Each cerebral hemisphere has a mantle of gray matter, the cortex or pallium, with a characteristic structure that consists of neuronal cell bodies and axons arranged in layers.
Histology is the study of tissues, as distinct from the study of individual cells, by microscopy. Three types of cortical tissue are recognized by microscopic examination of sections cut in a plane perpendicular to the surface of the brain. The names of the types of cortex are based on phylogeny, which is the graded variation of similar structures across different groups of organisms. The paleocortex is that of the olfactory system, and the archicortex is that of the hippocampal formation. Their locations in the temporal lobe are described inChapters 17 and 18. The remainder of the cerebral cortex is of the type known as neocortex.
The number of layers evident histologically in the paleocortex and archicortex varies according to region. There may be as many as five layers in the paleocortex, although the more superficial ones are indistinct. The largest number of layers in the archicortex is three. In the neocortex, which is the subject of this chapter, six layers are always recognizable at some stage of embryonic or fetal development. In some areas of the adult brain, however, the typical six layers cannot all be discerned.
Values obtained for the number of neurons in the human cerebral cortex vary widely because of the technical difficulties in their enumeration. They range from 2.6 × 109 to 1.6 × 1010, and the number of cortical neurons is therefore enormous.
The principal cells (neurons with long axons) are known as pyramidal cells. Their cell bodies range in height from 10 to 50 µm for most cells. Giant pyramidal cells, also known asBetz cells, have cell bodies up to 100 µm
high. These are present only in the primary motor area of the frontal lobe, where they are conspicuous but not numerous. Each pyramidal cell (Fig. 14-1) has conspicuous apical and lateral dendrites, with branches that are covered with dendritic spines. The axon emerges from the base of the pyramid or from one of the larger dendrites and gives off many collateral branches before it enters the subcortical white matter. About two thirds of cortical neurons are pyramidal cells, but the proportion is higher in motor areas of the frontal lobe and lower in the primary sensory areas. The axons of pyramidal neurons are excitatory at their synapses and are thought to use glutamate as their neurotransmitter. Fusiform cells, which are located in the deepest layer of the cortex, are atypical principal cells with irregularly elliptical cell bodies.
FIGURE 14-1 Cortical neurons: principal cells in red, interneurons in black. In reality, the dendrites are more numerous and more richly branched than shown in this drawing. (The letter A indicates the axon of each type of neuron.)
In addition to their local intracortical branches, the axons of the principal cells connect with other neurons in three ways. Projection neurons transmit impulses to subcortical locations such as the corpus striatum, brain stem, spinal cord, or thalamus (which receives the axons of the fusiform cells). Association neurons establish connections with cortical neurons elsewhere in the same hemisphere. The axons of commissural neurons proceed to the cortex of the opposite hemisphere. Most of the commissural fibers constitute the corpus callosum; smaller numbers connect cortical areas of the temporal lobes through the anterior commissure.
About 30 types of cortical interneurons are recognized, on the basis of dendritic architecture, by researchers who study Golgi preparations. A few of the major cell types are shown schematically in Figure 14-1. Stellate cells, which have dendritic spines, occur only in the fourth cortical layer (see the next section of this chapter). They are excitatory, and the transmitter is probably glutamate. All the other types of interneurons are inhibitory and probably all secrete gamma-aminobutyric acid at their synapses. Basket cells have axons that branch laterally and embrace the cell bodies of pyramidal cells. The Retzius-Cajal cells are confined to the most superficial layer of the cortex, and the cells of Martinotti are more deeply placed, with axons that project toward the pial surface.
The thickness of the neocortex varies from 4.5 mm in the primary motor area of the frontal lobe to 1.5 mm in the visual area of the occipital lobe. The cortex is thicker over the crest of a gyrus than in the depths of a sulcus. The cerebral cortex has its full complement of neurons by the 18th week of intrauterine life, and six layers, which differ in the density of cell population and in the size and shape of constituent neurons, can be recognized by about the 7th month. The layers, starting at the surface and omitting regional differences for the present, are as follows (Fig. 14-2A):
FIGURE 14-2 Cortical histology, as revealed by two staining methods. (A) Golgi method: 1. Molecular layer. 2. External granular layer. 3. External pyramidal layer. 4. Internal granular layer. 5. Internal pyramidal layer. 6. Multiform layer. (B) Weigert's method for myelin: 1. Outer line of Baillarger. 2. Inner line of Baillarger.
and dendrites. The molecular layer is essentially a synaptic field of the cortex.
The layers described are evident in sections stained by the Nissl or Golgi techniques (see Chapter 4). With silver staining methods for axons or the Weigert method for myelin sheaths, axons within the neocortex are seen in radial bundles and in tangential bands (see Fig. 14-2B). The radial bundles include axons entering and leaving the cortex. The tangential bands consist largely of collateral and terminal branches of afferent fibers. They leave the radial bundles and run parallel to the surface for some distance, branching again and making synaptic contacts with large numbers of cortical neurons. The most prominent tangential bands are the outer and inner lines of Baillarger, in layers 4 and 5, respectively. Axons originating in the thalamic sensory nuclei contribute heavily to the lines of Baillarger, especially the outer one, and they are therefore prominent in the primary sensory areas. In the primary visual area in the walls of the calcarine sulcus, the outer line of Baillarger on the cut surface is just visible to the unaided eye and is known as the line of Gennari (Fig. 14-3). Because of the presence of the line of Gennari, the primary visual cortex is known alternatively as the striate area.
Variations in Cytoarchitecture
Six layers can be identified in most areas of the neocortex. Exceptions are the primary visual area and parts of the primary auditory and primary somatic sensory areas, where layers 2 to 5 merge into a single layer of numerous small interneurons. The opposite extreme is found in the primary motor and premotor areas of the frontal lobe, where pyramidal cells are much more numerous than interneurons, and layers 2 to 6 appear as a single zone consisting almost entirely of pyramidal cells of different sizes, with the larger ones more deeply located.
