are necessary for the energy requirements of the cell but also carry genes coding for a group of traits which characteristically pass down to each new generation from the maternal side alone.
EARLY DEVELOPMENT OF THE EMBRYO
Following fertilization there is a period of about 24 hours during which profound and still poorly understood changes occur. The cell then divides into two adherent daughter cells and after another 18-24 hour period, becomes a four celled embryo. It seems probable that until this time, each of the daughter cells maintains the potential to continue development in its own right and become a separate and complete individual. This is the source of identical twins, triplets or quadruplets, when they occur. With successive divisions, this pluripotential quality is lost and the components of the growing cell cluster become progressively more specialized.
As the cells continue to divide and adhere to each other through the 8,16, 32 cell stages etc., the cluster begins to resemble a mulberry and, as a result, this is often referred to as the 'morula' (mulberry) stage. During the following sequence of divisions, the solid mass of daughter cells develop an inner cavity, thereby entering the 'blastocyst' (blast, developing; cyst, sac, stage. At one end of the now hollow, ball-like structure, a cluster of cells grows more rapidly than those around it, becoming the 'inner cell mass'. This is the beginning of the embryo. The remainder of the blastocyst will form the various parts of the embryo/fetus support system, i.e., placenta, amniotic sac, etc.
THE PRIMITIVE CELL LAYERS
Each individual is made up of three different types of tissue. Ectoderm includes all of the packaging elements of the organism, i.e., skin, hair, nails and, interestingly enough, the nervous system. Mesoderm makes up the the major structural components of the body including the great muscle masses, both the voluntary muscles which underlie all of our work, actions and behavior, and the involuntary muscles which make up the walls of all of our organs such as heart and blood vessels, respiratory and gastrointestinal systems, and our bones. Finally the endoderm includes all of the cell systems which line our organs and vessels.
APPEARANCE OF THE NOTOCHORD
The inner cell mass originally differentiates into a layer of primitive (presumptive) ectoderm and an underlying and roughly parallel-lying layer of endoderm. In the area between these two cell layers, a few new cells appear, apparently from the underlying endoderm. These most recent arrivals become the primitive mesoderm. Their first task is to come together to form a long cylindrical structure. In doing this, they are recapitulating the earliest event in the transition from invertebrates to vertebrate forms, a transition which occurred at least six hundred million years ago. This rod-like structure is the notochord, the progenitor of the backbone or vertebral column. We all still carry traces of the old notochord in our own bodies. Our vertebral column is made up of 32 separate vertebrae, piled on each other to form our flexible backbone. Between each vertebra is a small shock absorber or intervertebral disc. In the center of each of these fibrous disks is a small soft area like a cherry inside a hard chocolate. This is the nucleus pulposus, the divided up remnant of our notochord. When we suffer a herniated disc, it is the nucleus pulposus which has been squeezed out of the intervertebral disc and is now playing havoc by pressing on one or more spinal roots. We have literally been 'tripped up' by a vestigial organ more than half a billion years old!
In the case of the developing embryo, the notochord seems to have a highly specific "organizing influence" on the primitive ectoderm layer just above it. Through the release of special chemicals, the overlying ectoderm is induced to divide more rapidly, forming a thickened mass called the neural plate. A crease or fold soon appears in this plate. The crease rapidly deepens and becomes known as the neural groove. The entire embryo is lengthening as this happens. The neural groove continues to deepen until its sides, the neural folds, arch over and fuse with each other forming a short segment of completely enclosed tube. This newly formed "neural tube" will become the nervous system. The actual fusion of the walls to form the tube occurs first in the center of the embryo about midway between front and rear poles of the still rapidly lengthening little organism. However, you can probably visualize how the newly formed section of neural tube rapidly begins to roof over in both a frontward (anterior or rostral) and a backward (posterior or caudal) direction. It is as if there were two zippers in the newly formed roof of the developing neural tube. As these zippers are pulled simultaneously away from each other toward the two ends of the embryo, the neural folds come together and the neural tube lengthens progressively in both directions. Finally the neural tube is almost completely enclosed in both directions, leaving only a small unroofed portion or opening at each end. These residual openings are called neuropores and under normal developmental conditions will soon be closed, thereby forming a complete neural tube. During this process a front-back polarity has been established in the still-lengthening embryo. Accordingly, the small unroofed area of the neural tube at the front end is called the anterior neuropore; the one at the rear end, the posterior neuropore.
