The Human Body

THE BRAIN

The brain weighs about 1,500 grams (3 pounds) and constitutes about 2 percent of total body weight. It consists of three major divisions: (1) the massive paired hemispheres of the cerebrum, (2) the brainstem, consisting of the thalamus, hypothalamus, epithalamus, subthalamus, midbrain, pons, and medulla oblongata, and (3) the cerebellum.

CEREBRUM

The cerebrum, derived from the telencephalon, is the largest, uppermost portion of the brain. It is involved with sensory integration, control of voluntary movement, and higher intellectual functions, such as speech and abstract thought. The outer layer of the duplicate cerebral hemispheres is composed of a convoluted (wrinkled) outer layer of gray matter, called the cerebral cortex. Beneath the cerebral cortex is an inner core of white matter, which is composed of myelinated commissural nerve fibres connecting the cerebral hemispheres via the corpus callosum, and association fibres connecting different regions of a single hemisphere. Myelinated fibres projecting to and from the cerebral cortex form a concentrated fan-shaped band, known as the internal capsule. The internal capsule consists of an anterior limb and a larger posterior limb and is abruptly curved, with the apex directed toward the centre of the brain; the junction is called the genu. The cerebrum also contains groups of subcortical neuronal masses known as basal ganglia.

The cerebral hemispheres are partially separated from each other by a deep groove called the longitudinal fissure. At the base of the longitudinal fissure lies a thick band of white matter called the corpus callosum. The corpus callosum provides a communication link between corresponding regions of the cerebral hemispheres.

Each cerebral hemisphere supplies motor function to the opposite, or contralateral, side of the body from which it receives sensory input. In other words, the left hemisphere controls the right half of the body, and vice versa. Each hemisphere also receives impulses conveying the senses of touch and vision, largely from the contralateral half of the body, while auditory input comes from both sides. Pathways conveying the senses of smell and taste to the cerebral cortex are ipsilateral (that is, they do not cross to the opposite hemisphere).

In spite of this arrangement, the cerebral hemispheres are not functionally equal. In each individual, one hemisphere is dominant. The dominant hemisphere controls language, mathematical and analytical functions, and handedness. The nondominant hemisphere controls simple spatial concepts, recognition of faces, some auditory aspects, and emotion.

LOBES OF CEREBRAL CORTEX

The cerebral cortex is highly convoluted; the crest of a single convolution is known as a gyrus, and the fissure between two gyri is known as a sulcus. Sulci and gyri form a more or less constant pattern, on the basis of which the surface of each cerebral hemisphere is commonly divided into four lobes: (1) frontal, (2) parietal, (3) temporal, and (4) occipital. Two major sulci located on the lateral, or side, surface of each hemisphere distinguish these lobes. The central sulcus, or fissure of Rolando, separates the frontal and parietal lobes, and the deeper lateral sulcus, or fissure of Sylvius, forms the boundary between the temporal lobe and the frontal and parietal lobes.

The frontal lobe: The frontal lobe, the largest of the cerebral lobes, lies rostral to the central sulcus (that is, toward the nose from the sulcus). One important structure in the frontal lobe is the precentral gyrus, which constitutes the primary motor region of the brain. When parts of the gyrus are electrically stimulated in concious patients (under local anesthesia), they produce localized movements on the opposite side of the body that are interpreted by the patients as voluntary. Injury to parts of the precentral gyrus results in paralysis on the contralateral half of the body. Parts of the inferior frontal lobe (close to the lateral sulcus) constitute the Broca area, a region involved with speech.

The parietal lobe: The parietal lobe, posterior to the central sulcus, is divided into three parts: (1) the postcentral gyrus, (2) the superior parietal lobule, and (3) the inferior parietal lobule. The postcentral gyrus receives sensory input from the contralateral half of the body. The sequential representation is the same as in the primary motor area, with sensations from the head being represented in inferior parts of the gyrus and impulses from the lower extremities being represented in superior portions. The superior parietal lobule, located caudal to (that is, below and behind) the postcentral gyrus, lies above the intraparietal sulcus. This lobule is regarded as an association cortex, an area that is not involved in either sensory or motor processing, although part of the superior parietal lobule may be concerned with motor function. The inferior parietal lobule (composed of the angular and supramarginal gyri) is a cortical region involved with the integration of multiple sensory signals.

