The limbic system is concerned with memory and with visceral and motor responses involved in defense and reproduction.
The hippocampal formation consists of the hippocampus, the dentate gyrus, and most of the parahippocampal gyrus.
The hippocampus develops in the fetal brain by a process of continuing expansion of the medial edge of the temporal lobe in such a way that the hippocampus comes to occupy the floor of the temporal horn of the lateral ventricle (Figs. 18-1 and 18-2; see also Fig. 16-10). In the mature brain, therefore, the parahippocampal gyrus on the external surface is continuous with the concealed hippocampus. The hippocampus is C-shaped in coronal section. Because its outline bears some resemblance to a ram's horn, the hippocampus is also called the cornu ammonis; Ammon is an early Egyptian deity with a ram's head. The ventricular surface of the hippocampus is a thin layer of white matter called the alveus, which consists of axons that enter and leave the hippocampal formation. These fibers form the fimbria of the hippocampus along its medial border and then continue as the crus of the fornix after the hippocampus ends beneath the splenium of the corpus callosum (Fig. 18-3).
FIGURE 18-1 Stages in the embryonic development of the hippocampal formation at the margin of the pallium, showing how the external surfaces of the dentate gyrus and cornu ammonis become fused as a result of growth and folding.
Continued growth of the cortical tissue composing the hippocampus is responsible for the dentate gyrus (see Figs. 18-1 and 18-2). This gyrus occupies the interval between the fimbria of the hippocampus and the parahippocampal gyrus; its surface is toothed or beaded, hence the name.
Although the parahippocampal gyrus is included in the limbic lobe as defined anatomically, most of its cortex is of the six-layered type or nearly so. In the region of the gyrus known as the subiculum (see Figs. 18-1 and 18-2), there is a transition between neocortex and the three-layered archicortex of the hippocampus. The anterior end of the parahippocampal gyrus, medial to the rhinal sulcus (see Fig. 13-5), is the entorhinal area.
INTRINSIC ORGANIZATION AND CIRCUITRY
The hippocampus, as seen in transverse (coronal) section has three areas or sectors: CA1, CA2, and CA3. (CA stands for cornu ammonis.) Area CA1 is adjacent to the subiculum, and CA3 is nearest to the dentate gyrus (Fig. 18-4). Three layers are recognized in the hippocampal cortex.
many of them pyramidal in shape, which are the principal cells of the hippocampus. The dendrites of these cells extend into the molecular layer, and their axons traverse the alveus and fimbria on their way to the fornix. Branches, called Schaffer collaterals, pass through the polymorphic and pyramidal cell layers to synapse in the molecular layer with the dendrites of other pyramidal neurons. The pyramidal cell layer is continuous with layer 5 (internal pyramidal) of the neocortex.
FIGURE 18-2 Simplified coronal section through the hippocampal formation (medial surface at the left).
FIGURE 18-3 Fornix and related structures.
FIGURE 18-4 Some neuronal circuits within the hippocampal formation. The zone occupied by principal cells is shaded. Neurons of the hippocampus and dentate gyrus are red, and the axons of afferent neurons are blue. Small black arrows indicate a loop of connections formed by mossy fibers and Schaffer collaterals. CA1, CA2, and CA3 indicate sectors of the hippocampus; CN, tail of caudate nucleus; DG, dentate gyrus; Ent, entorhinal cortex; Fx, fimbria; h, hilus of dentate gyrus; Su, subiculum.
The dentate gyrus also has three layers. The cytoarchitecture differs from that of the hippocampus in that the pyramidal cell layer is replaced by a granule cell layer of small neurons, which are the principal cells of the region. Efferent fibers from the dentate gyrus are known as mossy fibers. They have many branches that synapse with the principal cells of sectors CA3 and CA2.
The large pyramidal cells in area CA1 are exceptionally sensitive to oxygen deprivation and die after only a few minutes without a supply of fresh arterial blood. Pathologists call area CA1 Sommer's sector. The hippocampal pyramidal cells are among the first to be affected in a variety of conditions that lead to loss of memory and intellectual functions, including Alzheimer's disease (see also Chapter 12).
