02 - 1.2 Functional Neuroanatomy
1.2 Functional Neuroanatomy
The human brain contains approximately 1011 neurons (nerve cells) and approximately 1012 glial cells. Neurons most classically consist of a soma, or cell body, which contains the nucleus; usually multiple dendrites, which are processes that extend from the cell body and receive signals from other neurons; and a single axon, which extends from the cell body and transmits signals to other neurons. Connections between neurons are made at axon terminals; there the axons of one neuron generally contact the dendrite or cell body of another neuron. Neurotransmitter release occurs within axon terminals and is one of the major mechanisms for intraneuronal communications, and also for the effects of psychotropic drugs. There are three types of glial cells, and although they have often been thought of as having only a supportive role for neuronal functioning, glia have been increasingly appreciated as potentially involved in brain functions that may contribute more directly to both normal and disease mental conditions. The most common type of glial cell are the astrocytes, which have a number of functions, including nutrition of neurons, deactivation of some neurotransmitters, and integration with the blood–brain barrier. The oligodendrocytes in the central nervous system and the Schwann cells in the peripheral nervous system wrap their processes around neuronal axons, resulting in myelin sheaths that facilitate the conduction of electrical signals. The third type of glial cells, the microglia, which are derived from macrophages, are involved in removing cellular debris following neuronal death. The neurons and glial cells are arranged in regionally distinct patterns within the brain. Neurons and their processes form groupings in many different ways, and these patterns of organization, or architecture, can be evaluated by several approaches. The pattern of distribution of nerve cell bodies, called cytoarchitecture, is revealed by aniline dyes called Nissl stains that stain ribonucleotides in the nuclei and the cytoplasm of neuronal cell bodies. The Nissl stains show the relative size and packing density of the neurons and, consequently, reveal the organization of the neurons into the different layers of the cerebral cortex. SENSORY SYSTEMS The external world offers an infinite amount of potentially relevant information. In this overwhelming volume of sensory information in the environment, the sensory systems must both detect and discriminate stimuli; they winnow relevant information from the mass of confounding input by applying filtration at all levels. Sensory systems first transform external stimuli into neural impulses and then filter out irrelevant information to create an internal image of the environment, which serves as a basis for reasoned thought. Feature extraction is the quintessential role of sensory systems, which achieve this goal with their hierarchical organizations, first by transforming physical stimuli into neural activity in the primary sense organs and then by refining and narrowing the neural activity in a series of higher cortical processing areas. This neural processing eliminates irrelevant data from higher representations and reinforces crucial features. At the highest levels of sensory processing, neural images are transmitted to the association areas to be acted on in the light of emotions, memories, and drives.
Somatosensory System The somatosensory system, an intricate array of parallel point-to-point connections from the body surface to the brain, was the first sensory system to be understood in anatomical detail. The six somatosensory modalities are light touch, pressure, pain, temperature, vibration, and proprioception (position sense). The organization of nerve bundles and synaptic connections in the somatosensory system encodes spatial relationships at all levels, so that the organization is strictly somatotopic (Fig. 1.2-1). FIGURE 1.2-1 Pathway of somatosensory information processing. (Adapted from Patestas MA, Gartner LP. A Textbook of Neuroanatomy. Malden, MA: Blackwell; 2006:149.) Within a given patch of skin, various receptor nerve terminals act in concert to mediate distinct modalities. The mechanical properties of the skin’s mechanoreceptors and thermoreceptors generate neural impulses in response to dynamic variations in the environment while they suppress static input. Nerve endings are either fast or slow responders; their depth in the skin also determines their sensitivity to sharp or blunt stimuli. Thus the representation of the external world is significantly refined at the level of the primary sensory organs.
The receptor organs generate coded neural impulses that travel proximally along the sensory nerve axons to the spinal cord. These far-flung routes are susceptible to varying systemic medical conditions and to pressure palsies. Pain, tingling, and numbness are the typical presenting symptoms of peripheral neuropathies. All somatosensory fibers project to, and synapse in, the thalamus. The thalamic neurons preserve the somatotopic representation by projecting fibers to the somatosensory cortex, located immediately posterior to the sylvian fissure in the parietal lobe. Despite considerable overlap, several bands of cortex roughly parallel to the sylvian fissure are segregated by a somatosensory modality. Within each band is the sensory “homunculus,” the culmination of the careful somatotopic segregation of the sensory fibers at the lower levels. The clinical syndrome of tactile agnosia (astereognosis) is defined by the inability to recognize objects based on touch, although the primary somatosensory modalities—light touch, pressure, pain, temperature, vibration, and proprioception—are intact. This syndrome, localized at the border of the somatosensory and association areas in the posterior parietal lobe, appears to represent an isolated failure of only the highest order of feature extraction, with preservation of the more basic levels of the somatosensory pathway. Reciprocal connections are a key anatomical feature of crucial importance to conscious perception—as many fibers project down from the cortex to the thalamus as project up from the thalamus to the cortex. These reciprocal fibers play a critical role in filtering sensory input. In normal states, they facilitate the sharpening of internal representations, but in pathological states, they can generate false signals or inappropriately suppress sensation. Such cortical interference with sensory perception is thought to underlie many psychosomatic syndromes, such as the hemisensory loss that characterizes conversion disorder. The prenatal development of the strict point-to-point pattern that characterizes the somatosensory system remains an area of active study. Patterns of sensory innervation result from a combination of axonal guidance by particular molecular cues and pruning of exuberant synaptogenesis on the basis of an organism’s experience. Leading hypotheses weigh contributions from a genetically determined molecular map—in which the arrangement of fiber projections is organized by fixed and diffusible chemical cues— against contributions from the modeling and remodeling of projections on the basis of coordinated neural activity. Thumbnail calculations suggest that the 30,000 to 40,000 genes in human deoxyribonucleic acid (DNA) are far too few to encode completely the position of all the trillions of synapses in the brain. In fact, genetically determined positional cues probably steer growing fibers toward the general target, and the pattern of projections is fine-tuned by activity-dependent mechanisms. Recent data suggest that well-established adult thalamocortical sensory projections can be gradually remodeled as a result of a reorientation of coordinated sensory input or in response to loss of part of the somatosensory cortex, for instance, in stroke. Development of the Somatosensory System A strict somatotopic representation exists at each level of the somatosensory system. During development, neurons extend axons to connect to distant brain regions; after arriving at the destination, a set of axons must therefore sort itself to preserve the somatotopic organization. A classic experimental paradigm for this developmental
process is the representation of a mouse’s whiskers in the somatosensory cortex. The murine somatosensory cortex contains a barrel field of cortical columns, each of which corresponds to one whisker. When mice are inbred to produce fewer whiskers, fewer somatosensory cortex barrels appear. Each barrel is expanded in area, and the entire barrel field covers the same area of the somatosensory cortex as it does in normal animals. This experiment demonstrates that certain higher cortical structures can form in response to peripheral input and that different input complexities determine different patterns of synaptic connectivity. Although the mechanisms by which peripheral input molds cortical architecture are largely unknown, animal model paradigms are beginning to yield clues. For example, in a mutant mouse that lacks monoamine oxidase A and, thus, has extremely high cortical levels of serotonin, barrels fail to form in the somatosensory cortex. This result indirectly implicates serotonin in the mechanism of barrel field development. In adults, the classic mapping studies of Wilder Penfield suggested the existence of a homunculus, an immutable cortical representation of the body surface. More recent experimental evidence from primate studies and from stroke patients, however, has promoted a more plastic conception than that of Penfield. Minor variations exist in the cortical pattern of normal individuals, yet dramatic shifts in the map can occur in response to loss of cortex from stroke or injury. When a stroke ablates a significant fraction of the somatosensory homunculus, the homuncular representation begins to contract and shift proportionately to fill the remaining intact cortex. Moreover, the cortical map can be rearranged solely in response to a change in the pattern of tactile stimulation of the fingers. The somatotopic representation of the proximal and distal segments of each finger normally forms a contiguous map, presumably because both segments contact surfaces simultaneously. However, under experimental conditions in which the distal segments of all fingers are simultaneously stimulated while contact of the distal and proximal parts of each finger is separated, the cortical map gradually shifts 90 degrees to reflect the new sensory experience. In the revised map, the cortical representation of the proximal segment of each finger is no longer contiguous with that of the distal segment. These data support the notion that the internal representation of the external world, although static in gross structure, can be continuously modified at the level of synaptic connectivity to reflect relevant sensory experiences. The cortical representation also tends to shift to fit entirely into the available amount of cortex. These results also support the notion that cortical representations of sensory input, or of memories, may be holographic rather than spatially fixed: The pattern of activity, rather than the physical structure, may encode information. In sensory systems, this plasticity of cortical representation allows recovery from brain lesions; the phenomenon may also underlie learning. Visual System Visual images are transduced into neural activity within the retina and are processed through a series of brain cells, which respond to increasingly complex features, from the