In both the parietal and frontal lobes, each primary sensory or motor area is close to, or surrounded by, a smaller secondary area. The primary sensory area receives input only from the thalamus, while the secondary sensory area receives input from the thalamus, the primary sensory area, or both. The motor areas receive input from the thalamus as well as the sensory areas of the cerebral cortex.

The temporal lobe: The temporal lobe, inferior to the lateral sulcus, fills the middle fossa, or hollow area, of the skull. The outer surface of the temporal lobe is an association area made up of the superior, middle, and inferior temporal gyri. Near the margin of the lateral sulcus, two transverse temporal gyri constitute the primary auditory area of the brain. The sensation of hearing is represented here in a tonotopic fashion—that is, with different frequencies represented on different parts of the area. The transverse gyri are surrounded by a less finely tuned secondary auditory area. A medial, or inner, protrusion near the ventral surface of the temporal lobe, known as the uncus, constitutes a large part of the primary olfactory area.

The occipital lobe: The occipital lobe lies caudal to the parieto-occipital sulcus, which joins the calcarine sulcus in a Y-shaped formation. Cortex on both banks of the calcarine sulcus constitutes the primary visual area, which receives input from the contralateral visual field via the optic radiation. The visual field is represented near the calcarine sulcus in a retinotopic fashion—that is, with upper quadrants of the visual field laid out along the inferior bank of the sulcus and lower quadrants of the visual field represented on the upper bank. Central vision is represented mostly caudally and peripheral vision rostrally.

Insular or central lobe: Not visible from the surface of the cerebrum is the insular, or central, lobe, an invaginated triangular area on the medial surface of the lateral sulcus; it can be seen in the intact brain only by separating the frontal and parietal lobes from the temporal lobe. The insular lobe is thought to be involved in sensory and motor visceral functions as well as taste perception.

The limbic lobe: The limbic lobe is a synthetic lobe located on the medial margin (or limbus) of the hemisphere. Composed of adjacent portions of the frontal, parietal, and temporal lobes that surround the corpus callosum, the limbic lobe is involved with autonomic and related somatic behavioral activities. The limbic lobe receives input from thalamic nuclei that are connected with parts of the hypothalamus and with the hippocampal formation, a primitive cortical structure within the inferior horn of the lateral ventricle.

CEREBRAL VENTRICLES

Deep within the white matter of the cerebral hemispheres are cavities filled with cerebrospinal fluid that form the ventricular system. These cavities include a pair of C-shaped lateral ventricles with anterior, inferior, and posterior “horns” protruding into the frontal, temporal, and occipital lobes, respectively. Most of the cerebrospinal fluid is produced in the ventricles, and about 70 percent of it is secreted by the choroid plexus, a collection of blood vessels in the walls of the lateral ventricles. The fluid drains via interventricular foramina, or openings, into a slitlike third ventricle, which, situated along the midline of the brain, separates the symmetrical halves of the thalamus and hypothalamus. From there the fluid passes through the cerebral aqueduct in the midbrain and into the fourth ventricle in the hindbrain. Openings in the fourth ventricle permit cerebrospinal fluid to enter subarachnoid spaces surrounding both the brain and the spinal cord.

BASAL GANGLIA

Deep within the cerebral hemispheres, large gray masses of nerve cells, called nuclei, form components of the basal ganglia. Four basal ganglia can be distinguished: (1) the caudate nucleus, (2) the putamen, (3) the globus pallidus, and (4) the amygdala. Phylogenetically, the amygdala is the oldest of the basal ganglia and is often referred to as the archistriatum; the globus pallidus is known as the paleostriatum, and the caudate nucleus and putamen are together known as the neostriatum, or simply striatum. Together, the putamen and the adjacent globus pallidus are referred to as the lentiform nucleus, while the caudate nucleus, putamen, and globus pallidus form the corpus striatum.

