Related Basal Forebrain Nuclei
The adjoining nuclei of the bed nucleus of the stria termi-nalis, nucleus accumbens, and substantia innominata also link these regions of the limbic forebrain with the hypothalamus and midbrain tegmentum (Fig. 25-7, see also Fig. 13-15). The bed nucleus of the stria terminalis receives significant inputs from various nuclei of the amygdala and projects its axons to both the hypothalamus and midbrain PAG. Thus, it serves as a parallel pathway by which the amygdala can modulate visceral functions of the hypothalamus and PAG. Some authors view the nucleus accumbens as a region that integrates motor and motivational processes associated with the basal ganglia and limbic system, respectively. Projections from this region include short axons to the substantia innominata, whose axons are then directed onto the hypothalamus and amygdala (as well as to wide regions of cortex). Other projections of the nucleus accumbens descend to the ventral tegmentum. The ventral tegmentum is a major source of dopaminergic fibers to the limbic system and neocortex. Thus, inputs into the ventral tegmentum from the nucleus accumbens can serve to regulate neuronal activity within much of the limbic system. Monoaminergic inputs into the limbic system are believed to provide a basis for the regulation of mood states. Accordingly, the inputs from the nucleus accumbens may play an important role in controlling this process.
A region of the substantia innominata, called the basal nucleus of Meynert (see Fig. 13-15), is of particular interest with respect to the development of Alzheimer’s disease. The basal nucleus of Meynert lies immediately lateral to the horizontal limb of the diagonal band. Like the diagonal band nuclei, the neurons of the basal nucleus are cholinergic and project to wide regions of the cerebral cortex and limbic system. Alzheimer’s disease, which is associated with severe loss of memory functions, is correlated with: (1) the presence of neurofibrillary tangles, (2) extracellular deposition of the abnormal amyloid protein P-amyloid cortex plaques in the cerebral cortex, and (3) cell loss in the basal nucleus and reduced cholinergic content of cortical tissue. Because of the widespread projections of the basal nucleus to limbic structures, it is possible that disruption of these connections may contribute to the affective changes seen in these Alzheimer’s patients. Moreover, evidence further suggests that neuronal cell damage may not be limited to the basal nucleus but may also include limbic nuclei as well. Limbic structures believed to contain cell loss in Alzheimer’s patients include the diagonal band of Broca and the subicular cortex. Recent studies have suggested that the amyloid deposits result from a mutation of the gene that encodes the amyloid precursor protein. Moreover, the e4 allele of the apol-ipoprotein E situated on chromosome 19 has been shown to be a risk factor for onset of Alzheimer’s disease. One approach to combating this disorder involves drug therapy.
FIGURE 25-7 Efferent projections of the amygdala. The diagram in the upper panel indicates the organization of the nuclei of the amygdala. Schematic diagram in the lower panel identifies the major efferent projections of the amygdala. One principal output includes the stria terminalis, which projects to the bed nucleus of the stria terminalis and to the rostro-caudal extent of the medial hypotha-lamus. Fibers from the bed nucleus also supply similar regions of the hypothalamus. Another important output to the hypothalamus and midbrain periaqueductal gray matter (PAG) uses the ventral amygdalofugal pathway. Other fibers pass rostrally from the amygdala to the prefrontal cortex.
One drug, called Alzhemed (still in clinical trials at the time of publication), has been reported to function as an anti-amyloid compound and may be effective in reducing the effects of amyloid fibers in the cerebral cortex. Another drug that has been used for the treatment of Alzheimer’s disease is Aricept, a reversible acetylcholinesterase inhibitor.It has met with some success with patients in nursing homes.
Amygdala
Histology
The amygdala is located deep to the uncus in humans and comprises various nuclei, which differ in their anatomical connections and neurochemical and physiological properties. The amygdala contains a cortical mantle called the pyri-form lobe that provides significant input to the amygdala and is, thus, functionally associated with it. The major groups of nuclei include the lateral, basal, medial, anterior, central, and cortical nuclei. However, from a functional point of view, it is convenient to divide the amygdaloid complex into two components: (1) a corticomedial group, which includes mainly the cortical, medial, and medial aspect of the basal nuclei that lie within its dorsal and medial aspects, and (2) a basola-teral group, which includes the lateral, central, and lateral aspects of the basal nuclei (see Figs. 1-7, 25-7). As indicated earlier, the amygdala is intimately related to the pyriform lobe. The cortex immediately adjacent to the amygdala at rostral levels of this structure is referred to as the prepyriform area, and more posterior regions of the pyriform lobe are referred to as the periamygdaloid cortex.