eye to the higher visual cortex. The neurobiological basis of feature extraction is best understood in finest detail in the visual system. Beginning with classic work in the 1960s, research in the visual pathway has produced two main paradigms for all sensory systems. The first paradigm, mentioned earlier with respect to the somatosensory system, evaluates the contributions of genetics and experience—or nature and nurture— in the formation of the final synaptic arrangement. Transplantation experiments, resulting in an accurate point-to-point pattern of connectivity, even when the eye was surgically inverted, have suggested an innate, genetically determined mechanism of synaptic pattern formation. The crucial role of early visual experience in establishing the adult pattern of visual connections, on the other hand, crystallized the hypothesis of activity-dependent formation of synaptic connectivity. The final adult pattern is the result of both factors. The second main paradigm, most clearly revealed in the visual system, is that of highly specialized brain cells that respond exclusively to extremely specific stimuli. Recent work, for example, has identified cells in the inferior temporal cortex that respond only to faces viewed at a specific angle. An individual’s response to a particular face requires the activity of large neural networks and may not be limited to a single neuron. Nevertheless, the cellular localization of specific feature extraction is of critical importance in defining the boundary between sensory and association systems, but only in the visual system has this significant question been posed experimentally. In the primary visual cortex, columns of cells respond specifically to lines of a specific orientation. The cells of the primary visual cortex project to the secondary visual cortex, where cells respond specifically to particular movements of lines and to angles. In turn, these cells project to two association areas, where additional features are extracted and conscious awareness of images forms. The inferior temporal lobe detects the shape, form, and color of the object—the what questions; the posterior parietal lobe tracks the location, motion, and distance—the where questions. The posterior parietal lobe contains distinct sets of neurons that signal the intention either to look into a certain part of visual space or to reach for a particular object. In the inferior temporal cortices (ITCs), adjacent cortical columns respond to complex forms. Responses to facial features tend to occur in the left ITC, and responses to complex shapes tend to occur in the right ITC. The brain devotes specific cells to the recognition of facial expressions and to the aspect and position of faces of others with respect to the individual. The crucial connections between the feature-specific cells and the association areas involved in memory and conscious thought remain to be delineated. Much elucidation of feature recognition is based on invasive animal studies. In humans, the clinical syndrome of prosopagnosia describes the inability to recognize faces, in the presence of preserved recognition of other environmental objects. On the basis of pathological and radiological examination of individual patients, prosopagnosia is thought to result from disconnection of the left ITC from the visual association area in the left parietal lobe. Such lesional studies are useful in identifying necessary components of a mental pathway, but they may be inadequate to define the entire pathway. One noninvasive
technique that is still being perfected and is beginning to reveal the full anatomical relation of the human visual system to conscious thought and memory is functional neuroimaging. As is true for language, there appears to be a hemispheric asymmetry for certain components of visuospatial orientation. Although both hemispheres cooperate in perceiving and drawing complex images, the right hemisphere, especially the parietal lobe, contributes the overall contour, perspective, and right-left orientation, and the left hemisphere adds internal detail, embellishment, and complexity. The brain can be fooled in optical illusions. Neurological conditions such as strokes and other focal lesions have permitted the definition of several disorders of visual perception. Apperceptive visual agnosia is the inability to identify and draw items using visual cues, with preservation of other sensory modalities. It represents a failure of transmission of information from the higher visual sensory pathway to the association areas and is caused by bilateral lesions in the visual association areas. Associative visual agnosia is the inability to name or use objects despite the ability to draw them. It is caused by bilateral medial occipitotemporal lesions and can occur along with other visual impairments. Color perception may be ablated in lesions of the dominant occipital lobe that include the splenium of the corpus callosum. Color agnosia is the inability to recognize a color despite being able to match it. Color anomia is the inability to name a color despite being able to point to it. Central achromatopsia is a complete inability to perceive color. Anton’s syndrome is a failure to acknowledge blindness, possibly owing to interruption of fibers involved in self-assessment. It is seen with bilateral occipital lobe lesions. The most common causes are hypoxic injury, stroke, metabolic encephalopathy, migraine, herniation resulting from mass lesions, trauma, and leukodystrophy. Balint’s syndrome consists of a triad of optic ataxia (the inability to direct optically guided movements), oculomotor apraxia (inability to direct gaze rapidly), and simultanagnosia (inability to integrate a visual scene to perceive it as a whole). Balint’s syndrome is seen in bilateral parietooccipital lesions. Gerstmann’s syndrome includes agraphia, calculation difficulties (acalculia), right–left disorientation, and finger agnosia. It has been attributed to lesions of the dominant parietal lobe. Development of the Visual System In humans, the initial projections from both eyes intermingle in the cortex. During the development of visual connections in the early postnatal period, there is a window of time during which binocular visual input is required for development of ocular dominance columns in the primary visual cortex. Ocular dominance columns are stripes of cortex that receive input from only one eye, separated by stripes innervated only by fibers from the other eye. Occlusion of one eye during this critical period completely eliminates the persistence of its fibers in the cortex and allows the fibers of the active eye to innervate the entire visual cortex. In contrast, when normal binocular vision is allowed during the critical development window, the usual dominance columns form; occluding one eye after the completion of innervation of the cortex produces no subsequent alteration of the ocular dominance columns. This paradigm crystallizes the importance of early childhood experience on the formation of adult brain circuitry. Auditory System
Sounds are instantaneous, incremental changes in ambient air pressure. The pressure changes cause the ear’s tympanic membrane to vibrate; the vibration is then transmitted to the ossicles (malleus, incus, and stapes) and thereby to the endolymph or fluid of the cochlear spiral. Vibrations of the endolymph move cilia on hair cells, which generate neural impulses. The hair cells respond to sounds of different frequency in a tonotopic manner within the cochlea, like a long, spiral piano keyboard. Neural impulses from the hair cells travel in a tonotopic arrangement to the brain in the fibers of the cochlear nerve. They enter the brainstem cochlear nuclei, are relayed through the lateral lemniscus to the inferior colliculi, and then to the medial geniculate nucleus (MGN) of the thalamus. MGN neurons project to the primary auditory cortex in the posterior temporal lobe. Dichotic listening tests, in which different stimuli are presented to each ear simultaneously, demonstrate that most of the input from one ear activates the contralateral auditory cortex and that the left hemisphere tends to be dominant for auditory processing. Sonic features are extracted through a combination of mechanical and neural filters. The representation of sound is roughly tonotopic in the primary auditory cortex, whereas lexical processing (i.e., the extraction of vowels, consonants, and words from the auditory input) occurs in higher language association areas, especially in the left temporal lobe. The syndrome of word deafness, characterized by intact hearing for voices but an inability to recognize speech, may reflect damage to the left parietal cortex. This syndrome is thought to result from disconnection of the auditory cortex from Wernicke’s area. A rare, complementary syndrome, auditory sound agnosia, is defined as the inability to recognize nonverbal sounds, such as a horn or a cat’s meow, in the presence of intact hearing and speech recognition. Researchers consider this syndrome the right hemisphere correlate of pure word deafness. Development of the Auditory System Certain children are unable to process auditory input clearly and therefore have impaired speech and comprehension of spoken language. Studies on some of these children have determined that, in fact, they can discriminate speech if the consonants and vowels—the phonemes—are slowed twofold to fivefold by a computer. Based on this observation, a tutorial computer program was designed that initially asked questions in a slowed voice and, as subjects answered questions correctly, gradually increased the rate of phoneme presentation to approximate normal rates of speech. Subjects gained some ability to discriminate routine speech over a period of 2 to 6 weeks and appeared to retain these skills after the tutoring period was completed. This finding probably has therapeutic applicability to 5 to 8 percent of children with speech delay, but ongoing studies may expand the eligible group of students. This finding, moreover, suggests that neuronal circuits required for auditory processing can be recruited and be made more efficient long after language is normally learned, provided that the circuits are allowed to finish their task properly, even if this requires slowing the rate of input. Circuits thus functioning with high fidelity can then be trained to speed their processing. A recent report has extended the age at which language acquisition may be acquired for the first time.