The caudate nucleus and the putamen are continuous rostrally and ventrally, and they have similar cellular compositions, cytochemical features, and functions but slightly different connections. The putamen lies deep within the cortex of the insular lobe, while the caudate nucleus has a C-shaped configuration that parallels the lateral ventricle. The head of the caudate nucleus protrudes into the anterior horn of the lateral ventricle, the body lies above and lateral to the thalamus, and the tail is in the roof of the inferior horn of the lateral ventricle. The tail of the caudate nucleus ends in relationship to the amygdaloid nuclear complex, which lies in the temporal lobe beneath the cortex of the uncus.

There are an enormous number of neurons within the caudate nucleus and putamen; they are of two basic types: spiny and aspiny. Spiny striatal neurons are medium-size cells with radiating dendrites that are studded with spines. Axons of these cells project beyond the boundaries of the caudate nucleus and putamen. All nerves providing input to the caudate nucleus and the putamen terminate upon the dendritic spines of spiny striatal neurons, and all output is via axons of the same neurons. Chemically, spiny striatal neurons are heterogeneous; that is, most contain more than one neurotransmitter. Gamma-aminobutyric acid (GABA) is the primary neurotransmitter contained in spiny striatal neurons. Other neurotransmitters found in spiny striatal neurons include substance P and enkephalin.

Aspiny striatal neurons have smooth dendrites and short axons confined to the caudate nucleus or putamen. Small aspiny striatal neurons secrete GABA, neuropeptide Y, somatostatin, or some combination of these. The largest aspiny neurons are evenly distributed neurons that also secrete neurotransmitters and are important in maintaining the balance of dopamine and GABA.

Because the caudate nucleus and putamen receive varied and diverse inputs from multiple sources that utilize different neurotransmitters, they are regarded as the receptive component of the corpus striatum. Most input originates from regions of the cerebral cortex, with the connecting corticostriate fibres containing the excitatory neurotransmitter glutamate. In addition, afferent fibres originating from a large nucleus located in the midbrain called the substantia nigra or from intralaminar thalamic nuclei project to the caudate nucleus or the putamen. Neurons in the substantia nigra are known to synthesize dopamine, but the neurotransmitter secreted by thalamostriate neurons has not been identified. All striatal afferent systems terminate in patchy areas called strisomes; areas not receiving terminals are called the matrix. Spiny striatal neurons containing GABA, substance P, and enkephalin project in a specific pattern onto the globus pallidus and the substantia nigra.

The globus pallidus, consisting of two cytologically similar wedge-shaped segments, the lateral and the medial, lies between the putamen and the internal capsule. Striatopallidal fibres from the caudate nucleus and putamen converge on the globus pallidus like spokes of a wheel. Both segments of the pallidum receive GABAergic terminals, but in addition the medial segment receives substance P fibres, and the lateral segment receives enkephalinergic projections. The output of the entire corpus striatum (i.e., the caudate nucleus, putamen, and globus pallidus together) arises from GABAergic cells in the medial pallidal segment and in the substantia nigra, both of which receive fibres from the striatum. GABAergic cells in the medial pallidal segment and the substantia nigra project to different nuclei in the thalamus; these in turn influence distinct regions of the cerebral cortex involved with motor function. The lateral segment of the globus pallidus, on the other hand, projects almost exclusively to the subthalamic nucleus, from which it receives reciprocal input. No part of the corpus striatum projects fibres to spinal levels.

Pathological processes involving the corpus striatum and related nuclei are associated with a variety of specific diseases characterized by abnormal involuntary movements (collectively referred to as dyskinesia) and significant alterations of muscle tone. Parkinson disease and Huntington disease are among the more prevalent syndromes; each appears related to deficiencies in the synthesis of particular neurotransmitters.