Afferent Connections
Like the hippocampal formation, the amygdala receives inputs from sensory and monoaminergic systems. Afferent fibers to the amygdala arise from structures linked with transmission of both olfactory and taste signals. These include direct inputs from the olfactory bulb, indirect inputs from the pyriform lobe (which also receives affer-ents from the olfactory bulb), and direct and indirect inputs from the solitary nucleus. The amygdala also receives inputs from the neocortex. These include auditory signals from the temporal neocortex and integrative signals from the prefrontal cortex. Additional regions of the forebrain projecting (nonsensory) information to the amygdala include the ventromedial hypothalamus, sub-stantia innominata, nuclei of the diagonal band of Broca, and medial thalamus.
Efferent Connections
The most significant projections of the amygdala are those that innervate the hypothalamus, bed nucleus of the stria terminalis, and midbrain PAG. These projections are deemed to be highly significant because they provide the anatomical substrate by which the amygdala regulates visceral processes normally associated with these structures.
Consider first the amygdaloid projections to the hypothalamus. Communication from the amygdala to the hypoth-alamus can be achieved by direct or indirect pathways. Direct routes involve the stria terminalis and ventral amygdalofugal pathway. The stria terminalis arises mainly from the corticomedial group of nuclei, and a primary projection of these fibers is directed to the rostro-caudal extent of the preopticomedial hypothalamus. The ventral amy-gdalofugal pathway arises mainly from the basolateral complex of amygdala, passes deep to the pyriform cortex, and supplies primarily the lateral hypothalamus and mid-brain PAG (Fig. 25-7). These two groups of fibers enable the corticomedial amygdala to directly control the medial hypothalamus and enable the basolateral amygdala to directly control the lateral hypothalamus and PAG. The amygdala can also modulate activity of the hypothalamus and PAG indirectly. It does so by virtue of its connections with the bed nucleus of the stria terminalis, which, in turn, project directly to these structures. The amygdala also maintains a significant anatomical relationship with the prefrontal cortex with which it shares reciprocal connections.
Functions and Dysfunctions of the Amygdala
Perhaps of all the limbic structures, it is the amygdala that exerts the most potent control over visceral processes of the hypothalamus. Many studies have been conducted that involved ablations, lesions, and electrical stimulation to identify the role of the amygdala in aggression and rage, feeding, and cardiovascular and endocrine functions.
One of the classic studies depicting the behavioral effects of amygdaloid ablations was carried out in 1937 by Kluver and Bucy. They described a constellation of behavioral response changes as a result of amygdaloid lesions in the monkey, which consisted of hypersexuality, a change in dietary habits, a decrease in anxiety toward fear-producing objects, a tendency to orally explore and contact inedible objects, and visual agnosia. These response tendencies are referred to as the Kluver-Bucy syndrome. However, in humans, only some of these symptoms are typically seen in a given patient.
Other studies, however, have demonstrated that the modulating properties of the amygdala on aggressive behavior are not uniform. Different regions of amygdala exert differential effects on different forms of aggressive behavior. For example, stimulation of the corticomedial amygdala has a powerful, facilitating effect on defensive rage behavior but has an equally potent suppression on predatory attack behavior. In contrast, stimulation of the basolateral region of amygdala has just the opposite effects on these forms of aggressive behavior. Some of the underlying mechanisms have also been discovered. Medial amygdaloid potentiation of defensive rage behavior is mediated by fibers of the stria terminalis that excite medial hypothalamic neurons and that use s ubstance P as a neurotransmitter, whereas central and lateral amygdaloid suppression of this form of aggression is mediated through an inhibitory enkephalinergic projection to the midbrain PAG.
Studies concerning the relationship of the amygdala to aggression and rage have also been reported in humans. In such studies, which are usually carried out in cases with intractable epilepsy, lesions have been reported to produce a general taming effect, with decreases in aggressive and explosive behaviors and decreases in hyperactivity. The loci of the lesions (presumably involving mainly the amygdala) have not been clearly identified. However, studies involving tumors of this region have often been associated with increases in rage behavior, impulsivity, and loss of emotional control in response to an event that normally would be perceived as a minor annoyance to most people.
Electrical stimulation of the amygdala in both animals and humans does not produce aggressive responses. In humans, it has been reported that stimulation can evoke different types of emotional feelings such as relief, relaxation, detachment, and a general pleasant sensation.