A boy who had intractable epilepsy of one hemisphere was mute because the uncontrolled seizure activity precluded the development of organized language functions. At the age of 9 years he had the abnormal hemisphere removed to cure the epilepsy. Although up to that point in his life he had not spoken, he initiated an accelerated acquisition of language milestones beginning at that age and ultimately gained language abilities only a few years delayed relative to his chronological age. Researchers cannot place an absolute upper limit on the age at which language abilities can be learned, although acquisition at ages beyond the usual childhood period is usually incomplete. Anecdotal reports document acquisition of reading skills after the age of 80 years. Olfaction Odorants, or volatile chemical cues, enter the nose, are solubilized in the nasal mucus, and bind to odorant receptors displayed on the surface of the sensory neurons of the olfactory epithelium. Each neuron in the epithelium displays a unique odorant receptor, and cells displaying a given receptor are arranged randomly within the olfactory epithelium. Humans possess several hundred distinct receptor molecules that bind the huge variety of environmental odorants; researchers estimate that humans can discriminate 10,000 different odors. Odorant binding generates neural impulses, which travel along the axons of the sensory nerves through the cribriform plate to the olfactory bulb. Within the bulb, all axons corresponding to a given receptor converge onto only 1 or 2 of 3,000 processing units called glomeruli. Because each odorant activates several receptors that activate a characteristic pattern of glomeruli, the identity of external chemical molecules is represented internally by a spatial pattern of neural activity in the olfactory bulb. Each glomerulus projects to a unique set of 20 to 50 separate columns in the olfactory cortex. In turn, each olfactory cortical column receives projections from a unique combination of glomeruli. The connectivity of the olfactory system is genetically determined. Because each odorant activates a unique set of several receptors and thus a unique set of olfactory bulb glomeruli, each olfactory cortical column is tuned to detect a different odorant of some evolutionary significance to the species. Unlike the signals of the somatosensory, visual, and auditory systems, olfactory signals do not pass through the thalamus but project directly to the frontal lobe and the limbic system, especially the pyriform cortex. The connections to the limbic system (amygdala, hippocampus, and pyriform cortex) are significant. Olfactory cues stimulate strong emotional responses and can evoke powerful memories. Olfaction, the most ancient sense in evolutionary terms, is tightly associated with sexual and reproductive responses. A related chemosensory structure, the vomeronasal organ, is thought to detect pheromones, chemical cues that trigger unconscious, stereotyped responses. In some animals, ablation of the vomeronasal organ in early life may prevent the onset of puberty. Recent studies have suggested that humans also respond to pheromones in a manner that varies according to the menstrual cycle. The structures of higher olfactory processing in phylogenetically more primitive animals have evolved in humans into the limbic system, the center of the emotional brain and the gate through which experience is admitted into memory according to emotional significance. The elusive basic animal drives with which clinical psychiatry
constantly grapples may therefore, in fact, originate from the ancient centers of higher olfactory processing. Development of the Olfactory System During normal development, axons from the nasal olfactory epithelium project to the olfactory bulb and segregate into about 3,000 equivalent glomeruli. If an animal is exposed to a single dominant scent in the early postnatal period, then one glomerulus expands massively within the bulb at the expense of the surrounding glomeruli. Thus, as discussed earlier with reference to the barrel fields of the somatosensory cortex, the size of brain structures may reflect the environmental input. Taste Soluble chemical cues in the mouth bind to receptors in the tongue and stimulate the gustatory nerves, which project to the nucleus solitarius in the brainstem. The sense of taste is believed to discriminate only broad classes of stimuli: sweet, sour, bitter, and salty. Each modality is mediated through a unique set of cellular receptors and channels, of which several may be expressed in each taste neuron. The detection and the discrimination of foods, for example, involve a combination of the senses of taste, olfaction, touch, vision, and hearing. Taste fibers activate the medial temporal lobe, but the higher cortical localization of taste is only poorly understood. Autonomic Sensory System The autonomic nervous system (ANS) monitors the basic functions necessary for life. The activity of visceral organs, blood pressure, cardiac output, blood glucose levels, and body temperature are all transmitted to the brain by autonomic fibers. Most autonomic sensory information remains unconscious; if such information rises to conscious levels, it is only as a vague sensation, in contrast to the capacity of the primary senses to transmit sensations rapidly and exactly. Alteration of Conscious Sensory Perception through Hypnosis Hypnosis is a state of heightened suggestibility attainable by a certain proportion of the population. Under a state of hypnosis, gross distortions of perception in any sensory modality and changes in the ANS can be achieved instantaneously. The anatomy of the sensory system does not change, yet the same specific stimuli may be perceived with diametrically opposed emotional value before and after induction of the hypnotic state. For example, under hypnosis a person may savor an onion as if it were a luscious chocolate truffle, only to reject the onion as abhorrently pungent seconds later, when the hypnotic suggestion is reversed. The localization of the hypnotic switch has not been determined, but it presumably involves both sensory and association areas of the brain. Experiments tracing neural pathways in human volunteers via functional neuroimaging have demonstrated that shifts in attention in an environmental setting determine changes in the regions of the brain that are activated, on an instantaneous time scale.
Thus the organizing centers of the brain may route conscious and unconscious thoughts through different sequences of neural processing centers, depending on a person’s ultimate goals and emotional state. These attention-mediated variations in synaptic utilization can occur instantaneously, much like the alteration in the routing of associational processing that may occur in hypnotic states. MOTOR SYSTEMS Body muscle movements are controlled by the lower motor neurons, which extend axons —some as long as 1 meter—to the muscle fibers. Lower motor neuron firing is regulated by the summation of upper motor neuron activity. In the brainstem, primitive systems produce gross coordinated movements of the entire body. Activation of the rubrospinal tract stimulates flexion of all limbs, whereas activation of the vestibulospinal tract causes all limbs to extend. Newborn infants, for example, have all limbs tightly flexed, presumably through the dominance of the rubrospinal system. In fact, the movements of an anencephalic infant, who completely lacks a cerebral cortex, may be indistinguishable from the movements of a normal newborn. In the first few months of life, the flexor spasticity is gradually mitigated by the opposite actions of the vestibulospinal fibers, and more limb mobility occurs. At the top of the motor hierarchy is the corticospinal tract, which controls fine movements and which eventually dominates the brainstem system during the first years of life. The upper motor neurons of the corticospinal tract reside in the posterior frontal lobe, in a section of cortex known as the motor strip. Planned movements are conceived in the association areas of the brain, and in consultation with the basal ganglia and cerebellum, the motor cortex directs their smooth execution. The importance of the corticospinal system becomes immediately evident in strokes, in which spasticity returns as the cortical influence is ablated and the actions of the brainstem motor systems are released from cortical modulation. Basal Ganglia The basal ganglia, a subcortical group of gray matter nuclei, appear to mediate postural tone. The four functionally distinct ganglia are the striatum, the pallidum, the substantia nigra, and the subthalamic nucleus. Collectively known as the corpus striatum, the caudate and putamen harbor components of both motor and association systems. The caudate nucleus plays an important role in the modulation of motor acts. Anatomical and functional neuroimaging studies have correlated decreased activation of the caudate with obsessive-compulsive behavior. When functioning properly, the caudate nucleus acts as a gatekeeper to allow the motor system to perform only those acts that are goal directed. When it fails to perform its gatekeeper function, extraneous acts are performed, as in obsessive-compulsive disorder or in the tic disorders, such as Tourette’s disorder. Overactivity of the striatum owing to lack of dopaminergic inhibition (e.g., in parkinsonian conditions) results in bradykinesia, an inability to initiate movements. The caudate, in particular, shrinks dramatically in Huntington’s disease. This disorder is characterized by rigidity, on which is gradually superimposed choreiform, or “dancing,”
movements. Psychosis may be a prominent feature of Huntington’s disease, and suicide is not uncommon. The caudate is also thought to influence associative, or cognitive, processes. The globus pallidus contains two parts linked in series. In a cross section of the brain, the internal and external parts of the globus pallidus are nested within the concavity of the putamen. The globus pallidus receives input from the corpus striatum and projects fibers to the thalamus. This structure may be severely damaged in Wilson’s disease and in carbon monoxide poisoning, which are characterized by dystonic posturing and flapping movements of the arms and legs. The substantia nigra is named the black substance because the presence of melanin pigment causes it to appear black to the naked eye. It has two parts, one of which is functionally equivalent to the globus pallidus interna. The other part degenerates in Parkinson’s disease. Parkinsonism is characterized by rigidity and tremor and is associated with depression in more than 30 percent of cases. Finally, lesions in the subthalamic nucleus yield ballistic movements, sudden limb jerks of such velocity that they are compared to projectile movement. Together, the nuclei of the basal ganglia appear capable of initiating and maintaining the full range of useful movements. Investigators have speculated that the nuclei serve to configure the activity of the overlying motor cortex to fit the purpose of the association areas. In addition, they appear to integrate proprioceptive feedback to maintain an intended movement. Cerebellum The cerebellum consists of a simple six-cell pattern of circuitry that is replicated roughly 10 million times. Simultaneous recordings of the cerebral cortex and the cerebellum have shown that the cerebellum is activated several milliseconds before a planned movement. Moreover, ablation of the cerebellum renders intentional movements coarse and tremulous. These data suggest that the cerebellum carefully modulates the tone of agonistic and antagonistic muscles by predicting the relative contraction needed for smooth motion. This prepared motor plan is used to ensure that exactly the right amount of flexor and extensor stimuli is sent to the muscles. Recent functional imaging data have shown that the cerebellum is active, even during the mere imagination of motor acts when no movements ultimately result from its calculations. The cerebellum harbors two, and possibly more, distinct “homunculi” or cortical representations of the body plan. Motor Cortex Penfield’s groundbreaking work defined a motor homunculus in the precentral gyrus, Brodmann’s area 4 (Fig. 1.2-2), where a somatotopic map of the motor neurons is found. Individual cells within the motor strip cause contraction of single muscles. The brain region immediately anterior to the motor strip is called the supplementary motor area, Brodmann’s area 6. This region contains cells that when individually stimulated
can trigger more complex movements by influencing a firing sequence of motor strip cells. Recent studies have demonstrated wide representation of motor movements in the brain. FIGURE 1.2-2 Drawing of the lateral view (A) and medial view (B) of the cytoarchitectonic subdivisions of the human brain as determined by Brodmann. (From Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009.) The skillful use of the hands is called praxis, and deficits in skilled movements are termed apraxias. The three levels of apraxia are limb-kinetic, ideomotor, and ideational. Limb-kinetic apraxia is the inability to use the contralateral hand in the presence of preserved strength; it results from isolated lesions in the supplementary motor area, which contains neurons that stimulate functional sequences of neurons in the motor strip. Ideomotor apraxia is the inability to perform an isolated motor act on command, despite preserved comprehension, strength, and spontaneous performance of the same act. Ideomotor apraxia simultaneously affects both limbs and involves functions so specialized that they are localized to only one hemisphere. Conditions in two separate areas can produce this apraxia. Disconnection of the language comprehension area, Wernicke’s area, from the motor regions causes an inability to follow spoken commands, and lesions to the left premotor area may impair the actual motor program as it is generated by the higher-order motor neurons. This program is transmitted across the corpus callosum to the right premotor area, which directs the movements of the left hand. A lesion in this callosal projection can also cause an isolated ideomotor apraxia in the left hand. This syndrome implies the representation of specific motor acts within discrete sections of the left premotor cortex. Thus just as some cells respond selectively to specific environmental features in the higher sensory cortices, some cells in the premotor cortex direct specific complex motor tasks. Ideational apraxia occurs when the individual components of a sequence of skilled acts can be performed in isolation, but the entire series cannot be organized and executed as a whole. For example, the sequence of opening an envelope, removing the letter, unfolding it, and placing it on the table cannot be performed in order, even though the individual acts can be performed in isolation. The representation of the concept of a motor sequence may involve several areas, specifically the left parietal cortex, but it likely also relies on the sequencing and executive functions of the prefrontal cortex. This apraxia is a typical finding of diffuse cortical degeneration, such as Alzheimer’s disease.
