11d association cortex frontal lobe

Editor's Notes

• #2: Frontal Lobe is the basis of our socialization and what makes us human. It gives rise to our capacity to feel empathy, sympathy, understand humor and when others are being ironic, sarcastic or even deceptive. It's a "theory of mind" that has been associated with the frontal lobes. Summary The majority of the human cerebral cortex is devoted to tasks that transcend encoding primary sensations or commanding motor actions. Collectively, the association cortices mediate these cognitive functions of the brain—broadly defined as the ability to attend to, identify, and act meaningfully in response to complex external or internal stimuli. Descriptions of patients with cortical lesions, functional brain imaging of normal subjects, and behavioral and electrophysiological studies of nonhuman primates have established the general purpose of the major association areas. Thus, parietal association cortex is involved in attention and awareness of the body and the stimuli that act on it; temporal association cortex is involved in the recognition and identification of highly processed sensory information; and frontal association cortex is involved in guiding complex behavior by planning responses to ongoing stimulation (or remembered information), matching such behaviors to the demands of a particular situation. More than any other brain regions, the association areas support the mental processes that make us human. The function of the frontal cortex was first suggested by a dramatic nineteenth century accident in which a tamping rod was driven through the frontal part of the brain of a railroad worker named Phineas P. Gage. Remarkably, Gage survived, and his behavioral deficits stimulated much early thinking about complexbrain functions. The illustration here is a reconstruction of the trajectory of the rod based on Gage's skull, which is housed in the Warren Museum at Harvard Medical School. (Courtesy of H. Damasio.) The awareness of physical and social circumstances, the ability to have thoughts and feelings (emotions), to be sexually attracted to others, to express these things to our fellow humans by language, and to store such information in memory certainly rank among the most intriguing functions of the human brain. Given their importance in our daily lives—and for human culture generally—it is not surprising that much of the human brain is devoted to these and othercomplex mental functions. The intrinsic interest of these aspects of human behavior is unfortunately equaled by the difficulty—both technical and conceptual—involved in unraveling their neurobiological underpinnings. Nonetheless, a good deal of progress has been made in deciphering the structural and functional organization of the relevant brain regions. Especially important has been the steady accumulation of case studies during the last century or more that, by the signs and symptoms resulting from damage to specific brain regions, have indicated much about the neural basis of complex brain functions. The advent of noninvasive brain imaging techniques has recently provided another way of understanding some of these abilities in normal human subjects as well as in neurological patients. Finally, complementary electrophysiological experiments in nonhuman primates have begun to elucidate the cellular correlates of some of these functions. Taken together, these observations have established a rapidly growing body of knowledge about these more complex aspects of the human brain. This domain of investigation has come to be called “cognitive neuroscience,” a field that promises to loom ever larger in the new century.
• #5: B. Profiles of electrical activity in some of the hind leg flexor and extensor muscles in the cat during stepping. Although activity of flexor and extensor muscles generally occurs during swing and stance, respectively, the overall pattern of activity is complex in both timing and amplitude. The positions of the muscles are illustrated on the right. IP = iliopsoas; LG and MG = lateral and medial gastrocnemius; PB = posterior biceps; RF = rectus femorus; Sartm and Sarta = medial and anterior sartorius; SOL = soleus; ST = semitendinosus; TA = tibialis anterior; VL, VM, and VI = vastus lateralis, medialis, and intermedialis.