The amygdala, located ventral to the corpus striatum in medial parts of the temporal lobe, is an almond-shaped nucleus underlying the uncus. Although it receives olfactory inputs, the amygdala plays no role in olfactory perception. This nucleus also has reciprocal connections with the hypothalamus, the basal forebrain, and regions of the cerebral cortex. It plays important roles in visceral, endocrine, and cognitive functions related to motivational behaviour.

BRAIN STEM

The brainstem is made up of all the unpaired structures that connect the cerebrum with the spinal cord. Most rostral in the brainstem are structures often collectively referred to as the diencephalon. These structures are the epithalamus, the thalamus, the hypothalamus, and the subthalamus. Directly beneath the diencephalon is the midbrain, or mesencephalon, and beneath the midbrain are the pons and medulla oblongata, often referred to as the hindbrain.

Epithalamus: The epithalamus is represented mainly by the pineal gland, which lies in the midline posterior and dorsal to the third ventricle. This gland synthesizes melatonin and enzymes sensitive to daylight. Rhythmic changes in the activity of the pineal gland in response to daylight suggest that the gland serves as a biological clock.

Thalamus: The thalamus has long been regarded as the key to understanding the organization of the central nervous system. It is involved in the relay and distribution of most, but not all, sensory and motor signals to specific regions of the cerebral cortex. Sensory signals generated in all types of receptors are projected via complex pathways to specific relay nuclei in the thalamus, where they are segregated and systematically organized. The relay nuclei in turn supply the primary and secondary sensory areas of the cerebral cortex. Sensory input to thalamic nuclei is contralateral for the sensory, or somesthetic, and visual systems, bilateral and contralateral for the auditory system, and ipsilateral for the gustatory and olfactory systems.

The sensory relay nuclei of the thalamus, collectively known as the ventrobasal complex, receive input from the medial lemniscus (originating in the medulla oblongata), from spinothalamic tracts, and from the trigeminal nerve. Fibres within these ascending tracts that terminate in the central core of the ventrobasal complex receive input from deep sensory receptors, while fibres projecting onto the outer shell receive input from cutaneous receptors. This segregation of deep and superficial sensation is preserved in projections of the ventrobasal complex to the primary sensory area of the cerebral cortex.

The metathalamus is composed of the medial and lateral geniculate bodies, or nuclei. Fibres of the optic nerve end in the lateral geniculate body, which consists of six cellular laminae, or layers, folded into a horseshoe configuration. Each lamina represents a complete map of the contralateral visual hemifield. Cells in all layers of the lateral geniculate body project via optic radiation to the visual areas of the cerebral cortex. The medial geniculate body receives auditory impulses from the inferior colliculus of the midbrain and relays them to the auditory areas of the temporal lobe. Only the ventral nucleus of the medial geniculate body is laminated and tonotopically organized; this part projects to the primary auditory area and is finely tuned. Other subdivisions of the medial geniculate body project to the belt of secondary auditory cortex surrounding the primary area.

Most output from the cerebellum projects to specific thalamic relay nuclei in a pattern similar to that for sensory input. The thalamic relay nuclei in turn provide input to the primary motor area of the frontal lobe. This system appears to provide coordinating and controlling influences that result in the appropriate force, sequence, and direction of voluntary motor activities. Output from the corpus striatum, on the other hand, is relayed by thalamic nuclei that have access to the supplementary and premotor areas. The supplementary motor area, located on the medial aspect of the hemisphere, exerts modifying influences upon the primary motor area and appears to be involved in programming skilled motor sequences. The premotor area, rostral to the primary motor area, plays a role in sensorially guided movements.

Other major thalamic nuclei include the anterior nuclear group, the mediodorsal nucleus, and the pulvinar. The anterior nuclear group receives input from the hypothalamus and projects upon parts of the limbic lobe (i.e., the cingulate gyrus). The mediodorsal nucleus, part of the medial nuclear group, has reciprocal connections with large parts of the frontal lobe rostral to the motor areas. The pulvinar is a posterior nuclear complex that, along with the mediodorsal nucleus, has projections to association areas of the cortex.