Autonomic Motor System The autonomic system is divided into a sensory component (described earlier) and a motor component. The autonomic motor system is divided into two branches: the sympathetic and the parasympathetic. As a rule, organs are innervated by both types of fibers, which often serve antagonistic roles. The parasympathetic system slows the heart rate and begins the process of digestion. In contrast, the sympathetic system mediates the fight or flight response, with increased heart rate, shunting of blood away from the viscera, and increased respiration. The sympathetic system is highly activated by sympathomimetic drugs, such as amphetamine and cocaine, and may also be activated by withdrawal from sedating drugs such as alcohol, benzodiazepines, and opioids. Investigators who have found an increased risk of heart attacks in persons with high levels of hostility have suggested that chronic activation of the sympathetic fight or flight response, with elevated secretion of adrenaline, may underlie this association. The brain center that drives the autonomic motor system is the hypothalamus, which houses a set of paired nuclei that appear to control appetite, rage, temperature, blood pressure, perspiration, and sexual drive. For example, lesions to the ventromedial nucleus, the satiety center, produce a voracious appetite and rage. In contrast, lesions to the upper region of the lateral nucleus, the hunger center, produce a profound loss of appetite. Numerous research groups are making intense efforts to define the biochemical regulation of appetite and obesity and frequently target the role of the hypothalamus. In the regulation of sexual attraction, the role of the hypothalamus has also become an area of active research. In the 1990s, three groups independently reported neuroanatomical differences between certain of the hypothalamic nuclei of heterosexual and homosexual men. Researchers interpreted this finding to suggest that human sexual orientation has a neuroanatomical basis, and this result has stimulated several follow-up studies of the biological basis of sexual orientation. At present, however, these controversial findings are not accepted without question, and no clear consensus has emerged about whether the structure of the hypothalamus consistently correlates with sexual orientation. In animal studies, early nurturing and sexual experiences consistently alter the size of specific hypothalamic nuclei. Primitive Reflex Circuit Sensory pathways function as extractors of specific features from the overwhelming multitude of environmental stimuli, whereas motor pathways carry out the wishes of the organism. These pathways may be linked directly, for example, in the spinal cord, where a primitive reflex arc may mediate the brisk withdrawal of a limb from a painful stimulus, without immediate conscious awareness. In this loop, the peripheral stimulus activates the sensory nerve, the sensory neuron synapses on and directly activates the motor neuron, and the motor neuron drives the muscle to contract. This response is strictly local and all-or-none. Such primitive reflex arcs, however, rarely generate an organism’s behaviors. In most behaviors, sensory systems project to association areas, where sensory information is interpreted in terms of internally determined memories, motivations, and drives. The exhibited behavior results from a plan of action determined by the association components and carried out by the motor systems. Localization of Brain Functions
Many theorists have subdivided the brain into functional systems. Brodmann defined 47 areas on the basis of cytoarchitectonic distinctions, a cataloging that has been remarkably durable as the functional anatomy of the brain has been elucidated. A separate function, based on data from lesion studies and from functional neuroimaging, has been assigned to nearly all Brodmann’s areas. At the other extreme, certain experts have distinguished only three processing blocks: The brainstem and the thalamic reticular activating system provide arousal and set up attention; the posterior cortex integrates perceptions and generates language; and, at the highest level, the frontal cortex generates programs and executes plans like an orchestra conductor. Hemispheric lateralization of function is a key feature of higher cortical processing. The primary sensory cortices for touch, vision, hearing, smell, and taste are represented bilaterally, and the first level of abstraction for these modalities is also usually represented bilaterally. The highest levels of feature extraction, however, are generally unified in one brain hemisphere only. For example, recognition of familiar and unfamiliar faces seems localized to the left inferior temporal cortex, and cortical processing of olfaction occurs in the right frontal lobe. Hypotheses about the flow of thought in the brain are based on few experimental data, although this scarcity of findings has not impeded numerous theoreticians from speculating about functional neuroanatomy. Several roles have been tentatively assigned to specific lobes of the brain, on the basis of the functional deficits resulting from localized injury. These data indicate that certain regions of cortex may be necessary for a specific function, but they do not define the complete set of structures that suffices for a complex task. Anecdotal evidence from surface electrocorticography for the study of epilepsy, for example, suggests that a right parietal seizure impulse may shoot immediately to the left frontal lobe and then to the right temporal lobe before spreading locally to the remainder of the parietal lobe. This evidence illustrates the limitations of naively assigning a mental function to a single brain region. Functional neuroimaging studies frequently reveal simultaneous activation of disparate brain regions during the performance of even a simple cognitive task. Nevertheless, particularly in the processing of vision and language, fairly well-defined lobar syndromes have been confirmed. Language The clearest known example of hemispheric lateralization is the localization of language functions to the left hemisphere. Starting with the work of Pierre Broca and Karl Wernicke in the 19th century, researchers have drawn a detailed map of language comprehension and expression. At least eight types of aphasias in which one or more components of the language pathway are inured have been defined. Prosody, the emotional and affective components of language, or “body language,” appears to be localized in a mirror set of brain units in the right hemisphere. Because of the major role of verbal and written language in human communication, the neuroanatomical basis of language is the most completely understood association function. Language disorders, also called aphasias, are readily diagnosed in routine conversation, whereas perceptual disorders may escape notice, except during detailed
neuropsychological testing, although these disorders may be caused by injury of an equal volume of cortex. Among the earliest models of cortical localization of function were Broca’s 1865 description of a loss of fluent speech caused by a lesion in the left inferior frontal lobe and Wernicke’s 1874 localization of language comprehension to the left superior temporal lobe. Subsequent analyses of patients rendered aphasic by strokes, trauma, or tumors have led to the definition of the entire language association pathway from sensory input through the motor output. Language most clearly demonstrates hemispheric localization of function. In most persons, the hemisphere dominant for language also directs the dominant hand. Ninety percent of the population is right-handed, and 99 percent of right-handers have left hemispheric dominance for language. Of the 10 percent who are left-handers, 67 percent also have left hemispheric language dominance; the other 33 percent have either mixed or right hemispheric language dominance. This innate tendency to lateralization of language in the left hemisphere is highly associated with an asymmetry of the planum temporale, a triangular cortical patch on the superior surface of the temporal lobe that appears to harbor Wernicke’s area. Patients with mixed hemispheric dominance for language lack the expected asymmetry of the planum temporale. That asymmetry has been observed in prenatal brains suggests a genetic determinant. Indeed, the absence of asymmetry runs in families, although both genetic and intrauterine influences probably contribute to the final pattern. Language comprehension is processed at three levels. First, in phonological processing, individual sounds, such as vowels or consonants, are recognized in the inferior gyrus of the frontal lobes. Phonological processing improves if lip reading is allowed, if speech is slowed, or if contextual clues are provided. Second, lexical processing matches the phonological input with recognized words or sounds in the individual’s memory. Lexical processing determines whether a sound is a word. Recent evidence has localized lexical processing to the left temporal lobe, where the representations of lexical data are organized according to semantic category. Third, semantic processing connects the words to their meaning. Persons with an isolated defect in semantic processing may retain the ability to repeat words in the absence of an ability to understand or spontaneously generate speech. Semantic processing activates the middle and superior gyri of the left temporal lobe, whereas the representation of the conceptual content of words is widely distributed in the cortex. Language production proceeds in the opposite direction, from the cortical semantic representations through the left temporal lexical nodes to either the oromotor phonological processing area (for speech) or the graphomotor system (for writing). Each of these areas can be independently or simultaneously damaged by stroke, trauma, infection, or tumor, resulting in a specific type of aphasia. The garbled word salad or illogical utterances of an aphasic patient leave little uncertainty about the diagnosis of left-sided cortical injury, but the right hemisphere contributes a somewhat more subtle, but equally important, affective quality to language. For example, the phrase “I feel good” may be spoken with an infinite variety of shadings, each of which is understood differently. The perception of prosody and the appreciation of the associated gestures, or “body language,” appear to require an intact