INCOMPLETE CLOSURE OF THE TUBE
We have already mentioned the remarkable capacity of the developing nervous system to follow an incredibly complex series of developmental rules laid down progressively by the genes. Nonetheless, errors occur, and the roofing over of the neural groove to form the neural tube represents one point where disturbed development can severely affect the growing embryo. Incomplete closure of the anterior or posterior neuropore represents two such developmental errors during the first trimester which radically alter the future life of the embryo/fetus and infant.
If the anterior neuropore fails to close, the resulting deficit leads to varying degrees of incomplete development of the cerebral hemispheres and brain stem. One of the most frequent and dramatic resulting anomalies is the fetus which is born without cerebral hemispheres and usually without any skull above the level of the eyes. This is the so-called anencephalic child (a- or an- without: cephalon- brain) Strangely enough, this type of extreme anomaly may come to term and under some conditions, live for a week or two following birth. Such a severely deformed infant has only a brain stem (the upward continuation of the spinal cord within the skull) on which to depend for its behavior. This takes care of its basic breathing, cardiovascular, suckling and elimination reflexes. However, little else is possible for the infant and it usually dies within a few days or weeks of birth.
If incomplete closure persists at the posterior neuropore, the fetus will be born with some variant of spina bifida (bifida- split). In the most severe of these, the posterior portion of the spinal cord is totally or partially undeveloped and the entire lower back may be open. Some defects of this sort may be amenable to restorative surgery while others are not compatible with life. There is a more subtle form of this anomaly known as spina bifida occulta (occulta- hidden) where the only residual pathology is a tract or canal, usually of microscopic size, running between the subdural space surrounding the lower tip of the spinal cord and the skin of the lower back. Often, the only sign of such an anomaly is a little patch of hair in the middle of the lower back just above the beginning of the cleft between the buttocks. Although usually asymptomatic, this tiny canal can become infected, usually through trauma, and can form a painful pus-filled sac known as a pilonidal cyst. Early in World War II, one of the more frequent surgical procedures was removal of pilonidal cysts caused by the rough and bouncy ride experienced by soldiers riding in earlier versions of the famous Army jeep.
CLOSURE OF THE NEURAL TUBE
With successful closure of the neural tube, the anterior or rostral (rostral- front) end develops three vesicles which demarcate the territory for cerebral hemispheres and brain stem. Of these, the first and third divide once more forming a series of five vesicles which will become the major portions of the central nervous system within the skull. These consist of the cerebral hemispheres, diencephalon, midbrain, pons and cerebellum and medulla oblongata.
CELL DIFFERENTIATION AND DIVISION
The most dramatic phase of development now shifts to the walls of the neural tube. Here, what is initially a single cell layer of primitive ectoderm begins to divide very rapidly and will in time form virtually all of the central nervous system (brain and spinal cord). Packets of cells 'left over' on each side of the midline, where fusion of the neural folds initially occurred, are known as neural crest cells. These will migrate to a number of sites throughout the body of the developing embryo and form the peripheral nerves, roots, and ganglion cells of the peripheral nervous system.
We have already mentioned how rapidly cell division occurs in the walls of the neural tube. The actual process of mitosis (division) occurs close to the inner edge of the wall. Following this, each daughter cell moves away from this inner boundary to 'put on weight' by synthesizing protein, developing DNA and RNA and the various organelles (tiny intracellular structures necessary for cell life and energy metabolism) involved in its continued existence. The cell then moves back toward the inner boundary or multiplication zone where it undergoes division, thereby producing two more daughter cells and continuing the process. During this period of rapid growth, the entire cycle from cell division to cell division may take as little as an hour and a half. The rapid, geometric increase in the number of these still-primitive cells results in progressive thickening of the walls of the neural tube and the enlargements or vesicles at the anterior end. As these primitive cells continue to divide, subtle decisions begin to be made as to their fate. Some will become neurons while others are fated to become glial cells. The way these decisions are made and the mechanisms involved remain areas of active research interest. The decisions are of more than academic concern, not only for the long-term functioning of the nervous system but for the immediate next step in brain development.