Output ascending from the reticular formation of the brainstem is relayed to the cerebral cortex by intralaminar thalamic nuclei, which are located in laminae separating the medial and ventrolateral thalamic nuclei. This ascending system is involved with arousal mechanisms, maintaining alertness, and directing attention to sensory events.
Hypothalamus: The hypothalamus lies below the thalamus in the walls and floor of the third ventricle. It is divided into medial and lateral groups by a curved bundle of axons called the fornix, which originate in the hippocampal formation and project to the mammillary body. The hypothalamus controls major endocrine functions by secreting hormones (i.e., oxytocin and vasopressin) that induce smooth muscle contractions of the reproductive, digestive, and excretory systems; other neurosecretory neurons convey hormone-releasing factors (e.g., growth hormone, corticosteroids, thyrotropic hormone, and gonadotropic hormone) via a vascular portal system to the adenohypophysis, a portion of the pituitary gland. Specific regions of the hypothalamus are also involved with the control of sympathetic and parasympathetic activities, temperature regulation, food intake, the reproductive cycle, and emotional expression and behaviour.

Subthalamus: The subthalamus is represented mainly by the subthalamic nucleus, a lens-shaped structure lying behind and to the sides of the hypothalamus and on the dorsal surface of the internal capsule. The subthalamic region is traversed by fibres related to the globus pallidus. Discrete lesions of the subthalmic nucleus produce hemiballismus, a violent form of dyskinesia in which the limbs are involuntarily flung about.

MID BRAIN

The midbrain (mesencephalon) contains the nuclear complex of the oculomotor nerve as well as the trochlear nucleus; these cranial nerves innervate muscles that move the eye and control the shape of the lens and the diameter of the pupil. In addition, between the midbrain reticular formation (known here as the tegmentum) and the crus cerebri is a large pigmented nucleus called the substantia nigra. The substantia nigra consists of two parts, the pars reticulata and the pars compacta. Cells of the pars compacta contain the dark pigment melanin; these cells synthesize dopamine and project to either the caudate nucleus or the putamen. By inhibiting the action of large aspiny striatal neurons in the caudate nucleus and the putamen (described above in the section Basal ganglia), the dopaminergic cells of the pars compacta influence the output of the neurotransmitter GABA from spiny striatal neurons. The spiny neurons in turn project to the cells of the pars reticulata, which, by projecting fibres to the thalamus, are part of the output system of the corpus striatum.

At the caudal midbrain, crossed fibres of the superior cerebellar peduncle (the major output system of the cerebellum) surround and partially terminate in a large centrally located structure known as the red nucleus. Most crossed ascending fibres of this bundle project to thalamic nuclei, which have access to the primary motor cortex. A smaller number of fibres synapse on large cells in caudal regions of the red nucleus; these give rise to the crossed fibres of the rubrospinal tract (see the section The spinal cord: Descending spinal tracts). The roof plate of the midbrain is formed by two paired rounded swellings, the superior and inferior colliculi. The superior colliculus receives input from the retina and the visual cortex and participates in a variety of visual reflexes, particularly the tracking of objects in the contralateral visual field. The inferior colliculus receives both crossed and uncrossed auditory fibres and projects upon the medial geniculate body, the auditory relay nucleus of the thalamus.

PONS

The pons (metencephalon) consists of two parts: the tegmentum, a phylogenetically older part that contains the reticular formation, and the pontine nuclei, a larger part composed of masses of neurons that lie among large bundles of longitudinal and transverse nerve fibres.

Fibres originating from neurons in the cerebral cortex terminate upon the pontine nuclei, which in turn project to the opposite hemisphere of the cerebellum. These massive crossed fibres, called crus cerebri, form the middle cerebellar peduncle and serve as the bridge that connects each cerebral hemisphere with the opposite half of the cerebellum. The fibres originating from the cerebral cortex constitute the corticopontine tract.