The neuronal circuitry is essentially the same in all mammals, and it has been studied in great detail by neuroscientists attempting to identify cellular events involved in the formation of new memories. One postulated mechanism is long-term potentiation (LTP), which is a property of certain synapses, including those of the Schaffer collaterals and the mossy fibers of the hippocampus. LTP is an increase in synaptic efficacy that follows a few seconds of high-frequency activity of a presynaptic terminal. Increased synaptic efficacy can be attributable to a change on either side of the synapse. The presynaptic terminal may release an increased amount of transmitter with the arrival of an action potential; this happens at synapses of the mossy fibers. Insertion of an increased number
of receptor molecules into the postsynaptic membrane occurs at the synapses of Schaffer collaterals in area CA1. Fewer afferent impulses are then needed to depolarize the postsynaptic cell because more of the transmitter molecules released into the synaptic cleft can bind to postsynaptic receptors. LTP, which lasts for several days, leads to increased activity of affected postsynaptic neurons. A suitable pattern of activity in axons afferent to the hippocampal formation may lead to LTP in certain connected pyramidal and granule cells. These then continue to transmit impulses more frequently than before, even though the original external stimulus has ceased.
The hippocampal formation has four main sources of afferents: the cerebral neocortex, septal area, contralateral hippocampus, and various nuclei in the reticular formation of the brain stem.
The largest contingent of fibers is from the entorhinal area. These fibers follow two routes to the hippocampus (see Fig. 18-4). The axons of the perforant path from the entorhinal area pass through the subiculum and across the base of the hippocampal sulcus to end in the dentate gyrus. The alvear path traverses the subcortical white matter and the alveus to end in the hippocampus. The entorhinal area is part of the primary olfactory area, and it also receives association fibers from the neocortex of the temporal lobe, which, in turn, communicates with widespread areas of neocortex, including the sensory association areas. Through these connections, as well as through others that involve the parahippocampal cortex generally, the perforant and alvear paths keep the hippocampal formation informed of all forms of sensation and of the higher activities of the brain.
Afferent fibers for the hippocampal formation are also present in the fornix and fimbria. They come from the contralateral hippocampus and from the septal area and the closely related basal forebrain cholinergic nuclei of the substantia innominata (see Chapter 12). Commissural fibers cross the midline in the hippocampal commissure, which is described in the next section of this chapter. Other hippocampal afferent fibers in the fornix are from various thalamic and hypothalamic nuclei, the ventral tegmental area (dopaminergic), thelocus coeruleus (noradrenergic), and the serotonergic raphe nuclei (see Chapter 9).
The connections through which the hippocampal formation receives information from the entorhinal area and neocortex are paralleled by connections that provide for spread of activity from the hippocampal formation to the same cortex, and descending projections to the diencephalon and brain stem are also present. The fornix contains numerous afferent fibers, as described in the previous section of this chapter, but it also is the largest efferent pathway of the hippocampal formation.
The human fornix contains more than 1 million myelinated axons. Most of these axons originate in the subiculum. The rest of the axons originate in the hippocampus or are afferent to the hippocampal formation. The efferent fibers first traverse the alveus on the ventricular surface of the hippocampus on their way to the fimbria. The fimbria continues as thecrus of the fornix, which begins at the posterior limit of the hippocampus beneath the splenium of the corpus callosum (see Fig. 18-3). The crus curves around the posterior end of the thalamus and joins its partner to form the body of the fornix beneath the corpus callosum. Here the dorsal hippocampal commissure, which is attached to the ventral surface of the splenium of the corpus callosum, carries fibers from the parahippocampal gyrus of one hemisphere to the hippocampal formation of the opposite hemisphere. (The human brain has only a vestigial ventral hippocampal commissure.)
Above the third ventricle, the body of the fornix separates into columns, each of which curves ventrally in front of the interventricular foramen. Here the anterior commissure lies immediately in front of the column of the fornix (see Fig. 16-7). Some fibers separate from the column just above the anterior commissure; these are distributed to the septal area, anterior part of the hypothalamus, and substantia innominata. The branch of the column of the fornix posterior to the anterior commissure is much larger. It gives off some fibers that end in the lateral dorsal thalamic nucleus and then continues through the
hypothalamus, where most of the axons terminate in the mamillary body.