right hemisphere. Behavioral neurologists have mapped an entire pathway for prosody association in the right hemisphere that mirrors the language pathway of the left hemisphere. Patients with right hemisphere lesions, who have impaired comprehension or expression of prosody, may find it difficult to function in society despite their intact language skills. Developmental dyslexia is defined as an unexpected difficulty with learning in the context of adequate intelligence, motivation, and education. Whereas speech consists of the logical combination of 44 basic phonemes of sounds, reading requires a broader set of brain functions and, thus, is more susceptible to disruption. The awareness of specific phonemes develops at about the age of 4 to 6 years and appears to be prerequisite to acquisition of reading skills. Inability to recognize distinct phonemes is the best predictor of a reading disability. Functional neuroimaging studies have localized the identification of letters to the occipital lobe adjacent to the primary visual cortex. Phonological processing occurs in the inferior frontal lobe, and semantic processing requires the superior and middle gyri of the left temporal lobe. A recent finding of uncertain significance is that phonological processing in men activates only the left inferior frontal gyrus, whereas phonological processing in women activates the inferior frontal gyrus bilaterally. Careful analysis of an individual’s particular reading deficits can guide remedial tutoring efforts that can focus on weaknesses and thus attempt to bring the reading skills up to the general level of intelligence and verbal skills. In children, developmental nonverbal learning disorder is postulated to result from right hemisphere dysfunction. Nonverbal learning disorder is characterized by poor finemotor control in the left hand, deficits in visuoperceptual organization, problems with mathematics, and incomplete or disturbed socialization. Patients with nonfluent aphasia, who cannot complete a simple sentence, may be able to sing an entire song, apparently because many aspects of music production are localized to the right hemisphere. Music is represented predominantly in the right hemisphere, but the full complexity of musical ability seems to involve both hemispheres. Trained musicians appear to transfer many musical skills from the right hemisphere to the left as they gain proficiency in musical analysis and performance. Arousal and Attention Arousal, or the establishment and maintenance of an awake state, appears to require at least three brain regions. Within the brainstem, the ascending reticular activating system (ARAS), a diffuse set of neurons, appears to set the level of consciousness. The ARAS projects to the intralaminar nuclei of the thalamus, and these nuclei in turn project widely throughout the cortex. Electrophysiological studies show that both the thalamus and the cortex fire rhythmical bursts of neuronal activity at rates of 20 to 40 cycles per second. During sleep, these bursts are not synchronized. During wakefulness, the ARAS stimulates the thalamic intralaminar nuclei, which in turn coordinate the oscillations of different cortical regions. The greater the synchronization, the higher the level of wakefulness. The absence of arousal produces stupor and coma. In general,
small discrete lesions of the ARAS can produce a stuporous state, whereas at the hemispheric level, large bilateral lesions are required to cause the same depression in alertness. One particularly unfortunate but instructive condition involving extensive, permanent, bilateral cortical dysfunction is the persistent vegetative state. Sleep–wake cycles may be preserved, and the eyes may appear to gaze; but the external world does not register and no evidence of conscious thought exists. This condition represents the expression of the isolated actions of the ARAS and the thalamus. The maintenance of attention appears to require an intact right frontal lobe. For example, a widely used test of persistence requires scanning and identifying only the letter A from a long list of random letters. Healthy persons can usually maintain performance of such a task for several minutes, but in patients with right frontal lobe dysfunction, this capacity is severely curtailed. Lesions of similar size in other regions of the cortex usually do not affect persistence tasks. In contrast, the more generally adaptive skill of maintaining a coherent line of thought is diffusely distributed throughout the cortex. Many medical conditions can affect this skill and may produce acute confusion or delirium. One widely diagnosed disorder of attention is attention-deficit/hyperactivity disorder (ADHD). No pathological findings have been consistently associated with this disorder. Functional neuroimaging studies, however, have variously documented either frontal lobe or right hemisphere hypometabolism in patients with ADHD, compared with normal controls. These findings strengthen the notion that the frontal lobes—especially the right frontal lobe—are essential to the maintenance of attention. Memory The clinical assessment of memory should test three periods, which have distinct anatomical correlates. Immediate memory functions over a period of seconds; recent memory applies on a scale of minutes to days; and remote memory encompasses months to years. Immediate memory is implicit in the concept of attention and the ability to follow a train of thought. This ability has been divided into phonological and visuospatial components, and functional imaging has localized them to the left and right hemispheres, respectively. A related concept, incorporating immediate and recent memory, is working memory, which is the ability to store information for several seconds, whereas other, related cognitive operations take place on this information. Recent studies have shown that single neurons in the dorsolateral prefrontal cortex not only record features necessary for working memory, but also record the certainty with which the information is known and the degree of expectation assigned to the permanence of a particular environmental feature. Some neurons fire rapidly for an item that is eagerly awaited, but may cease firing if hopes are dashed unexpectedly. The encoding of the emotional value of an item contained in the working memory may be of great usefulness in determining goal-directed behavior. Some researchers localize working memory predominantly to the left frontal cortex. Clinically, however, bilateral prefrontal cortex lesions are required for severe impairment of working memory. Other types of memory have been described: episodic, semantic, and procedural. Three brain structures are critical to the formation of memories: the medial temporal lobe, certain diencephalic nuclei, and the basal forebrain. The medial temporal lobe
houses the hippocampus, an elongated, highly repetitive network. The amygdala is adjacent to the anterior end of the hippocampus. The amygdala has been suggested to rate the emotional importance of an experience and to activate the level of hippocampal activity accordingly. Thus an emotionally intense experience is indelibly etched in memory, but indifferent stimuli are quickly disregarded. Animal studies have defined a hippocampal place code, a pattern of cellular activation in the hippocampus that corresponds to the animal’s location in space. When the animal is introduced to a novel environment, the hippocampus is broadly activated. As the animal explores and roams, the firing of certain hippocampal regions begins to correspond to specific locations in the environment. In about 1 hour, a highly detailed internal representation of the external space (a “cognitive map”) appears in the form of specific firing patterns of the hippocampal cells. These patterns of neuronal firing may bear little spatial resemblance to the environment they represent; rather, they may seem randomly arranged in the hippocampus. If the animal is manually placed in a certain part of a familiar space, only the corresponding hippocampal regions show intense neural activity. When recording continues into sleep periods, firing sequences of hippocampal cells outlining a coherent path of navigation through the environment are registered, even though the animal is motionless. If the animal is removed from the environment for several days and then returned, the previously registered hippocampal place code is immediately reactivated. A series of animal experiments have dissociated the formation of the hippocampal place code from either visual, auditory, or olfactory cues, although each of these modalities may contribute to place code generation. Other factors may include internal calculations of distances based on counting footsteps or other proprioceptive information. Data from targeted genetic mutations in mice have implicated both the N-methyl-D-aspartate (NMDA) glutamate receptors and the calciumcalmodulin kinase II (CaMKII) in the proper formation of hippocampal place fields. These data suggest that the hippocampus is a significant site for formation and storage of immediate and recent memories. Although no data yet support the notion, it is conceivable that the hippocampal cognitive map is inappropriately reactivated during a déjà vu experience. The most famous human subject in the study of memory is H. M., a man with intractable epilepsy, who had both his hippocampi and amygdalae surgically removed to alleviate his condition. The epilepsy was controlled, but he was left with a complete inability to form and recall memories of facts. H. M.’s learning and memory skills were relatively preserved, which led to the suggestion that declarative or factual memory may be separate within the brain from procedural or skill-related memory. A complementary deficit in procedural memory with preservation of declarative memory may be seen in persons with Parkinson’s disease, in whom dopaminergic neurons of the nigrostriatal tract degenerate. Because this deficit in procedural memory can be ameliorated with treatment with levodopa (Larodopa), which is thought to potentiate dopaminergic neurotransmission in the nigrostriatal pathway, a
role has been postulated for dopamine in procedural memory. Additional case reports have further implicated the amygdala and the afferent and efferent fiber tracts of the hippocampus as essential to the formation of memories. In addition, lesional studies have suggested a mild lateralization of hippocampal function in which the left hippocampus is more efficient at forming verbal memories and the right hippocampus tends to form nonverbal memories. After unilateral lesions in humans, however, the remaining hippocampus may compensate to a large extent. Medical causes of amnesia include alcoholism, seizures, migraine, drugs, vitamin deficiencies, trauma, strokes, tumors, infections, and degenerative diseases. The motor system within the cortex receives directives from the association areas. The performance of a novel act requires constant feedback from the sensory and association areas for completion, and functional neuroimaging studies have demonstrated widespread activation of the cortex during unskilled acts. Memorized motor acts initially require activation of the medial temporal lobe. With practice, however, the performance of ever-larger segments of an act necessary to achieve a goal become encoded within discrete areas of the premotor and parietal cortices, particularly the left parietal cortex, with the result that a much more limited activation of the cortex is seen during highly skilled acts, and the medial temporal lobe is bypassed. This process is called the corticalization of motor commands. In lay terms, the process suggests a neuroanatomical basis for the adage “practice makes perfect.” Within the diencephalon, the dorsal medial nucleus of the thalamus and the mammillary bodies appear necessary for memory formation. These two structures are damaged in thiamine deficiency states usually seen in chronic alcoholics, and their inactivation is associated with Korsakoff’s syndrome. This syndrome is characterized by severe inability to form new memories and a variable inability to recall remote memories. The most common clinical disorder of memory is Alzheimer’s disease. Alzheimer’s disease is characterized pathologically by the degeneration of neurons and their replacement by senile plaques and neurofibrillary tangles. Clinicopathological studies have suggested that the cognitive decline is best correlated with the loss of synapses. Initially, the parietal and temporal lobes are affected, with relative sparing of the frontal lobes. This pattern of degeneration correlates with the early loss of memory, which is largely a temporal lobe function. Also, syntactical language comprehension and visuospatial organization, functions that rely heavily on the parietal lobe, are impaired early in the course of Alzheimer’s disease. In contrast, personality changes, which reflect frontal lobe function, are relatively late consequences of Alzheimer’s disease. A rarer, complementary cortical degeneration syndrome, Pick’s disease, first affects the frontal lobes while sparing the temporal and parietal lobes. In Pick’s disease, disinhibition and impaired language expression, which are signs of frontal dysfunction, appear early, with relatively preserved language comprehension and memory. Memory loss can also result from disorders of the subcortical gray matter structures, specifically the basal ganglia and the brainstem nuclei, from disease of the white matter, or from disorders that affect both gray and white matter.