The reticular formation (an inner core of gray matter found in the midbrain, pons, and medulla oblongata) of the pontine tegmentum contains multiple cell groups that influence motor function. It also contains the nuclei of several cranial nerves. The facial nerve and the two components of the vestibulocochlear nerve, for example, emerge from and enter the brainstem at the junction of the pons, medulla, and cerebellum. In addition, motor nuclei of the trigeminal nerve lie in the upper pons. Long ascending and descending tracts that connect the brain to the spinal cord are located on the periphery of the pons.

MEDULLA OBLONGATA

The medulla oblongata (myelencephalon), the most caudal segment of the brainstem, appears as a conical expansion of the spinal cord. The roof plate of both the pons and the medulla is formed by the cerebellum and a membrane containing a cellular layer called the choroid plexus, located in the fourth ventricle. Cerebrospinal fluid entering the fourth ventricle from the cerebral aqueduct passes into the cisterna magna, a subarachnoid space surrounding the medulla and the cerebellum, via openings in the lateral recesses in the midline of the ventricle.

At the transition of the medulla to the spinal cord, there are two major decussations, or crossings, of nerve fibres. The corticospinal decussation is the site at which 90 percent of the fibres of the medullary pyramids cross and enter the dorsolateral funiculus of the spinal cord. Signals conveyed by this tract provide the basis for voluntary motor function on the opposite side of the body (see the section The spinal cord: Descending spinal tracts). In the other decussation, two groups of ascending sensory fibres in the fasciculus gracilis and the fasciculus cuneatus of the spinal cord terminate upon large nuclear masses on the dorsal surface of the medulla. Known as the nuclei gracilis and cuneatus, these masses give rise to fibres that decussate above the corticospinal tract and form a major ascending sensory pathway known as the medial lemniscus that is present in all brainstem levels. The medial lemniscus projects upon the sensory relay nuclei of the thalamus.

The medulla contains nuclei associated with the hypoglossal, accessory, vagus, and glossopharyngeal cranial nerves. In addition, it contains portions of the vestibular nuclear complex, parts of the trigeminal nuclear complex involved with pain and thermal sense, and solitary nuclei related to the vagus, glossopharyngeal, and facial nerves that subserve the sense of taste.

CEREBELLUM

The cerebellum (“little brain”) overlies the posterior aspect of the pons and medulla oblongata and fills the greater part of the posterior fossa of the skull. This distinctive part of the brain is derived from the rhombic lips, thickenings along the margins of the embryonic hindbrain. It consists of two paired lateral lobes, or hemispheres, and a midline portion known as the vermis. The cerebellar cortex appears very different from the cerebral cortex in that it consists of small leaflike laminae called folia. The cerebellum consists of a surface cortex of gray matter and a core of white matter containing four paired intrinsic (i.e., deep) nuclei: the dentate, globose, emboliform, and fastigial. Three paired fibre bundles—the superior, middle, and inferior peduncles—connect the cerebellum with the midbrain, pons, and medulla, respectively.

On an embryological basis the cerebellum is divided into three parts: (1) the archicerebellum, related primarily to the vestibular system, (2) the paleocerebellum, or anterior lobe, involved with control of muscle tone, and (3) the neocerebellum, known as the posterior lobe. Receiving input from the cerebral hemispheres via the middle cerebellar peduncle, the neocerebellum is the part most concerned with coordination of voluntary motor function.

The three layers of the cerebellar cortex are an outer synaptic layer (also called the molecular layer), an intermediate discharge layer (the Purkinje layer), and an inner receptive layer (the granular layer). Sensory input from all sorts of receptors is conveyed to specific regions of the receptive layer, which consists of enormous numbers of small nerve cells (hence the name granular) that project axons into the synaptic layer. There the axons excite the dendrites of the Purkinje cells, which in turn project axons to portions of the four intrinsic nuclei and upon dorsal portions of the lateral vestibular nucleus. Because most Purkinje cells are GABAergic and therefore exert strong inhibitory influences upon the cells that receive their terminals, all sensory input into the cerebellum results in inhibitory impulses' being exerted upon the deep cerebellar nuclei and parts of the vestibular nucleus. Cells of all deep cerebellar nuclei, on the other hand, are excitatory (secreting the neurotransmitter glutamate) and project upon parts of the thalamus, red nucleus, vestibular nuclei, and reticular formation.