The mamillary body projects to the anterior nuclei of the thalamus through the mamillothalamic fasciculus (bundle of Vicq d'Azyr), which is readily demonstrable by dissection (seeFig. 11-15). The anterior and lateral dorsal thalamic nuclei are in reciprocal communication with the cingulate gyrus through fibers that travel around the lateral side of the lateral ventricle. The cingulate gyrus is also in reciprocal communication with the parahippocampal gyrus through the cingulum, a prominent association bundle in the limbic lobe (seeChapter 16). The anterior end of the cingulate gyrus and sulcus are connected by association fibers with much of the cortex of the frontal and temporal lobes, and a motor area (seeChapter 15) is also located in this region. There is increased activity in the anterior cingulate cortex when anticipating a movement or a purely cognitive task and also in association with pain and other unpleasant emotional experiences.
FIGURE 18-5 Connections of the hippocampal formation and amygdala in the forebrain and diencephalon, including the circuit of Papez (red) and other connections (blue).
The largest components of the limbic system contain a ring of interconnected neurons. It is named after Papez (the circuit of Papez), who postulated in 1937 that these parts of the brain “constitute a harmonious mechanism, which may elaborate functions of central emotion, as well as participate in emotional expression.” These functions are now believed to be associated more with the amygdala than with the hippocampus. The sequence of components of Papez' circuit, with the names of fiber tracts italicized, is as follows: entorhinal area of parahippocampal gyrus, perforant and alvear paths, hippocampal formation, fimbria and fornix, mamillary body, mamillothalamic fasciculus, anterior thalamic nuclei,internal capsule, cingulate gyrus, cingulum, entorhinal area (Fig. 18-5).
The input to the circuit of Papez (see Fig. 18-5) is from the neocortex, thalamus, septal area, raphe nuclei, ventral tegmental area, and catecholamine nuclei of the reticular formation.
The output is partly to the neocortex but also to regions of the reticular formation that have extensive connections with many parts of the central nervous system. The largest descending pathway is the mamillotegmental fasciculus, which consists of collateral branches of axons in the mamillothalamic fasciculus. These descending fibers terminate in the raphe nuclei of the reticular formation of the midbrain (Fig. 18-6). When thinking of the circuit of Papez, with its inputs and outputs, it is important to remember that ring-like circuits of neurons also exist within the hippocampal formation itself (see Fig. 18-4).
HIPPOCAMPAL FUNCTION: MEMORY
Psychologists and behavioral scientists recognize different types of long-term memory that are processed differently in the brain. Declarative (or explicit) memory is the knowledge and recall of facts or events that can be recalled to consciousness. The acquisition of an item into declarative memory typically occurs on a single occasion. Any fact or event is initially held in short-term memory. It may be forgotten during the course of the next hour or so; if not, it is moved into long-term storage. If declarative memories are not recalled from time to time, the process of recall will require mental effort or the memories may be forgotten. Procedural (or implicit) memory is for learned skills, including regularly performed motor tasks and mental activities such as using the common vocabulary and grammatical rules of a language. The learning occurs gradually, and recall is improved with repetition and practice. The best understood functions of the hippocampal formation are the retention of information in short-term memory and its transfer into long-term declarative memory.
FIGURE 18-6 Pathways leading into (blue) and out of (red) the telencephalic and diencephalic components of the limbic system.
The consolidation of recent memories may occur during sleep when the serotonergic raphe neurons that project to the hippocampal formation are active (see Chapter 9). In deep sleep, when the electroencephalogram (EEG) recorded over the neocortex shows regular, synchronized rhythms, the hippocampal EEG (recorded with a needle electrode) is desynchronized. In the waking state, the neocortical record is desynchronized, and the hippocampus generates a slow, regular rhythm.
Synaptic long-term potentiation was mentioned earlier as a postulated mechanism for the storage of recent memories by the hippocampus. The formation of permanent memory traces may involve the synthesis of new proteins and the formation of new synapses. The neuronal changes (sometimes called engrams)
representing long-term memory, both declarative and procedural, are believed to be present throughout the parieto-occipitotemporal and frontal association cortex, and some investigators suspect that the corpus striatum, thalamus, and cerebellum are also involved.