After a period of active replication, some of these primitive daughter cells initiate the next step in brain development. This involves leaving the old 'home neighborhood' and moving permanently away from the inner multiplication zone to the outer edges of the growing wall of the neural tube. By this process of migration, the walls of the neural tube thicken selectively, coming to resemble increasingly the spinal cord, brain stem, cerebellum and cerebral hemispheres of the mature nervous system. As this thickening occurs, the trip from inner boundary of the neural tube to the outer portions becomes longer and increasingly fraught with potential difficulty. For this reason, some of these daughter cells unselfishly develop into a specialized type of "rope ladder" configuration, the radial glial guide cells, along which the primitive nerve cells (neuroblasts) can migrate. A number of these migrating cells may use the same glial guide cells, literally gliding up the glial 'rope' one after the other. The migration process is a complex one, driven and controlled by a number of different chemical substances. As remarkable as this cooperative process appears, even more remarkable must be the chemical messages which inform the migrating neuroblasts where to stop climbing and get off the ladder.
The most dramatic thickening of the original neural tube occurs in the area of the developing cerebral hemispheres. Here the migratory voyage is the longest and most complex. There are several principles of cortical development which have become apparent in the past several decades and they are worthy of our consideration.
INSIDE OUT DEVELOPMENT
As the primitive neurons or neuroblasts migrate away from the ventricular border where they have undergone multiplication, they move outward toward the external border of the thickening neural tube vesicle (the telencephalon) which is becoming the cortex where most of the higher level mental activity occurs (perception, cognition, etc.) The cerebral cortex of most higher forms is made up of six cell layers. Each layer has its distinct pattern of organization and connections. During the developmental phase which we are following, the cells initially move in to form the deepest or sixth layer. Each successive migration ascends farther, progressively forming more superficial (fifth, fourth, third second and first) layers beyond the layer that was initially laid down. Thus each group of migrating cells must pass through the layers already laid down by the earlier arrivals, thereby following an inside-out sequence of development.
The later arriving cells appear to migrate out along the same radial glial guide cells originally used by the earlier immigrants. It is accordingly very important, that the earlier groups succeed in "getting off" the glial guide cell before the next wave of immigrant cells tries to come up and through. We still do not completely understand how these cells successfully ascend the glial "rope ladder " nor how they know when to get off the ladder, move a little to the side and start to form the appropriate cortical layer. But it should be clear that unless they do release their hold, the next wave of cells coming up the ladder may not be able to get by on their way to a more distant destination. When this happens, the ensuing traffic pile up produces developmental anomalies which can lead to abnormal neuronal connections and disturbed behavior. Two species of mutant mice called, "reeler" and "staggerer" because of their bizarre motor behavior, are believed to result from this type of developmental abnormality. Similar problems in the growing human fetus may contribute to the development of certain types of schizophrenia, temporal lobe epilepsy and, perhaps some forms of dyslexia.
At this point, it can only be speculation, but it is conceivable that some types of severe character disorders may also reflect developmental anomalies. A limited group of data suggest that some individuals with intractable sociopathic deficits show brain changes which could be interpreted as developing during this period of brain formation. This is clearly an area which awaits further exploration.