Stimulation of the amygdala has likewise produced different effects on the cardiovascular system. Generally, pressor responses appear to be dominant, such as increases in blood pressure, heart rate, and pupillary dilation, especially in regions that facilitate defensive rage behavior (i.e., corticomedial amygdala). Stimulation of the amygdala has also been reported to produce micturition and occasional depressor responses.
The amygdala has also been shown to play a role in other functions. This area of the limbic system modulates feeding and drinking functions associated with the hypoth-alamus. Stimulation and lesion studies suggest that the basolateral amygdala has a facilitative effect, whereas the corticomedial region is inhibitory. The amygdala also affects endocrine function. Stimulation of the corticome-dial amygdala can induce ovulation, whereas transection of the stria terminalis abolishes this response. Moreover, activation of the basolateral amygdala facilitates growth hormone release, whereas the corticomedial amygdala inhibits growth hormone release. Basolateral amygdaloid stimulation and lesions of the corticomedial region also facilitate the release of ACTH. Collectively, it appears that the pathways arising from basolateral and corticomedial amygdala that target the lateral and medial regions of hypothalamus (and midbrain PAG) serve to differentially modulate the various visceral functions normally associated with the hypothalamus.
The amygdala also plays an important role in the organization and regulation of fear responses. Specifically, experimental studies have identified circuits that include the amygdala in mediating conditioned fear responses in rodents to auditory stimuli. In brief, the regions of the central and related amygdaloid nuclei receive direct auditory inputs from the medial geniculate nucleus and indirect auditory inputs from the temporal (auditory) cortex. The neural circuits mediating the conditioned fear response to auditory stimuli are integrated in the amygdaloid nuclei and are expressed through the outputs of the amygdala to the brainstem and, ultimately, to spinal cord and cranial nerve sensory and motor nuclei, which provide the basis for the associated emotional responses. Damage to components of this circuit lead to a diminution or loss of the fear responses. It is also of interest to note that, in humans, there is a rare disorder involving calcification of parts of the anterior aspect of the temporal lobe which includes the amygdala. Patients with this disease (referred to as the Urbach-Wiethe disease), may have difficulties in recognizing stimuli that one would normally characterize as fearful.
Limbic Components of the Cerebral Cortex
Anatomical Connections
The prefrontal cortex and the anterior cingulate gyrus are included as parts of the limbic system principally because they send indirect projections to the hypothalamus and have been shown to modulate functions normally associated with the hypothalamus. It should be noted, however, that some of the functions of both the prefrontal cortex and anterior cingulate gyrus are likely mediated through projections to other parts of the brain as well. These include the basal ganglia, other regions of cerebral cortex, brainstem nuclei, and thalamic structures.
As a cortical structure, the prefrontal cortex is unique in that it receives afferent fibers from all regions of the cerebral cortex. It also receives inputs from all brainstem monoaminergic systems and limbic-related structures. These structures include the mediodorsal thalamic nucleus (with which it shares reciprocal connections), lateral hypothalamus, nuclei of the diagonal band of Broca, baso-lateral amygdala, and subicular cortex. Fibers arising from the prefrontal cortex project to the temporal neocortex and to deep temporal lobe structures, which include the amygdala and subicular cortex. The influence of the pre-frontal cortex on hypothalamic functions is mediated via both direct and indirect routes. The direct route has recently been discovered and involves a monosynaptic projection from the prefrontal cortex to the hypothalamus. The indirect route involves an initial projection to the mediodorsal nucleus, and through a series of interneurons directed rostrally from the mediodorsal nucleus and mid-line thalamus, impulses from the prefrontal cortex can also reach the anterior lateral hypothalamus (see Fig. 24-3).
The anterior cingulate gyrus receives inputs from the following areas: (1) the anterior thalamic nucleus, (2) dopaminergic fibers that arise in the ventral tegmental area, and (3) the diagonal band of Broca. Efferent fibers of the anterior cingulate gyrus project to the mediodorsal thalamic nucleus and to the subicular cortex. In this manner, the anterior cingulate gyrus can also modulate visceral processes by using the same circuitry to the hypothalamus as is used by the prefrontal cortex (i.e., mediodorsal thalamic nucleus ^ midline thalamic nuclei ^ anterior lateral hypothalamus). Other parts of the cingulate gyrus project through the cingulum bundle to the hippocampal formation, forming a component of the Papez circuit (Fig. 25-4), and may function to modulate memory functions.
Functions of the Cerebral Cortex
Prefrontal Cortex
The prefrontal cortex experiences significant evolutionary changes. It is rudimentary in rodents; is more clearly identifiable in the cat; and becomes considerably larger in primates, reaching its largest relative size in humans, which suggests an increasingly important role for this region.