Emotion Individual emotional experiences occupy the attention of all mental health professionals. Emotion derives from basic drives, such as feeding, sex, reproduction, pleasure, pain, fear, and aggression, which all animals share. The neuroanatomical basis for these drives appears to be centered in the limbic system. Distinctly human emotions, such as affection, pride, guilt, pity, envy, and resentment, are largely learned and most likely are represented in the cortex (see Color Plate 1.2-3). The regulation of drives appears to require an intact frontal cortex. The complex interplay of the emotions, however, is far beyond the understanding of functional neuroanatomists. Where, for example, are the representations of the id, the ego, and the superego? Through what pathway are ethical and moral judgments shepherded? What processes allow beauty to be in the eye of the beholder? These philosophical questions represent a true frontier of human discovery. Several studies have suggested that within the cortex exists a hemispheric dichotomy of emotional representation. The left hemisphere houses the analytical mind but may have a limited emotional repertoire. For example, lesions to the right hemisphere, which cause profound functional deficits, may be noted with indifference by the intact left hemisphere. The denial of illness and of the inability to move the left hand in cases of right hemisphere injury is called anosognosia. In contrast, left hemisphere lesions, which cause profound aphasia, can trigger a catastrophic depression, as the intact right hemisphere struggles with the realization of the loss. The right hemisphere also appears dominant for affect, socialization, and body image. Damage to the left hemisphere produces intellectual disorder and loss of the narrative aspect of dreams. Damage to the right hemisphere produces affective disorders, loss of the visual aspects of dreams, and a failure to respond to humor, shadings of metaphor, and connotations. In dichotic vision experiments, two scenes of varied emotional content were displayed simultaneously to each half of the visual field and were perceived separately by each hemisphere. A more intense emotional response attended the scenes displayed to the left visual field that were processed by the right hemisphere. Moreover, hemisensory changes representing conversion disorders have been repeatedly noted to involve the left half of the body more often than the right, an observation that suggests an origin in the right hemisphere. Within the hemispheres, the temporal and frontal lobes play a prominent role in emotion. The temporal lobe exhibits a high frequency of epileptic foci, and temporal lobe epilepsy (TLE) presents an interesting model for the role of the temporal lobe in behavior. In studies of epilepsy, abnormal brain activation is analyzed, rather than the deficits in activity analyzed in classic lesional studies. TLE is of particular interest in psychiatry because patients with temporal lobe seizures often manifest bizarre behavior without the classic grand mal shaking movements caused by seizures in the motor cortex. A proposed TLE personality is characterized by hyposexuality, emotional intensity, and a perseverative approach to interactions, termed viscosity. Patients with left TLE may generate references to personal destiny and philosophical themes and display a humorless approach to life. In contrast, patients with right TLE may display excessive emotionality, ranging from elation to sadness. Although patients with TLE may display excessive aggression between seizures, the seizure itself
may evoke fear. The inverse of a TLE personality appears in persons with bilateral injury to the temporal lobes after head trauma, cardiac arrest, herpes simplex encephalitis, or Pick’s disease. This lesion resembles the one described in the Klüver-Bucy syndrome, an experimental model of temporal lobe ablation in monkeys. Behavior in this syndrome is characterized by hypersexuality, placidity, a tendency to explore the environment with the mouth, inability to recognize the emotional significance of visual stimuli, and constantly shifting attention, called hypermetamorphosis. In contrast to the aggression– fear spectrum sometimes seen in patients with TLE, complete experimental ablation of the temporal lobes appears to produce a uniform, bland reaction to the environment, possibly because of an inability to access memories. The prefrontal cortices influence mood in a complementary way. Whereas activation of the left prefrontal cortex appears to lift the mood, activation of the right prefrontal cortex causes depression. A lesion to the left prefrontal area, at either the cortical or the subcortical level, abolishes the normal mood-elevating influences and produces depression and uncontrollable crying. In contrast, a comparable lesion to the right prefrontal area may produce laughter, euphoria, and witzelsucht, a tendency to joke and make puns. Effects opposite to those caused by lesions appear during seizures, in which occurs abnormal, excessive activation of either prefrontal cortex. A seizure focus within the left prefrontal cortex can cause gelastic seizures, for example, in which the ictal event is laughter. Functional neuroimaging has documented left prefrontal hypoperfusion during depressive states, which normalized after the depression was treated successfully. Limbic System Function The limbic system was delineated by James Papez in 1937. The Papez circuit consists of the hippocampus, the fornix, the mammillary bodies, the anterior nucleus of the thalamus, and the cingulate gyrus (Fig. 1.2-4). The boundaries of the limbic system were subsequently expanded to include the amygdala, septum, basal forebrain, nucleus accumbens, and orbitofrontal cortex.