DEVELOPMENT OF TEMPORARY CONNECTIONS
Another curious mechanism which seems to be involved in cortical development, is the stratagem of developing temporary connections or holding patterns for incoming, cortex-bound fibers until the proper target cells are available for them. A large number of significant fiber connections from structures below the cerebral cortex, particularly in the thalamus, begin to grow into the primitive cortex (or the area where it will develop), before the nerve cells have been able to migrate into their proper layers to receive them. Without target cells, such fibers would turn away or wither. To avoid this, groups of special 'decoy' cells are quickly sent into position before the main migrations begin. One group of decoy neurons locates itself at what will be the margin between the the cortical or gray matter, and the underlying white (fiber-rich) matter. A second group of decoys lines up at the outermost edge of the neural tube wall, at what will be the most superficial layer of the cortex. These serve as temporary targets for the incoming fibers which enthusiastically establish synaptic connections with them. Several weeks later when the great neuroblast migrations have been successfully accomplished, these decoy cells unselfishly disappear, a process which is fascinating in its own right and is now under investigation. The fibers which have been synaptically attached to them are released and are now attracted to a more appropriate, and permanent, set of target cells. This remarkable sequence of processes culminating in a 'change of partners' and the establishment of more definitive cortical connections is also subject to error and the results may include a number of major and minor cognitive and emotional disorders which will show up at various stages in the life of the individual. We are only at the beginning of our understanding of these complex phenomena but certain types of dyslexia may be one of the results of problems during this change of cortical connections.
MATURATION OF NERVE CELLS
Once the primitive migrating nerve cells have reached their final position, they begin to develop extensions from their cell bodies. These will progressively become longer and form the two major types of processes or branches which characterize almost all neurons. Dendritic branches will emerge from many points along the cell body. In the case of most cortical cells, these will become apical and basilar dendrite branches, depending on whether they emerge at the apical end of the somewhat triangular (pyramidal) shaped cell or at the bases. The former will lengthen and grow toward the surface while the latter will branch more profusely and grow to the sides (laterally) and/or somewhat deeper into the cortex. As dendritic branches multiply, they provide an increasing surface area for fiber terminals (synaptic terminals) from other neurons. In general, the larger the number of neuronal connections, the richer the possibilities for neural, and therefore cognitive activity.
The second major type of cell extension, the axon, will set out on a journey of variable length to establish connections with many other neurons, some adjacent to the cell body of origin, others quite distant. Imagine how far an axon must migrate from the cortex if its target area is the lower spinal cord of a basketball player! The distance may be as much as five feet!
One of the more interesting pathways which must be developed during the late prenatal and early postnatal period is the one which crosses from one hemisphere to the other and connects similar (mirror image) point on the two hemispheres. This massive bundle, called the corpus callosum, exerts powerful though subtle effects on the cortex and special modes of examination are necessary to reveal them. The two hemispheres have differing, though complementary, roles and it has been speculated that the corpus callosum facilitates the interaction of these effects. For example, for most of us, specific portions of the left hemisphere (Broca's and Wernicke's areas) are primarily responsible for the semantic and computational aspects of language. Corresponding areas of the right hemisphere are involved in the emotional and prosodic activities and the interweaving of these two facets of language behavior make for interesting and comprehensible narration. If activity of the right hemisphere and its interaction with the left is compromised, either by cortical damage (e.g. a stroke) or by surgical interruption of the corpus callosal fibers, this relationship breaks down. Speech then sounds mechanical and flat, without personal warmth and emotion.
DEVELOPMENT OF MYELIN SHEATHS
A significant aspect of brain development is the continued growth of myelin sheaths around the axons of the cerebral cortex. Myelin is a fatty substance which is deposited around many (though not all) axons as an insulating sheath. Its presence allows conduction of nerve impulses to occur from ten to one hundred times as rapidly as would occur along a non-myelinated axon. Since this obviously increases the efficiency of the axon system (just as increased computing speed enhances the efficiency of a computer), the development of axonal sheaths are taken as a measure of increasing maturity of the neural system involved. Myelin sheath development, or myelinization as it is called, has a rather well recognized time table in the cerebral hemispheres. Fibers serving the primary sensory (touch, vision, audition etc.) and motor areas are myelinated shortly after birth while those which are involved with more complex associative and cognitive functions myelinate later. It is generally believed that fiber systems of the prefrontal lobes (executive functions, intentions, future planning, etc.) are among the latest to myelinate, a process that may go on into young adulthood.