The cerebral cortex has been divided into cytoarchitectural areas based on differences
in the thickness of individual layers, neuronal morphology in the layers, and the distribution of axonal bundles. Different investigators have divided the cortex into 20 to 200 areas, depending on the criteria used. Brodmann's numbered map, which was published in 1909 and consists of 52 areas, provides the most widely used scheme of cortical cytoarchitectural areas. Some areas of Brodmann's map referred to later in the text are shown in Figures 15-1 and 15-2.
FIGURE 14-3 Vertical section through the medial surface of the occipital lobe at the site of the calcarine sulcus. The line of Gennari, extending from A to B, identifies the primary visual area: the striate cortex (Weigert stain).
Some of the cortical areas recognized histologically correspond closely with areas whose functions are known from clinical and experimental investigations (see Chapter 15). These areas are summarized in Table 14-1.
Investigations of cortical neurons using the Golgi technique, electron microscopy, and immunohistochemical methods, combined with electrical recording from microelectrodes placed in the cortex, have yielded much information concerning intrinsic circuits. These are summarized in simplified form in Figure 14-4.
Afferent and Efferent Fibers
The major sources of afferent fibers entering the cortex are as follows:
TABLE 14-1 Some Cytoarchitectonic Areas and Associated Functions
and fusiform cells, enter the white matter for distribution as projection, association, or commissural fibers (see Chapter 16).
FIGURE 14-4 Some intracortical connections. Axons of neurons in other cortical areas (magenta) excite the apical dendrites of pyramidal cells. Afferents from specific thalamic nuclei (blue) excite basal dendrites of pyramidal cells in layers 3, 5, and 6 and the stellate cells (green) in layer 4, which, in turn, excite pyramidal cells (red) in the same column.Also in layer 4, branches of thalamic afferent and pyramidal cell axons excite basket cells (black), which inhibit pyramidal cells in adjacent columns (pink). (Reprinted with permission from Martin JH. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science, 3rd ed. New York: Elsevier, 1991:781.)
Recordings from microelectrodes inserted into the cortex have shown that it is organized functionally as minute vertical units, known as columns or modules, that include neurons of all layers. This has been demonstrated best in sensory areas. All the neurons in a module are selectively activated by the same peripheral stimulus, whether it originates in a particular type of cutaneous receptor at a particular location or in a specific point on the retina. Each module is 200 to 500 µm in diameter and is composed of about 100 mini-columns. A mini-column is a string of neurons formed by outward migration during development.
Vertically organized functional modules corresponding to those detected with microelectrodes can also be defined by autoradiography (see Chapter 4). To do this, a labeled amino acid is injected into the appropriate thalamic nucleus, or labeled 2-deoxyglucose is given systemically while a sensory system is receiving stimuli. Columns with increased metabolic activity can also be made visible by staining histochemically for the activity of cytochrome oxidase, the enzyme that enables cells to use oxygen.
The columnar organization of the neocortex is established in fetal life, but the synaptic connections increase in number postnatally in
response to external sensory stimuli. This maturation occurs in an early critical period in response to adequate sensory stimulation. If sensory stimuli are lacking in number and variety during the first year of life, the functions of the cerebral cortex fail to develop normally. For example, if refractive errors or misalignment (strabismus) of the eyes is not corrected early in childhood, visual acuity is permanently impaired because of inadequate development of neuronal circuitry in the primary visual cortex of the occipital lobe.
Clinical Uses of Electroencephalography
Electroencephalography (EEG) is informative in the clinical investigation of epilepsy, a group of maladies in which abnormal spread of neuronal excitation occurs through the brain, typically leading to loss of consciousness and convulsions. Abnormalities in the EEG characterize the different types of epilepsy and can help to localize the epileptogenic focus in which the abnormal discharges begin. The EEG is also useful in the study of sleep (see Chapter 9). A technique known as magnetoencephalography records the magnetic fields associated with intracortical electric currents. This procedure can localize activity in smaller areas of the cortex than can EEG.
A “flat” EEG 2 days or more after cardiac arrest and resuscitation is associated with halving of the cortical oxygen consumption and is an almost certain indicator of permanent loss of function of the cerebral cortex. The diagnosis of brain death in comatose patients is made on the basis of absence of functions of the brain stem: failure of spontaneous respiration and absence of reflexes mediated by any of the cranial nerves. This must not be confused with vegetative states, in which no communication exists between the brain stem and the cerebrum, although breathing, swallowing, chewing, and cranial nerve reflexes are largely preserved. Recovery from a vegetative state of long duration can occur, but there is no reliable way to distinguish the patients who will recover from the majority in whom the condition is permanent.
Visual stimuli are easily controlled in the laboratory, so the organization of cortical neurons has been most intensively studied in the primary visual cortex. There, distinct columns of cells respond to neural input associated with one or both eyes (ocular dominance columns) and to meaningful features in the observed image, such as edges, horizontal lines, and right angles. Populations of the different kinds of cell columns form stripes that extend across the surface of the calcarine cortex.
Changes in electrical potential recorded from a point on the surface of the scalp are caused by summed membrane potentials in the apical dendrites of thousands of underlying pyramidal cells. Whereas activity in thalamic afferents to the cortex stimulates (depolarizes) the pyramidal cell dendrites in layer 4, input from association and commissural fibers causes depolarization in layer 1 (see Fig. 14-4). The magnitude and direction of flow of electric current across the thickness of the cortex depend on the differences in membrane potential of the proximal and distal ends of the apical dendrites.
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