The cerebellum thus functions as a kind of computer, providing a quick and clear response to sensory signals. It plays no role in sensory perception, but it exerts profound influences upon equilibrium, muscle tone, and the coordination of voluntary motor function. Because the input and output pathways both cross, a lesion of a lateral part of the cerebellum will have an ipsilateral effect on coordination.

PRENATAL AND POSTNATAL DEVELOPMENT OF HUMAN NERVOUS SYSTEM

Almost all nerve cells, or neurons, are generated during prenatal life, and in most cases they are not replaced by new neurons thereafter. Morphologically, the nervous system first appears about 18 days after conception, with the genesis of a neural plate. Functionally, it appears with the first sign of a reflex activity during the second prenatal month, when stimulation by touch of the upper lip evokes a withdrawal response of the head. Many reflexes of the head, trunk, and extremities can be elicited in the third month.

During its development the nervous system undergoes remarkable changes to attain its complex organization. In order to produce the estimated 1 trillion neurons present in the mature brain, an average of 2.5 million neurons must be generated per minute during the entire prenatal life. This includes the formation of neuronal circuits comprising 100 trillion synapses, as each potential neuron is ultimately connected with either a selected set of other neurons or specific targets such as sensory endings. Moreover, synaptic connections with other neurons are made at precise locations on the cell membranes of target neurons. The totality of these events is not thought to be the exclusive product of the genetic code, for there are simply not enough genes to account for such complexity. Rather, the differentiation and subsequent development of embryonic cells into mature neurons and glial cells are achieved by two sets of influences: (1) specific subsets of genes and (2) environmental stimuli from within and outside the embryo. Genetic influences are critical to the development of the nervous system in ordered and temporally timed sequences. Cell differentiation, for example, depends on a series of signals that regulate transcription, the process in which deoxyribonucleic acid (DNA) molecules give rise to ribonucleic acid (RNA) molecules, which in turn express the genetic messages that control cellular activity. Environmental influences derived from the embryo itself include cellular signals that consist of diffusible molecular factors (see below Neuronal development). External environmental factors include nutrition, sensory experience, social interaction, and even learning. All of these are essential for the proper differentiation of individual neurons and for fine-tuning the details of synaptic connections. Thus, the nervous system requires continuous stimulation over an entire lifetime in order to sustain functional activity.

Neuronal development
In the second week of prenatal life, the rapidly growing blastocyst (the bundle of cells into which a fertilized ovum divides) flattens into what is called the embryonic disk. The embryonic disk soon acquires three layers: the ectoderm (outer layer), mesoderm (middle layer), and endoderm (inner layer). Within the mesoderm grows the notochord, an axial rod that serves as a temporary backbone. Both the mesoderm and notochord release a chemical that instructs and induces adjacent undifferentiated ectoderm cells to thicken along what will become the dorsal midline of the body, forming the neural plate. The neural plate is composed of neural precursor cells, known as neuroepithelial cells, which develop into the neural tube (see below Morphological development). Neuroepithelial cells then commence to divide, diversify, and give rise to immature neurons and neuroglia, which in turn migrate from the neural tube to their final location. Each neuron forms dendrites and an axon; axons elongate and form branches, the terminals of which form synaptic connections with a select set of target neurons or muscle fibres.

The remarkable events of this early development involve an orderly migration of billions of neurons, the growth of their axons (many of which extend widely throughout the brain), and the formation of thousands of synapses between individual axons and their target neurons. The migration and growth of neurons are dependent, at least in part, on chemical and physical influences. The growing tips of axons (called growth cones) apparently recognize and respond to various molecular signals, which guide axons and nerve branches to their appropriate targets and eliminate those that try to synapse with inappropriate targets. Once a synaptic connection has been established, a target cell releases a trophic factor (e.g., nerve growth factor) that is essential for the survival of the neuron synapsing with it. Physical guidance cues are involved in contact guidance, or the migration of immature neurons along a scaffold of glial fibres.