Impairment of memory is evident after bilateral temporal lobectomy (described later in this chapter) or lesser degrees of injury that bilaterally affect the hippocampal formation or its associated pathways. The hippocampus and its connections are necessary for the consolidation of new or short-term memories. The evidence for this function comes from many clinical observations, which generally agree with experimental results obtained in animals.
Loss of hippocampal function can occur if an arterial occlusion has caused an infarction in the hippocampal formation of one side and is followed at a later time by a similar infarction in the other hemisphere. More commonly, the intact hippocampus is deprived of oxygen for only a short time, after which the patient suddenly becomes unaware of the events of the preceding few hours and is temporarily unable to form new memories. The condition is known as transient global amnesia. Cerebral anoxia from any cause can, as mentioned earlier, cause death of the principal neurons of Sommer's sector (i.e., CA1) of the hippocampus bilaterally. Many patients resuscitated after cardiac arrest of more than a few minutes' duration are left with defective memory for this reason.
Concussion is loss of consciousness and retrograde amnesia for events immediately preceding a head injury. It is not caused by permanent brain damage. The hippocampi can be damaged by hemorrhage when a head injury causes the temporal poles to strike the greater wings of the sphenoid bone, which form the anterior wall of the middle cranial fossa. Anterograde amnesia, with impaired consolidation of new declarative memories, is a common consequence of more severe head injuries.
Bilateral hippocampal lesions interrupt the major circuit of the limbic system. Interruption of the same pathway outside the hippocampal formation, such as occurs when both mamillary bodies are involved in a destructive lesion, also results in a memory defect. Amnesia may also occur after development of bilateral lesions in the mediodorsal nuclei of the thalamus. The mediodorsal nuclei are connected with the prefrontal cortices, and these are involved in higher mental functions, although not specifically with memory. Medial thalamic lesions are likely to interrupt the mamillothalamic fibers as well, however. Bilateral surgical transection of the fornix, performed in attempts to limit the spread of epileptic discharges or in the course of removing tumors from the region of the third ventricle, has caused severe amnesia.
Animal experiments indicate that the cholinergic neurons of the substantia innominata in the basal forebrain (see Chapter 12), which project to the hippocampus and all parts of the cerebral cortex, are involved in memory. The inability to form new memories in Alzheimer's diseasemay be caused partly by loss of these cholinergic projections (see Chapter 12), but degenerative changes in the entorhinal cortex and hippocampus also occur early in the course of this disorder, and in the late stages, extensive neocortical atrophy occurs.
Patients with any of these lesions forget information obtained recently but retain the ability to recall old memories. When the hippocampi or the circuits of Papez are no longer functional, memories of earlier events are retained because these have already been established, presumably as macromolecular changes throughout the cerebral cortex. These patients have amnesia for events that occurred more recently than the lesion because the mechanism for retention or consolidation of new or short-term memory is no longer operating. Most lesions in the diencephalon (thalamus and mamillary bodies) are attributable to metabolic disturbances caused by alcoholism. In the resulting syndrome (Korsakoff's psychosis), the patient inserts remembered events from the remote past into fluent but blatantly untrue stories, attempting to compensate for the absence of more recent memories.
Localized lesions do not affect old memories, although these are eventually lost along with other mental capabilities when advanced dementia caused by severe and widespread degeneration of the cerebral cortex is present.
Amygdaloid Body (Amygdala)
The amygdaloid body consists of several groups of neurons situated between the anterior end of the temporal horn of the lateral ventricle and
the ventral surface of the lentiform nucleus (Fig. 18-7). The dorsomedial division of the amygdaloid body, known as the corticomedial group of nuclei, blends with the cortex of the uncus. Its afferent fibers come from the olfactory bulb, and it is part of the lateral olfactory area (see Chapter 17). The larger ventrolateral division consists of the basolateral andcentral groups of nuclei, which have no direct input from the olfactory bulb, although they connect with the corticomedial nuclei and with the cortex of the entorhinal area. The central and basolateral groups are included in the limbic system on the basis of the results of experiments that involve stimulation and ablation in laboratory animals and clinical observations in humans.