• #6: Visceral Motor Reflex Functions Many examples of specific autonomic functions could be used to illustrate in more detail how the visceral motor system operates. The three outlined here—control of cardiovascular function, control of the bladder, and control of sexual function—have been chosen primarily because of their importance in human physiology and clinical practice Autonomic Regulation of Cardiovascular Function The cardiovascular system is subject to precise reflex regulation so that an appropriate supply of oxygenated blood can be reliably provided to different body tissues under a wide range of circumstances. The sensory monitoring for this critical homeostatic process entails primarily mechanical (barosensory) information about pressure in the arterial system and, secondarily, chemical (chemosensory) information about the level of oxygen and carbon dioxide in the blood. The parasympathetic and sympathetic activity relevant to cardiovascular control is determined by the information supplied by these sensors. The mechanoreceptors (called baroreceptors) are located in the heart and major blood vessels; the chemoreceptors are located primarily in the carotid bodies, which are small, highly specialized organs located at the bifurcation of the common carotid arteries (some chemosensory tissue is also found in the aorta). The nerve endings in baroreceptors are activated by deformation as the elastic elements of the vessel walls expand and contract. The chemoreceptors in the carotid bodies and aorta respond directly to the partial pressure of oxygen and carbon dioxide in the blood. Both afferent systems convey their status via the vagus nerve to the nucleus of the solitary tract ( Figure 21.7 ), which relays this information to the hypothalamus and the relevant brainstem tegmental nuclei (see earlier). The afferent information from changes in arterial pressure and blood gas levels reflexively modulates the activity of the relevant visceral motor pathways and, ultimately, of target smooth and cardiac muscles and other more specialized structures. For example, a rise in blood pressure activates baroreceptors that, via the pathway illustrated in  Figure 21.7 , inhibit the tonic activity of sympathetic preganglionic neurons in the spinal cord. In parallel, the pressure increase stimulates the activity of the parasympathetic preganglionic neurons in the dorsal motor nucleus of the vagus and the nucleus ambiguus that influence heart rate. The carotid chemoreceptors also have some influence, but this is a less important drive than that stemming from the baroreceptors. As a result of this shift in the balance of sympathetic and parasympathetic activity, the stimulatory noradrenergic effects of postganglionic sympathetic innervation on the cardiac pacemaker and cardiac musculature is reduced (an effect abetted by the decreased output of catecholamines from the adrenal medulla and the decreased vasoconstrictive effects of sympathetic innervation on the peripheral blood vessels). At the same time, activation of the cholinergic parasympathetic innervation of the heart decreases the discharge rate of the cardiac pacemaker in the sinoatrial node and slows the ventricular conduction system. These parasympathetic influences are mediated by an extensive series of parasympathetic ganglia in and near the heart, which release acetylcholine onto cardiac pacemaker cells and cardiac muscle fibers. As a result of this combination of sympathetic and parasympathetic effects, heart rate and the effectiveness of the atrial and ventricular mycoardial contraction are reduced and the peripheral arterioles dilate, thus lowering the blood pressure. In contrast to this sequence of events, a drop in blood pressure, as might occur from blood loss, has the opposite effect, inhibiting parasympathetic activity while increasing sympathetic activity. As a result, norepinephrine is released from sympathetic postganglionic terminals, increasing the rate of cardiac pacemaker activity and enhancing cardiac contractility, at the same time increasing release of catecholamines from the adrenal medulla (which further augments these and many other sympathetic effects that enhance the response to this threatening situation). Norepinephrine released from the terminals of sympathetic ganglion cells also acts on the smooth muscles of the arterioles to increase the tone of the peripheral vessels, particularly those in the skin, subcutaneous tissues, and muscles, thus shunting blood away from these tissues to those organs where oxygen and metabolites are urgently needed to maintain function (e.g., brain, heart, and kidneys in the case of blood loss). If these reflex sympathetic responses fail to raise the blood pressure sufficiently (in which case the patient is said to be in shock), the vital functions of these organs begin to fail, often catastrophically. A more mundane circumstance that requires a reflex autonomic response to a fall in blood pressure is standing up. Rising quickly from a prone position produces a shift of some 300–800 milliliters of blood from the thorax and abdomen to the legs, resulting in a sharp (approximately 40%) decrease in the output of the heart. The adjustment to this normally occurring drop in blood pressure (called orthostatic hypotension) must be rapid and effective, as evidenced by the dizziness sometimes experienced in this situation. Indeed, normal individuals can briefly lose consciousness as a result of blood pooling in the lower extremities, which is the usual cause of fainting among healthy individuals who must stand still for abnormally long periods (the “Beefeaters” who guard Buckingham Palace, for example). The sympathetic innervation of the heart arises from the preganglionic neurons in the intermediolateral column of the spinal cord, extending from roughly the first through fifth thoracic segments (see  Table 21.1 ). The primary visceral motor neurons are in the adjacent thoracic paravertebral and prevertebral ganglia of the cardiac plexus. The parasympathetic preganglionics, as already mentioned, are in the dorsal motor nucleus of the vagus nerve and the nucleus ambiguus, projecting to parasympathetic ganglia in and around the heart and great vessels Cardiovascular Reflexes Arterial blood pressure is determined by the rate of output of blood from the heart and the resistance to blood flow through the blood vessels. The sympathetic system increases heart rate