FIGURE 1.2-4 Schematic drawing of the major anatomic structures of the limbic system. The cingulate and parahippocampal gyri form the “limbic lobe,” a rim of tissue located along the junction of the diencephalon and the cerebral hemispheres. (Adapted from Hendelman WJ. Student’s Atlas of Neuroanatomy. Philadelphia: WB Saunders; 1994:179.) Although this schema creates an anatomical loop for emotional processing, the specific contributions of the individual components other than the hippocampus or even whether a given train of neural impulses actually travels along the entire pathway is unknown. The amygdala appears to be a critically important gate through which internal and external stimuli are integrated. Information from the primary senses is interwoven with internal drives, such as hunger and thirst, to assign emotional significance to sensory experiences. The amygdala may mediate learned fear responses, such as anxiety and panic, and may direct the expression of certain emotions by producing a particular affect. Neuroanatomical data suggest that the amygdala exerts a more powerful influence on the cortex, to stimulate or suppress cortical activity, than the cortex exerts on the amygdala. Pathways from the sensory thalamic relay stations separately send sensory data to the amygdala and the cortex, but the subsequent effect of the amygdala on the cortex is the more potent of the two reciprocal connections. In contrast, damage to the amygdala has been reported to ablate the ability to distinguish fear and anger in other persons’ voices and facial expressions. Persons with such injuries may have a preserved ability to recognize happiness, sadness, or disgust. The limbic system appears
to house the emotional association areas, which direct the hypothalamus to express the motor and endocrine components of the emotional state. Fear and Aggression Electrical stimulation of animals throughout the subcortical area involving the limbic system produces rage reactions (e.g., growling, spitting, and arching of the back). Whether the animal flees or attacks depends on the intensity of the stimulation. Limbic System and Schizophrenia The limbic system has been particularly implicated in neuropathological studies of schizophrenia. Eugen Bleuler’s well-known four A’s of schizophrenia—affect, associations, ambivalence, and autism—refer to brain functions served in part by limbic structures. Several clinicopathological studies have found a reduction in the brain weight of the gray matter but not of the white matter in persons with schizophrenia. In pathological as well as in magnetic resonance imaging (MRI) reports, persons with schizophrenia may have reduced volume of the hippocampus, amygdala, and parahippocampal gyrus. Schizophrenia may be a late sequela of a temporal epileptic focus, with some studies reporting an association in 7 percent of patients with TLE. Functional neuroimaging studies have demonstrated decreased activation of the frontal lobes in many patients with schizophrenia, particularly during tasks requiring willed action. A reciprocal increase in activation of the temporal lobe can occur during willed actions, such as finger movements or speaking, in persons with schizophrenia. Neuropathological studies have shown a decreased density of neuropil, the intertwined axons and dendrites of the neurons, in the frontal lobes of these patients. During development, the density of neuropil is highest around age 1 year and then is reduced somewhat through synaptic pruning; the density plateaus throughout childhood and is further reduced to adult levels in adolescence. One hypothesis of the appearance of schizophrenia in the late teenage years is that excessive adolescent synaptic pruning occurs and results in too little frontolimbic activity. Some experts have suggested that hypometabolism and paucity of interneuronal connections in the prefrontal cortex may reflect inefficiencies in working memory, which permits the disjointed discourse and loosening of associations that characterize schizophrenia. At present, the molecular basis for the regulation of the density of synapses within the neuropil is unknown. Other lines of investigation aimed at understanding the biological basis of schizophrenia have documented inefficiencies in the formation of cortical synaptic connections in the middle of the second trimester of gestation, which may result from a viral infection or malnutrition. Neurodevelopmental surveys administered during childhood have found an increased incidence of subtle neurological abnormalities before the appearance of the thought disorder in persons who subsequently exhibited signs of schizophrenia. In one intriguing study, positron emission tomography (PET) scanning was used to identify the brain regions that are activated when a person hears spoken language. A consistent set of cortical and subcortical structures demonstrated increased metabolism
when speech was processed. The researchers then studied a group of patients with schizophrenia who were experiencing active auditory hallucinations. During the hallucinations, the same cortical and subcortical structures were activated as were activated by the actual sounds, including the primary auditory cortex. At the same time, decreased activation was seen of areas thought to monitor speech, including the left middle temporal gyrus and the supplementary motor area. This study raises the questions of what brain structure is activating the hallucinations and by what mechanism do neuroleptic drugs suppress the hallucinations. Clearly, functional imaging has much to tell about the neuroanatomical basis of schizophrenia. Frontal Lobe Function The frontal lobes, the region that determines how the brain acts on its knowledge, constitute a category unto themselves. In comparative neuroanatomical studies, the massive size of the frontal lobes is the main feature that distinguishes the human brain from that of other primates and that lends it uniquely human qualities. There are four subdivisions of the frontal lobes. The first three—the motor strip, the supplemental motor area, and Broca’s area—are mentioned in the preceding discussion of the motor system and language. The fourth, most anterior, division is the prefrontal cortex. The prefrontal cortex contains three regions in which lesions produce distinct syndromes: the orbitofrontal, the dorsolateral, and the medial. Dye-tracing studies have defined dense reciprocal connections between the prefrontal cortex and all other brain regions. Therefore, to the extent that anatomy can predict function, the prefrontal cortex is ideally connected to allow sequential use of the entire palette of brain functions in executing goal-directed activity. Indeed, frontal lobe injury usually impairs the executive functions: motivation, attention, and sequencing of actions. Bilateral lesions of the frontal lobes are characterized by changes in personality—how persons interact with the world. The frontal lobe syndrome, which is most commonly produced by trauma, infarcts, tumors, lobotomy, multiple sclerosis, or Pick’s disease, consists of slowed thinking, poor judgment, decreased curiosity, social withdrawal, and irritability. Patients typically display apathetic indifference to experience that can suddenly explode into impulsive disinhibition. Unilateral frontal lobe lesions may be largely unnoticed because the intact lobe can compensate with high efficiency. Frontal lobe dysfunction may be difficult to detect by means of highly structured, formal neuropsychological tests. Intelligence, as reflected in the intelligence quotient (IQ), may be normal, and functional neuroimaging studies have shown that the IQ seems to require mostly parietal lobe activation. For example, during administration of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the highest levels of increased metabolic activity during verbal tasks occurred in the left parietal lobe, whereas the highest levels of increased metabolic activity during performance skills occurred in the right parietal lobe. In contrast, frontal lobe pathology may become apparent only under unstructured, stressful, real-life situations.
A famous case illustrating the result of frontal lobe damage involves Phineas Gage, a 25-year-old railroad worker. While he was working with explosives, an accident drove an iron rod through Gage’s head. He survived, but both frontal lobes were severely damaged. After the accident, his behavior changed dramatically. The case was written up by J. M. Harlow, M.D., in 1868, as follows: [George] is fitfull, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires...His mind was radically changed, so decidedly that his friends and acquaintances said he was “no longer Gage.” (see Fig. 1.2-5) FIGURE 1.2-5 The life mask and skull of Phineas Gage. Note damage to the frontal region. “A famous case illustrating the result of frontal lobe damage involves Phineas Gage, a 25-year-old railroad worker. While he was working with explosives, an accident drove an iron rod through Gage’s head. He survived, but both frontal lobes were severely damaged. After the accident, his behavior changed dramatically. The case was written up by J.M. Harlow, M.D., in 1868, as follows: [Gage] is fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts his desires… His mind was radically changed, so decidedly that his friends and acquaintances said he was ‘no longer Gage.’” (Courtesy of Anthony A. Walsh, Ph.D.) In one study of right-handed males, lesions of the right prefrontal cortex eliminated the tendency to use internal, associative memory cues and led to an extreme tendency to interpret the task at hand in terms of its immediate context. In contrast, right-handed males who had lesions of the left prefrontal cortex produced no context-dependent interpretations and interpreted the tasks entirely in terms of their own internal drives. A mirror image of the functional lateralization appeared in left-handed subjects. This test thus revealed the clearest known association of higher cortical functional
lateralization with the subjects’ dominant hand. Future experiments in this vein will attempt to reproduce these findings with functional neuroimaging. If corroborated, these studies suggest a remarkable complexity of functional localization within the prefrontal cortex and may also have implications for the understanding of psychiatric diseases in which prefrontal pathology has been postulated, such as schizophrenia and mood disorders. The heavy innervation of the frontal lobes by dopamine-containing nerve fibers is of interest because of the action of antipsychotic medications. At the clinical level, antipsychotic medications may help to organize the rambling associations of a patient with schizophrenia. At the neurochemical level, most typical antipsychotic medications block the actions of dopamine at the D2 receptors. The frontal lobes, therefore, may be a major therapeutic site of action for antipsychotic medications. DEVELOPMENT The nervous system is divided into the central and peripheral nervous systems (CNS and PNS). The CNS consists of the brain and spinal cord; the PNS refers to all the sensory, motor, and autonomic fibers and ganglia outside the CNS. During development, both divisions arise from a common precursor, the neural tube, which in turn is formed through folding of the neural plate, a specialization of the ectoderm, the outermost of the three layers of the primitive embryo. During embryonic development, the neural tube itself becomes the CNS; the ectoderm immediately superficial to the neural tube becomes the neural crest, which gives rise to the PNS. The formation of these structures requires chemical communication between the neighboring tissues in the form of cell surface molecules and diffusible chemical signals. In many cases, an earlier-formed structure, such as the notochord, is said to induce the surrounding ectoderm to form a later structure, in this case the neural plate (see Color Plate 1.2-6). Identification of the chemical mediators of tissue induction is an active area of research. Investigators have begun to examine whether failures of the interactions of these mediators and their receptors could underlie errors in brain development that cause psychopathology. Neuronal Migration and Connections The life cycle of a neuron consists of cell birth, migration to the adult position, extension of an axon, elaboration of dendrites, synaptogenesis, and, finally, the onset of chemical neurotransmission. Individual neurons are born in proliferative zones generally located along the inner surface of the neural tube. At the peak of neuronal proliferation in the middle of the second trimester, 250,000 neurons are born each minute. Postmitotic neurons migrate outward to their adult locations in the cortex, guided by radially oriented astrocytic glial fibers. Glia-guided neuronal migration in the cerebral cortex occupies much of the first 6 months of gestation. For some neurons in the prefrontal cortex, migration occurs over a distance 5,000 times the diameter of the neuronal cell body. Neuronal migration requires a complex set of cell–cell interactions and is susceptible to errors in which neurons fail to reach the cortex and instead reside in ectopic positions. A group of such incorrectly placed neurons is called a heterotopia. Neuronal heterotopias have been shown to cause epilepsy and are highly associated with mental retardation. In a neuropathological study of the planum temporale of four
