The term limbic lobe was coined by Broca in 1878 to describe a series of structures that envelop the brain stem. The word limbic is derived from limbus, meaning border in Latin, and the limbic system encompasses the amygdala, hippocampus, septum, cingulate gyrus, cingulate cortex, hypothalamus, epithalamus, anterior thalamus, mammillary bodies, and fornix. The limbic system has rich connections throughout the brain, particularly with the primary sensory cortices, including the rhinencephalon for smell, the autonomic nervous system via the hypothalamus, and memory areas. Papez, in 1937, was first to use clinical information obtained from patients with brain tumors in support of his proposed limbic mechanism of emotion and memory. Since that time, others have reported a correlation of abnormalities of this region with disorders of emotion, mood, and thought.
Starkstein and colleagues studied 11 patients with manic syndromes associated with brain injuries and demonstrated that secondary mania correlated with the presence of either anterior subcortical atrophy or a focal lesion of a limbic or limbic-connected region of the right hemisphere. [6 Follow-up studies of additional patients along with analysis of other cases of secondary mania from the literature indicated that the causative brain lesions were located mainly in limbic and limbic-related areas that have connections with the frontal lobes.  ,  More recently, positron emission tomography (PET) studies performed on subjects experiencing transient sadness with recall of unhappy memories showed bilateral activation of paralimbic structures, whereas happy memories were associated with a widespread reduction in cortical cerebral blood flow.
The limbic system has also been implicated in such thought disorders as schizophrenia. In one study reporting magnetic resonance imaging (MRI) and cerebral blood flow studies in twins who were discordant for schizophrenia, the hippocampal area of nearly all affected individuals was smaller. Additionally, a number of well-controlled observations of postmortem brain samples of schizophrenics revealed a decrease in the size of the region including the amygdala, the hippocampus, and the parahippocampal gyrus.
The amygdala, a core part of the limbic system, has been the focus of particular research attention in the evaluation of mood and emotion. This structure, named for its almond shape, sits medially in the anterior temporal lobe above the hippocampal formation. It consists of two main nuclear regions and about a dozen individual nuclei, each with distinct cytological and histochemical features. The amygdala is in contact with the tail of the caudate nucleus, but it is dissimilar from this region from both structural and evolutionary viewpoints. Afferent inputs to the amygdala are varied and include projections from the olfactory cortex, hypothalamus, and thalamus. The two major efferent projections from the amygdala are the stria terminalis and the ventral amygdalofugal pathway. The former supplies the hypothalamus, the nucleus accumbens, and the bed nucleus of the stria terminalis. The latter projects to the hypothalamus, dorsal medial nucleus of the thalamus, and the cingulate gyrus. The amygdala also projects in a reciprocal fashion to brain stem nuclei involved in the autonomic changes that accompany fear and stress-related responses. Projections to somatosensory cortex and most of the temporal lobe have also been demonstrated.
The connections between the amygdala and the hypothalamus and visceral brain stem nuclei explain the complex physiological responses that occur with mood changes in general, specifically fear and the "fight or flight" response. Stimulation experiments in animals produce a variety of autonomic responses. The most common response is an accelerated respiratory rate with shallow breathing associated with increases or decreases in blood pressure and pulse. Gastric motility may increase or decrease, and urination as well as defecation may be induced. Piloerection, pupillary changes, salivation, and altered body temperature may also occur. These autonomic changes may result from sympathetic or parasympathetic systems. The amygdala is additionally implicated in modulation of the hypothalamic control over food intake. Lesions of the basolateral nucleus of the amygdala or bilateral destruction of the amygdala induces hyperphagia. Stimulation of the basolateral nucleus causes decreased appetite and arrest of feeding behavior.
In 1939, Kluver and Bucy described primates with bilateral anterior temporal lobectomies, including removal of the uncus, amygdala, and part of the hippocampus. [9 These animals became tame, and they lost the responses of fear and aggression. They mouthed all objects, regardless of how familiar or inappropriate, and they ate everything, including nonfood items. Sexual behavior increased dramatically for appropriate and inappropriate targets, and self-stimulation also occurred. A visual agnosia combined with an inability to screen out unimportant visual stimuli caused the animals to react to all stimuli in their visual field. Subsequent studies revealed that damage to the amygdala was the most important source of these behaviors. These data suggest that the amygdala gives sensory stimuli affective and motivational significance. In other experimental models, aggression has been provoked by stimulation of the amygdala, hypothalamus, and fornix and inhibited by stimulation of the frontal lobes.
Amygdala damage in humans usually occurs in patients undergoing elective surgery for controlling epilepsy, and in such cases these regions are presumed to be abnormal before ablation. Decreased aggression, increased placidity, or no emotional changes result. y In one case of amygdalectomy, the patient lost the ability to interpret facial emotions as well as the emotions conveyed by the nonverbal aspects of speech. In contrast, amygdala stimulation in humans has produced fear, confusion, amnesia, and altered awareness.