DEVELOPMENT OF SYNAPTIC CONNECTIONS AMONG NEURONS
The elaborate ensembles of neurons, their dendritic branches, and their projective axons communicate via a myriad of connections known as synapses. Each synapse is a point of contiguity (but not continuity) between two neural elements The most usual elements which form synaptic connections are axon terminals with either dendrites or cell bodies although other combinations are possible. In the vast majority of these synapses, small amounts of chemicals (neurotransmitters) are released, crossing the infinitesimal gap between the two elements, thereby carrying the neural message to the next element. Tens of thousands of synapses may cover the dendrites and cell body surface of a single neuron. From this you can easily see that there are enormous numbers of synapses in the entire nervous system, probably trillions! There may be as many as one hundred neurotransmitters and neuromodulators associated with these synapses providing a vast range of possible interaction patterns at these junctions.
The process of synapse formation probably starts in the mid or late second trimester and continues during the life of the individual. Careful ultramicroscopic studies show that synapse formation proceeds at its highest rate during the first 6-8 years of postnatal life, then plateaus and begins to decrease with the onset of puberty. This process of numerical decrease can be thought of as a pruning process in which excess or unwanted connections are discarded. During the first 6-10 years of life, the young individual undoubtedly achieves the highest density of synapses per unit volume of neural tissue (and the highest level of cortical glucose metabolism as revealed by PET scans) that he/she will ever have. This is also a period of enormous information input and acquisition, social, environmental, linguistic, etc. The growing brain may well be in its most sponge-like phase of learning as the child becomes acquainted with the endless range of symbols, rules, facts and behaviors that make it a member of its culture.
DETERMINANTS OF GROWTH AND DEVELOPMENT
We have already suggested that during much of the embryonic and fetal stages of life, genetic influences are of primary significance in development. It must also be realized, however, that the complexity of organization and connections of the nervous system far exceeds the capacity of the genome to specify each cell location, axon trajectory and connection. Instead, a very wide range of diffusible substances and markers are generated at appropriate times by primitive neural components as well as adnexal tissue. These directly affect certain classes of cells or processes, and facilitate the organization and development of the growing system. For instance, the young notochord seems to release factors which stimulate the overlying ectoderm to thicken and invaginate, thereby beginning formation of the neural tube. A little later, cells in the ventral portion of the developing neural tube release factors which specifically direct the trajectory of axons of primitive spinal neurons, thereby initiating the development of the long ascending sensory tracts as well as the peripherally projecting ventral roots. Many such axons, upon reaching their general target zones, carry retrograde substances from these areas back to the cell body of origin, thereby further refining the patterning and terminal distribution of these projecting elements. Thus the local chemical milieu works in complementary fashion with genetic plans to specify central nervous system organization.
A broad range of exogenous factors are also involved, including the health and nutrition of the mother and possible contact with potentially toxic substances (e.g. tobacco, alcohol and other drugs of abuse, certain viruses, etc.) The local dynamic mechanisms of intrauterine life may also be significant, a fact especially noticeable in the case of multiple births where intrauterine position may markedly affect the size and vigor of the newborn. Even the maternal state of mind may be significant, a factor long recognized in the widespread 'old wives' tale' that the infant will bear the visible imprint of an object that frightens its mother during her pregnancy. In a more positive vein, Japanese mothers think happy thoughts (taikyo) during pregnancy to ensure the health and well-being of their infant. Recent data suggest that newborn infants are more likely to respond to sound combinations (words) characteristic of the mother's language than to those of a foreign tongue. By implication, the unborn fetus, especially in the third trimester, may already be sensitive to stimuli in the maternal external environment.
The effects of genetic and epigenetic factors are thus inextricably mingled, from the earliest stages of embryonic development. The remarkable combination of gene-controlled factors, some of them conserved for over a billion years, together with an enormous range of idiosyncratic factors, both internal and external, help account for the uniqueness of each individual.
About the Author
Arnold B. Scheibel, MD, is professor of Neurobiology and Psychiatry and former Director of the Brain Research Institute, UCLA Medical Center, Los Angeles, CA.
His major interests focus on the manner in which brain organization and connections determine cognitive activity and behavior. He has worked on problems of consciousness, development of the central nervous system, aging, and Alzheimer's Disease, and schizophrenia.
He is particularly interested in the relationship between brain, learning, and education.
Copyright © 1997
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