CONNECTIONS OF THE AMYGDALA
The basolateral group has widespread connections, most of which are not in the form of well-defined fiber bundles. Using the shortest routes, reciprocal connections with cortex of the frontal and temporal lobes and the cingulate gyrus are present. Subcortical afferent fibers come from the thalamus (intralaminar nuclei) and the catecholamine nuclei, raphe nuclei, and parabrachial nuclei of the reticular formation. Some of these afferents carry signals relating to painful stimuli. Also present are dopaminergic afferents, mostly from theventral tegmental area and some from the substantia nigra, and cholinergic fibers from the basal forebrain nuclei in the substantia innominata.
FIGURE 18-7 Coronal section through the amygdaloid body and neighboring parts of the brain, stained by a method that differentiates gray matter (dark) from white matter (light).
The central nuclei of the amygdala receive afferent fibers from both the olfactory corticomedial and the nonolfactory basolateral nuclei. The projections of the central nuclei are similar to those of the basolateral group, described in the following paragraphs.
The principal connections of the basolateral and central groups of nuclei of the amygdala are shown in Figures 18-5 and 18-6. Reciprocal connections with neocortical areas (prefrontal and temporal lobes and anterior cingulate gyrus) are prominent. The projections to the
prefrontal cortex are modulated by circuitry involving the nucleus accumbens and ventral pallidum, explained in Chapter 12.
The most conspicuous efferent bundle of the amygdala is the stria terminalis. This slender bundle of axons (see Fig. 16-9) follows the curvature of the tail of the caudate nucleus, continuing along the groove between the caudate nucleus and thalamus in the floor of the central part of the lateral ventricle. Most of the constituent fibers terminate in the septal area and in the preoptic area and anterior hypothalamus. Other axons in the stria terminalis enter the medial forebrain bundle and go to various parts of the brain stem, including the dorsal nucleus of the vagus nerve and the solitary nucleus, which have visceral functions (see Chapters 8 and 24).
The stria terminalis is a long tract because it follows the curve of the lateral ventricle. Other efferent fibers of the amygdala form a shorter ventral amygdalofugal pathway, which passes through the diagonal band of Broca, a body of white matter within the anterior perforated substance. The ventral amygdalofugal pathway carries axons from the amygdala to the septal area; to the nucleus accumbens (ventral striatum); and to the dorsomedial nucleus of the thalamus, which projects to the prefrontal cortex. There are also direct connections between the amygdala and the prefrontal cortex (Fig. 18-5).
The septal area is a major target of projections from the amygdala. The septal area sends fibers in the stria medullaris thalami to the habenular nuclei. These project through thefasciculus retroflexus (habenulointerpeduncular tract) to the interpeduncular nucleus, and the pathway continues through the reticular formation to autonomic nuclei. The habenular nuclei also receive some afferent fibers from the globus pallidus, providing a pathway through which the neocortex and the corpus striatum can influence autonomic functions. Direct hypothalamospinal fibers in the dorsal longitudinal fasciculus provide another pathway whereby the limbic system is able to influence preganglionic autonomic neurons.
FUNCTIONS OF THE AMYGDALA
The behavioral and emotional functions of the limbic system are chiefly associated with the central and basolateral nuclei of the amygdala. In ordinary speech, the word emotionrefers to subjective feelings that are difficult to define. Neuroscientists also use this word for activities of the brain evoked by incentives for survival. Emotional responses, therefore, include running away from a potential predator, drinking when thirsty, sweating when hot, and responses to the presence of a potential mate or rival.
Functional nuclear magnetic resonance imaging (fMRI) studies show variation in activity of the amygdala when a person is looking at pictures that evoke different emotional feelings. Electrical stimulation of the amygdala in conscious humans evokes feelings of fear and sometimes of general irritability or even anger. Injury or disease of the amygdala is usually combined with damage to the hippocampal formation and sometimes also the visual association cortex of the temporal lobe, thereby causing a mixture of behavioral and cognitive disturbances.