In some regions of the developing nervous system, synaptic contacts are not initially precise or stable and are followed later by an ordered reorganization, including the elimination of many cells and synapses. The instability of some synaptic connections persists until a so-called critical period is reached, prior to which environmental influences have a significant role in the proper differentiation of neurons and in fine-tuning many synaptic connections. Following the critical period, synaptic connections become stable and are unlikely to be altered by environmental influences. This suggests that certain skills and sensory activities can be influenced during development (including postnatal life), and for some intellectual skills this adaptability presumably persists into adulthood and late life.

Morphological development
By 18 days after fertilization, the ectoderm of the embryonic disk thickens along what will become the dorsal midline of the body, forming the neural plate and, slightly later, the primordial eye, ear, and nose. The neural plate elongates, and its lateral edges rise and unite in the midline to form the neural tube, which will develop into the central nervous system. The neural tube detaches from the skin ectoderm and sinks beneath the surface. At this stage, groupings of ectodermal cells, called neural crests, develop as a column on each side of the neural tube. The cephalic (head) portion of the neural tube differentiates into the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain), and the caudal portion becomes the spinal cord. The neural crests develop into most of the elements (e.g., ganglia and nerves) of the peripheral nervous system. This stage is reached at the end of the first embryonic month.

The cells of the central nervous system originate from the ventricular zone of the neural tube—that is, the layer of neuroepithelial cells lining the central cavity of the tube. These cells differentiate and proliferate into neuroblasts, which are the precursors of neurons, and glioblasts, from which neuroglia develop. With a few exceptions, the neuroblasts, glioblasts, and their derived cells do not divide and multiply once they have migrated from the ventricular zone into the gray and white matter of the nervous system. Most neurons are generated before birth, although not all are fully differentiated. (One exception is the neurons of the olfactory nerve, which are generated continuously throughout life.) This effectively implies that an individual is born with a full complement of nerve cells.

By mid-fetal life the slender primordial brain of the neural-tube stage differentiates into a globular-shaped brain. Although fully mature size and shape are not obtained until puberty, the main outlines of the brain are recognizable by the end of the third fetal month. This early development is the product of several factors: the formation of three flexures (cephalic, pontine, and cervical); the differential enlargement of various regions, especially the cerebrum and the cerebellum; the massive growth of the cerebral hemispheres over the sides of the midbrain and of the cerebellum at the hindbrain; and the formations of convolutions (sulci and gyri) in the cerebral cortex and folia of the cerebellar cortex. The central and calcarine sulci are discernible by the fifth fetal month, and all major gyri and sulci are normally present by the seventh month. Many minor sulci and gyri appear after birth.

Postnatal changes

The postnatal growth of the human brain is rapid and massive, especially during the first two years. By two years after birth, the size of the brain and the proportion of its parts are basically those of an adult. The typical brain of a full-term infant weighs 350 grams (12 ounces) at birth, 1,000 grams at the end of the first year, about 1,300 grams at puberty, and about 1,500 grams at adulthood. This increase is attributable mainly to the growth of preexisting neurons, new glial cells, and the myelination of axons. The trebling of weight during the first year (a growth rate unique to humans) may be an adaptation that is essential to the survival of humans as a species with a large brain. Birth occurs at a developmental stage when the infant is not so helpless as to be unable to survive, yet is small enough to be delivered out of the maternal pelvis. If the brain was much larger (enough, say, to support intelligent behaviour), normal delivery would not be possible.

Between the ages of 20 and 75, it is estimated that an average of 50,000 neurons atrophy or die each day. In a healthy person, this loss is roughly equal to 10 percent of the original neuronal complement. By the age of 75, the weight of the brain is reduced from its maximum at maturity by about one-tenth, the flow of blood through the brain by almost one-fifth, and the number of functional taste buds by about two-thirds. A loss of neurons does not necessarily imply a comparable loss of function; however, some loss may be compensated for by the formation from viable neurons of new branches of nerve fibres and by the formation of new synapses.