consecutive patients with dyslexia, heterotopias were a common finding. Recently, heterotopic neurons within the frontal lobe have been postulated to play a causal role in some cases of schizophrenia. Many neurons lay down an axon as they migrate, whereas others do not initiate axon outgrowth until they have reached their cortical targets. Thalamic axons that project to the cortex initially synapse on a transient layer of neurons called the subplate neurons. In normal development, the axons subsequently detach from the subplate neurons and proceed superficially to synapse on the true cortical cells. The subplate neurons then degenerate. Some brains from persons with schizophrenia reveal an abnormal persistence of subplate neurons, suggesting a failure to complete axonal pathfinding in the brains of these persons. This finding does not correlate with the presence of schizophrenia in every case, however. A characteristic branched dendritic tree elaborates once the neuron has completed migration. Synaptogenesis occurs at a furious rate from the second trimester through the first 10 years or so of life. The peak of synaptogenesis occurs within the first 2 postnatal years, when as many as 30 million synapses form each second. Ensheathment of axons by myelin begins prenatally; it is largely complete in early childhood, but does not reach its full extent until late in the third decade of life. Myelination of the brain is also sequential. Neuroscientists are tremendously interested in the effect of experience on the formation of brain circuitry in the first years of life. As noted earlier, many examples are seen of the impact of early sensory experience on the wiring of cortical sensory processing areas. Similarly, early movement patterns are known to reinforce neural connections in the supplemental motor area that drive specific motor acts. Neurons rapidly form a fivefold excess of synaptic connections; then, through a Darwinian process of elimination, only those synapses that serve a relevant function persist. This synaptic pruning appears to preserve input in which the presynaptic cell fires in synchrony with the postsynaptic cell, a process that reinforces repeatedly activated neural circuits. One molecular component that is thought to mediate synaptic reinforcement is the postsynaptic NMDA glutamate receptor. This receptor allows the influx of calcium ions only when activated by glutamate at the same time as the membrane in which it sits is depolarized. Thus, glutamate binding without membrane depolarization or membrane depolarization without glutamate binding fails to trigger calcium influx. NMDA receptors open in dendrites that are exposed to repeated activation, and their activation stimulates stabilization of the synapse. Calcium is a crucial intracellular messenger that initiates a cascade of events, including gene regulation and the release of trophic factors that strengthen particular synaptic connections. Although less experimental evidence exists for the role of experience in modulating synaptic connectivity of association areas than has been demonstrated in sensory and motor areas, neuroscientists assume that similar activity-dependent mechanisms may apply in all areas of the brain. Adult Neurogenesis A remarkable recent discovery has been that new neurons can be generated in certain brain regions (particularly the dentate gyrus of the hippocampus) in adult animals, including humans. This is in marked contrast to the previous belief that no neurons were produced after birth in most species. This discovery has a potentially profound impact on our understanding of normal development, incorporation of experiences, as well as the ability of the brain to repair itself after various types of injuries (see Color Plates
1.2-7 and 1.2-8). Neurological Basis of Development Theories In the realm of emotion, early childhood experiences have been suspected to be at the root of psychopathology since the earliest theories of Sigmund Freud. Freud’s psychoanalytic method aimed at tracing the threads of a patient’s earliest childhood memories. Franz Alexander added the goal of allowing the patient to relive these memories in a less pathological environment, a process known as a corrective emotional experience. Although neuroscientists have no data demonstrating that this method operates at the level of neurons and circuits, emerging results reveal a profound effect of early caregivers on an adult individual’s emotional repertoire. For example, the concept of attunement is defined as the process by which caregivers “play back a child’s inner feelings.” If a baby’s emotional expressions are reciprocated in a consistent and sensitive manner, certain emotional circuits are reinforced. These circuits likely include the limbic system, in particular, the amygdala, which serves as a gate to the hippocampal memory circuits for emotional stimuli. In one anecdote, for example, a baby whose mother repeatedly failed to mirror her level of excitement emerged from childhood an extremely passive girl, who was unable to experience a thrill or a feeling of joy. The relative contributions of nature and nurture are perhaps nowhere more indistinct than in the maturation of emotional responses, partly because the localization of emotion within the adult brain is only poorly understood. It is reasonable to assume, however, that the reactions of caregivers during a child’s first 2 years of life are eventually internalized as distinct neural circuits, which may be only incompletely subject to modification through subsequent experience. For example, axonal connections between the prefrontal cortex and the limbic system, which probably play a role in modulating basic drives, are established between the ages of 10 and 18 months. Recent work suggests that a pattern of terrifying experiences in infancy may flood the amygdala and drive memory circuits to be specifically alert to threatening stimuli, at the expense of circuits for language and other academic skills. Thus infants raised in a chaotic and frightening home may be neurologically disadvantaged for the acquisition of complex cognitive skills in school. An adult correlate to this cascade of detrimental overactivity of the fear response is found in posttraumatic stress disorder (PTSD), in which persons exposed to an intense trauma involving death or injury may have feelings of fear and helplessness for years after the event. A PET scanning study of patients with PTSD revealed abnormally high activity in the right amygdala while the patients were reliving their traumatic memories. The researchers hypothesized that the stressful hormonal milieu present during the registration of the memories may have served to burn the memories into the brain and to prevent their erasure by the usual memory modulation circuits. As a result, the traumatic memories exerted a pervasive influence and led to a state of constant vigilance, even in safe, familiar settings.
Workers in the related realms of mathematics have produced results documenting the organizing effects of early experiences on internal representations of the external world. Since the time of Pythagoras, music has been considered a branch of mathematics. A series of recent studies has shown that groups of children who were given 8 months of intensive classical music lessons during preschool years later had significantly better spatial and mathematical reasoning in school than a control group. Nonmusical tasks, such as navigating mazes, drawing geometric figures, and copying patterns of twocolor blocks, were performed significantly more skillfully by the musical children. Early exposure to music, thus, may be ideal preparation for later acquisition of complex mathematical and engineering skills. These tantalizing observations suggest a neurological basis for the developmental theories of Jean Piaget, Erik Erikson, Margaret Mahler, John Bowlby, Sigmund Freud, and others. Erikson’s epigenetic theory states that normal adult behavior results from the successful, sequential completion of each of several infantile and childhood stages. According to the epigenetic model, failure to complete an early stage is reflected in subsequent physical, cognitive, social, or emotional maladjustment. By analogy, the experimental data just discussed suggest that early experience, particularly during the critical window of opportunity for establishing neural connections, primes the basic circuitry for language, emotions, and other advanced behaviors. Clearly, miswiring of an infant’s brain may lead to severe handicaps later when the person attempts to relate to the world as an adult. These findings support the vital need for adequate public financing of Early Intervention and Head Start programs, programs that may be the most cost-effective means of improving persons’ mental health. REFERENCES Björklund A, Dunnett SB. Dopamine neuron systems in the brain: An update. Trends Neurosci. 2007;30:194. Blond BN, Fredericks CA, Blumberg HP. Functional neuroanatomy of bipolar disorder: Structure, function, and connectivity in an amygdala-anterior paralimbic neural system. Bipolar Disord. 2012;14(4):340. Green S, Lambon Ralph MA, Moll J, Deakin JF, Zahn R. Guilt-selective functional disconnection of anterior temporal and subgenual cortices in major depressive disorder. Arch Gen Psychiatry. 2012;69(10):1014. Katschnig P, Schwingenschuh P, Jehna M, Svehlík M, Petrovic K, Ropele S, Zwick EB, Ott E, Fazekas F, Schmidt R, Enzinger C. Altered functional organization of the motor system related to ankle movements in Parkinson’s disease: Insights from functional MRI. J Neural Transm. 2011;118:783. Kringelbach ML, Berridge KC. The functional neuroanatomy of pleasure and happiness. Discov Med. 2010;9:579. Melchitzky DS, Lewis DA. Functional Neuroanatomy. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009. Morris CA. The behavioral phenotype of Williams syndrome: A recognizable pattern of neurodevelopment. Am J Med Genet C Semin Med Genet. 2010;154C:427. Nguyen AD, Shenton ME, Levitt JJ. Olfactory dysfunction in schizophrenia: A review of neuroanatomy and psychophysiological measurements. Harv Rev Psychiatry. 2010;18:279. Prats-Galino A, Soria G, de Notaris M, Puig J, Pedraza S. Functional anatomy of subcortical circuits issuing from or integrating at the human brainstem. Clin Neurophysiol. 2012;123:4. Sapara A, Birchwood M, Cooke MA, Fannon D, Williams SC, Kuipers E, Kumari V. Preservation and compensation: The functional neuroanatomy of insight and working memory in schizophrenia. Schizophr Res. 2014;152:201–209. Vago DR, Epstein J, Catenaccio E, Stern E. Identification of neural targets for the treatment of psychiatric disorders: The role of functional neuroimaging. Neurosurg Clin N Am. 2011;22:279. Watson CE, Chatterjee A. The functional neuroanatomy of actions. Neurology. 2011;76:1428. Weis S, Leube D, Erb M, Heun R, Grodd W, Kircher T. Functional neuroanatomy of sustained memory encoding performance in healthy aging and in Alzheimer’s disease. Int J Neurosci. 2011;121:384.
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