Temporal Lobe Disorders
EFFECTS OF DESTRUCTIVE LESIONS IN BOTH TEMPORAL LOBES
In monkeys, complete removal of both temporal lobes leads to the Klüver-Bucy syndrome, consisting of docility, loss of the ability to learn, excessive exploratory behavior using the mouth more than the hands, visual agnosia, and (in males) abnormal sexual activity. Smaller lesions have less bizarre consequences, with dysfunction partly attributable to the loss of individual parts of the limbic system.
Bilateral removal of the temporal pole, including the amygdaloid body and much of the hippocampal formation, is followed by docility and lack of emotional responses such as fear or anger to situations that normally arouse those responses. Male animals exhibit increased sexual activity, and the sexual drive may be perverted, being directed toward either gender, a member of another species, or even inanimate objects. Lesions confined to the amygdaloid bodies produce similar changes, with sexual behavior less affected. With lesions that also include the
hippocampi, the animals can no longer be trained to perform tricks or carry out tasks, having evidently lost the ability to learn anything new.
Human Bilateral Lesions
In humans, removal or destructive disease of both temporal lobes sometimes results in a voracious appetite, increased (sometimes perverse) sexual activity, and flattened affect. These abnormalities, together with visual agnosia, can occur also after head injury, in viral infections of the brain, and in some patients with Alzheimer's disease. An intensively studied individual case is “H.M.,” who underwent removal of the medial parts of both temporal lobes as treatment for epilepsy in 1953 at age 27 years. Since the operation, H.M. has been unable to remember any new fact or event for more than 5 minutes. Despite the large sizes of his temporal lobe lesions, H.M. does not have other features of the Klüver-Bucy syndrome.
TEMPORAL LOBE EPILEPSY
Epilepsy is a condition in which abnormal synaptic excitation causes uncontrolled propagation of action potentials in the brain. Such an episode (variously called an attack, fit, or seizure) may begin with sensory symptoms or a subjective feeling of strangeness, known as anaura. The nature of the aura may provide a clue to the location of the epileptogenic focus in which the abnormal activity is initiated. During the attack, a loss of consciousness or at least of full awareness of the surroundings occurs, and generalized convulsions attributable to stimulation of motor neurons commonly occur. Jacksonian epilepsy, arising from a focus in the primary motor cortex, was mentioned inChapter 15. Petit mal is a type of childhood epilepsy that causes frequent episodes of loss of consciousness, each lasting less than 1 second, known as absence seizures. It is associated with a characteristic spike-and-wave appearance in the EEG, and it may arise from a focus in the thalamus. The term grand mal is applied to forms of epilepsy associated with convulsions. Between attacks, the EEG includes bursts of high-voltage spikes and large low-frequency waves.
The most frequent site of an epileptogenic focus is the medial surface of the temporal lobe, which can be damaged by the nearby tentorium cerebelli (see Chapter 25) when the head is squeezed during birth. Neurons near the resulting scar constitute the focus, which is often in the amygdala, the anterior end of the hippocampus, or the entorhinal area. In many cases, the seizure activity does not spread to the whole brain, and the diagnosis may be overlooked because of the absence of convulsions. An attack often begins with a hallucination of a nasty but unidentifiable smell caused by stimulation of the cortex of uncus and corticomedial nuclei of amygdala. The aura commonly includes déjà vu,which is an unnatural feeling of familiarity with the surroundings and circumstances, attributed to activity in the hippocampal formation, amygdala, and sensory association cortex of the temporal lobe. As the attack continues, there are feelings of fear and anxiety (stimulation of central and basolateral nuclei of the amygdala) and autonomic manifestations such as sweating, tachycardia (fast heart rate), and peculiar abdominal sensations (stimulation of amygdala, insular cortex, hypothalamus, and preganglionic sympathetic neurons). Rarely, there may be irrational speech and behavior that the patient does not remember afterward.
Antiepileptic drugs act by various mechanisms, including partial blockade of sodium and other ion channels and potentiation of the action of GABA, the transmitter at most inhibitory synapses (see Chapter 2). The drugs reduce the frequency and severity of attacks. It is sometimes feasible to cure the condition by locating the epileptogenic focus and removing it surgically. The anterior part of one temporal lobe may be removed for this purpose, but the surgeon must first ensure that the other temporal lobe is intact. It is also necessary to avoid damage to Wernicke's receptive speech area (see Chapter 15), which is located in the temporal lobe of the cerebral hemisphere that is dominant for language.