Emotional attributes have also been associated with temporal lobe abnormalities in humans, even when the nature, localization, and extent of the abnormalities have been unknown. Most of these data involve epileptics with known seizure foci of the temporal lobe. Researchers have posited that patients with temporal lobe epilepsy who have not undergone surgery may have a "temporal lobe personality." In such studies, patients with right temporal lobe abnormalities have been thought to be more introspective and "obsessive," and those with left temporal lobe defects have been said to be extroverted and often concerned with "personal destiny." Additional features perceived to be more common in temporal lobe epileptics than in normal controls include emotionality (more intense and sustained emotional response), euphoria, sadness, anger, guilt, hypermoralism, religiosity, hypergraphia, and passivity. These studies have been criticized on methodological grounds but suggest that emotionality, mood, and thought processes involve temporal lobe function albeit in complicated and still poorly understood ways.
Various reviews and long-term follow-up studies of patients with epilepsy who have undergone temporal lobectomies have led to several conclusions about the temporal lobe and psychotic behavior. Most reports suggest that when psychosis is present preoperatively, no improvement is demonstrated following the operation. In fact, psychosis may actually develop postoperatively, especially when the surgery involves the right temporal lobe. Postoperative depression and both early and late suicide are also reported as possible complications of temporal lobectomy. Improvement, however, may occur in other behaviors, particularly excessive aggression, irritability, and social misconduct.
Mood, emotions, and thought also involve structures outside the limbic system, and the frontal lobes in particular have a major role. The famous 1868 case of Phineas Gage, in which the subject survived an explosion in which a metal bar 3 cm wide by 1 meter long went through his left frontal lobe but then demonstrated a marked alteration in personality, clearly indicated the importance of the frontal lobe in behavior.
The frontal cortex of interest can be divided into three major domains: precentral, prefrontal, and limbic. The precentral cortex is composed primarily of the motor strip and premotor cortex. Further anterior is the prefrontal cortex, which is the largest region of the frontal lobe and includes the anterior pole. The prefrontal cortex may be further divided into mesial, dorsal, and orbital parts. The orbitofrontal region of the cortex is one of the main limbic efferent channels to the hypothalamic-hypophysial complex and the visceral motor system. The prefrontal cortex has connections with the association, premotor, and limbic cortices as well as with the amygdala, hippocampus, and dorsomedial thalamic nuclei. Although the prefrontal cortex projects to the striatum, it does not receive reciprocal fibers from this structure. Cummings has proposed three major circuits connecting the frontal lobes with the subcortical structures, providing a framework for understanding the role of the frontal lobes in behavioral disorders. y Based on analyses of lesions, the dorsolateral prefrontal-subcortical circuit appears to be involved with executive function (see Chapter^ ). This type of function includes the process of supervising other brain functions related to developing and implementing a plan. The orbitofrontal-subcortical circuit is necessary for social behaviors and inhibition of inappropriate activities, and lesions of this area have been associated with obsessive compulsive disorders. Finally, the medial frontal-subcortical circuit is involved with motivation; consequently, lesions of this region have been associated with apathy syndromes.
Lesions of the frontal lobe may cause different behavioral syndromes depending on their location, depth, and size. Bilateral disturbances of the frontal lobes, particularly slowly developing abnormalities such as tumors, can cause significant intellectual and affective decline that simulates the signs of Alzheimer's disease or other dementing disorders. Bilateral ventromedial frontal lobe damage produces inappropriate, uncontrolled histrionic displays of affect, with laughing or crying fits that are not precipitated by obvious stimuli and are unrelated to the subject's mood. y More commonly, frontal lobe lesions in humans cause a dulling or shallowness of response or a lability of mood, classically termed witzelsucht. This term refers to the inappropriate jocularity and facetiousness seen with such disorders. The humor is quite changeable, and the affect may be labile. There is a loss of pleasure but no depressed affect, as seen in patients with affective disorders. Increased volatility, especially in patients with orbital lesions, has led to hypotheses that dysfunction of the frontal-orbital cortex may be involved in mania, especially when the right hemisphere is involved.
Other focal lesions of the frontal cortex have also been associated with mood and emotion abnormalities. In a selected group of right-handed patients with a single stroke lesion in either the right or left hemisphere and no previous psychiatric history, Robinson and associates found that the severity of depression in these patients was significantly increased in those with left anterior lesions as opposed to any other location. y Additionally, the severity of depression correlated significantly with the proximity of the lesion to the frontal pole in the left anterior group. Patients with a right hemisphere lesion showed the reverse. These findings caused the authors to suggest that the location of the intrahemisphere lesion is in some way related to mood disorders in stroke patients, and the neuroanatomy of the biogenic amine-containing pathways in the cortex might explain the graded effect.
Figure 3-1 (Figure Not Available) Catecholamine biosynthetic pathwafReproduced with permission from Siegel GJ, Agranoff BW, Albers RW, Molinoff PB: Basic Neurochemistry, 5th ed. New York, Raven Press, 1994.)
In the presence of frontal lobe dysfunction, patients are often impulsive and have little insight into their difficulties. They are also characterized by a lack of originality and creativity, an inability to focus attention, recent memory problems, and a tendency to display inappropriate emotional reactions (disinhibitions). y
Investigations of patients with thought disorders such as schizophrenia have also consistently shown frontal lobe dysfunction. Morphological and imaging studies in these patients have shown other abnormalities including ventricular enlargement with atrophy involving the amygdala, parahippocampal gyrus, and superior temporal gyrus.y Single-photon emission computed tomography (SPECT) and PET have further revealed the presence of low metabolic rates in medial frontal regions y and in the dorsolateral prefrontal cortex. y
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