The prefrontal cortex is associated with both emotional and intellectual processes. Concerning emotional behavior, stimulation of either the orbital frontal region or the medial aspect of the prefrontal cortex powerfully suppresses predatory attack and defensive rage responses elicited from the hypothalamus as well as spontaneously elicited aggressive behavior. The inhibitory effects of the prefrontal cortex on the attack response are dependent on an intact pathway from the prefrontal cortex to the mediodorsal nucleus. When this pathway is severed or when a lesion is placed in the mediodorsal nucleus, the inhibitory effects of prefrontal cortex stimulation are blocked.
The importance of the human prefrontal cortex in the control of human aggression has also been recognized for many years. The first reported case of prefrontal damage was reported in the middle of the 19th century as a result of an industrial accident in Vermont of a railroad worker named Phineas Gage. Gage was wounded by a spike that pierced through his skull, severing the prefrontal region of his brain. Amazingly, he was able to recover from the incident without significant motor damage. However, soon afterwards, he began to experience significant emotional and personality changes, characterized principally by irritable, irrational, and hostile behavior, all of which were absent prior to the accident. Therefore, these observations would suggest that the prefrontal cortex normally inhibits aggression and rage behavior.
Therefore, it was surprising that a technique called pre-frontal lobotomy was developed in 1936 by Egaz Moniz for controlling human violence and manifestations of psychotic behavior that involved the undercutting of the afferent and efferent connections of the prefrontal cortex. For developing this procedure, Moniz received a Nobel prize. The procedure had met with some minor success, and some mild personality changes were reported on varying occasions. However, consistent effects in reducing aggressive tendencies were never reported over extended periods of time. The use of prefrontal lobotomies has been replaced by other (noninvasive) therapeutic measures such as antipsychotic drugs. Accordingly, such surgical procedures are rarely performed at the present time.
The prefrontal cortex also exerts a powerful modulatory effect on other processes associated with the hypothalamus. For example, lesions of the prefrontal cortex lead to an increase in feeding behavior, while stimulation of this region inhibits feeding. Electrical stimulation also inhibits respiratory movements, changes blood pressure, inhibits gastric motility, and raises the temperature of the extremities.
With respect to intellectual functions, lesions of the prefrontal cortex also have profound effects. Perhaps one of the clear-cut demonstrations of loss of function following prefrontal lesions involves experiments conducted on animals in which delayed alternation tests were used. In this type of experiment, the animal is shown which of two places food has been placed. However, the animal must learn to postpone its response for a specific length of time. Normally, an intact animal will master this task within a short period of time. However, animals sustaining lesions of the prefrontal cortex commit many errors, mostly relating to failure to wait the requisite amount of time before eliciting the response. In addition, if the prefrontal damaged animal has to discriminate between two sounds or between two visual signals, many more errors are committed than by intact animals.
In humans, patients sustaining damage to the prefrontal cortex also display a number of characteristic intellectual and perceptual deficits. The patients experience difficulty in accurately identifying the perceived vertical when the body is placed in a tilted position. If these patients are given a card-sorting task in which they are asked to sort the cards on the basis of color, shape, or number of figures on the card, they can easily master this task until they are requested to shift the criterion for categorization (i.e., change from shape to numbers). Under these circumstances, these patients tend to persevere with their original strategies and appear to lose sight of the original purpose of their goals and objectives. These behavioral dysfunctions can be characterized as a "derangement in behavioral programming," which likely involves a disruption of the connections between the frontal lobe and parietal and temporal cortices.
Anterior Cingulate Gyrus
Experimental evidence suggests that the anterior cingulate gyrus also plays an important role in the regulation of visceral processes, which are, in part, associated with the hypothalamus. For example, electrical stimulation of this region of cortex suppresses predatory attack behavior elicited from the lateral hypothalamus in the cat, whereas lesions facilitate the occurrence of this response in several species. Case history studies have revealed that, in humans, tumors of this region have been associated with aggressive responses, whereas electrical stimulation produces respiratory arrest, a fall in blood pressure, and cardiac slowing. Thus, it would appear that the anterior cingulate gyrus functions similarly to the prefrontal cortex in that it exerts a general suppressive effect on a variety of visceral processes associated with hypothalamic functions, in addition to its reported effects on aggressive behavior. However, as noted earlier, it is quite possible that the modulating effects of the prefrontal cortex and cingulate gyrus with respect to these functions are also mediated through different circuits on other groups of neurons in the forebrain and brainstem.