When bilateral ablations extend to the posterior parts of the temporal lobes, the animal has all the abnormalities mentioned previously and is also unable to recognize things that it sees. It compensates by exploring objects with its mouth. This visual agnosia, termed “psychic blindness” by Klüver and Bucy in 1937, is now attributed to loss of visual association cortex concerned with formed images in the posterior part of the inferior temporal gyrus (see Chapters 15 and 20). The excessive oral exploration leads to excessive eating.
Inappropriate activity of the amygdala may occur in abnormal mental states with excessive symptoms of anxiety. Patients may experience severe episodes (panic attacks) of excessive activity of the sympathetic nervous system or a generalized condition dominated by subjective feelings of worry with motor manifestations such as muscle tension and jitteriness. Anxiolytic drugs (useful for the treatment of anxiety states) include the benzodiazepines such as chlordiazepoxide, diazepam, and several others with names ending in -azepam. These drugs enhance the action of the inhibitory neurotransmitter GABA by binding to a subtype of its postsynaptic receptor that occurs abundantly on the surfaces of neurons in the amygdala and other parts of the limbic system.
In several psychiatric disorders, great suffering results from depression, which is an abnormal condition quite different from the sadness anyone can experience in appropriate circumstances. Drugs that relieve depression enhance the synaptic actions of noradrenaline and serotonin, either by blocking the reuptake of the amines into presynaptic terminals (tricyclic antidepressants such as amitriptyline and imipramine) or by inhibiting monoamine oxidase, an enzyme that catalyzes the oxidative degradation of noradrenaline and serotonin. Other antidepressive drugs selectively inhibit serotonin reuptake (SSRIs such as fluoxetine and paroxetine). Most of the neurons that use amines as transmitters are located in the brain stem (see Chapter 9). Their greatly branched axons end in gray matter throughout the forebrain, including all parts of the limbic system.
EMOTIONAL AND VISCERAL RESPONSES
Experimental and clinical studies have led to the view that the normal limbic system, especially the amygdala, is responsible for such strong affective reactions as fear and anger and the emotions associated with sexual behavior. Changes in visceral and somatic motor function accompany these emotions, and electrical stimulation of the amygdala has been shown to produce similar responses. These include increased heart rate, suppression of salivation, increased gastrointestinal movements, and pupillary dilatation. Respiratory and facial movements also are changed, and patients have generalized irritability, typically manifested as sudden movements (startle reaction) in response
to a slight sensory stimulus. Electrical stimulation of the amygdala in humans induces feelings of fear or anger. These observations may indicate that activity in the amygdala gives rise to the autonomic and somatic accompaniments of fear and anxiety.
Abnormalities of the limbic system have also been found in schizophrenia. In this disease, the processes of thinking are profoundly disturbed, with delusions, auditory hallucinations, inability to make associations between ideas, and reduced emotional expression. Careful anatomical measurements show that the hippocampal formation, amygdala, and parahippocampal gyrus are smaller than normal in the brains of schizophrenic patients, possibly as a result of abnormal growth of these parts of the brain.
Drugs that alleviate the clinical features of schizophrenia (antipsychotic agents) antagonize the actions of dopamine, which is the principal neurotransmitter of the neurons in the ventral tegmental area that project to the amygdala, nucleus accumbens, hippocampal formation, and prefrontal cortex. None of these drugs are entirely selective in their actions on dopamine receptors; they also block noradrenaline and serotonin receptors. Antipsychotics of one group, the dibenzodiazepines typified by clozapine, antagonize the actions of noradrenaline and serotonin more strongly than those of serotonin. Not surprisingly (see Chapter 7), the drugs that strongly antagonize dopamine (especially the butyrophenones, typified by haloperidol) can cause parkinsonism as a side effect. Prolonged treatment may also lead to a movement disorder called tardive dyskinesia in which choreiform movements (see Chapter 12) of the lips and tongue are prominent. Unlike the parkinsonian side effect, tardive dyskinesia quite frequently persists after withdrawal of the drug.
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