and strength of contraction; the parasympathetic slows the heart. Sympathetic stimulation increases blood pressure by increasing cardiac output and peripheral resistance (by constricting small arterioles). Parasympathetic stimulation has a smaller effect on peripheral resistance, although some vasodilatory responses occur, as in blushing. Parasympathetic vasodilation may involve unconventional chemical messengers such as nitric oxide. Under resting conditions almost all systemic arterioles are constricted to approximately half maximal diameter by ongoing sympathetic tonic activity. A decrease in sympathetic output leads to vasodilation; an increase, to further constriction. Without ongoing tonic activity of the sympathetic system, sympathetic output could only increase and thus control only constriction. Sympathetic vasoconstrictor tone results from continuous firing of mainly adrenergic neurons in the rostral ventrolateral medulla, which innervate sympathetic vasoconstrictor preganglionic neurons. Activation of pressure-sensitive ( baroreceptor ) neurons that innervate the aortic arch and the carotid sinus signal an increase in blood pressure to the nucleus of the solitary tract. Neurons of this nucleus excite interneurons in the caudal ventrolateral medulla, which in turn both inhibit the tonic vasomotor neurons and excite vagal cardiomotor neurons. The result, the baroreceptor reflex , is a fall in both arterial blood pressure and heart rate. The actions of norepinephrine and acetylcholine (ACh) on the heart are worth considering in detail as examples of the complex cellular regulatory systems involved in autonomic control. Norepinephrine acts on cardiac muscle to stimulate heart rate and force of contraction. It increases the force of contraction by acting on b-adrenergic receptors that activate the cyclic adenosine monophosphate (cAMP) second-messenger system, which in turn increases the long-lasting (L-type) Ca2+ channel current in the muscle (Chapter 14). Activation of the b-adrenergic receptors also decreases the threshold for firing the cardiac pacemaker cells in the sinoatrial node, thereby increasing heart rate. These effects of norepinephrine can be potently reinforced by circulating epinephrine released from the adrenal medulla. ACh is released from parasympathetic nerve terminals, as first shown by Otto Loewi in his classic experiment proving the existence of chemical neurotransmitters (Box 49-1). ACh slows the heart by acting on muscarinic receptors in the cardiocytes of the sinoatrial and atrioventricular nodes of cardiac muscle, thus increasing a resting K+ conductance in these cells. The increase in K+ conductance hyperpolarizes sinoatrial cells, thus slowing conductance through the atrioventricular node. Hyperpolarization of the sinoatrial cells appears to involve direct gating of a K+ channel by a G protein activated by the muscarinic receptor. ACh also decreases heart rate by increasing the threshold for firing the pacemaker cells in a manner opposite to that of norepinephrine, thereby slowing the heart rate (Figure 49-5). ACh also reduces the force of contraction by decreasing intracellular cAMP, thus reducing the L-type Ca2+ current.
• #7: Papez argued that sensory messages concerning emotional stimuli that arrive at the thalamus are then directed to both the cortex (stream of thinking) and the hypothalamus (stream of feeling). Papez proposed a series of connections from the hypothalamus to the anterior thalamus (1) and on to the cingulate cortex (2). Emotional experiences or feelings occur when the cingulate cortex integrates these signals from the hypothalamus with information from the sensory cortex. Output from the cingulate cortex to the hippocampus (3) and then to the hypothalamus (4) allows top–down cortical control of emotional responses. Modified, with permission, from Ref. 17 © (1996) Joseph Ledoux. Used by permission of Simon and Schuster. . Papez argued that, since the hypothalamus communicates reciprocally with areas of the cerebral cortex, information about the conscious and peripheral aspects of emotion affect each other. Papez proposed that the neocortex influences the hypothalamus by means of connections to the cingulate gyrus and from the cingulate gyrus to the hippocampal formation. According to this idea, the hippocampal formation processes information from the cingulate gyrus and conveys it to the mammillary bodies of the hypothalamus by way of the fornix (a fiber bundle that carries part of the outflow of the hippocampus; see Figure 50-4). In turn, the hypothalamus provides information to the cingulate gyrus by a pathway from the mammillary bodies to the anterior thalamic nuclei (the mammillothalamic tract) and from there to the cingulate gyrus (Figure 50-5). Consistent with this idea is the clinical observation that patients who have been infected with the rabies virus—which characteristically attacks the hippocampus—show profound changes in emotional state, including bouts of terror and rage.
• #12: Figure 26.1. Lateral and medial views of the human brain, showing the extent of the association cortices in blue. The primary sensory and motor regions of the neocortex are shaded in pink. Notice that the primary cortices occupy a relatively small fraction of the total area of the cortical mantle. The remainder of the neocortex—defined by exclusion as the association cortices—is the seat of human cognitive ability. The term “association” refers to the fact that these regions of the cortex integrate (associate) information derived from other brain regions. The Association Cortices Overview The association cortices include most of the cerebral surface of the human brain and are largely responsible for the complex processing that goes on between the arrival of input in the primary sensory cortices and the generation of behavior. The diverse functions of the association cortices are loosely referred to as “cognition,” which literally means the process by which we come to know the world (“cognition” is perhaps not the best word to indicate this wide range of neural functions, but it has already become part of the working vocabulary of neurologists and neuroscientists). More specifically, cognition refers to the ability to attend to external stimuli or internal motivation, to identify the significance of such stimuli, and to plan meaningful responses to them. Given the complexity of these tasks, it is not surprising that the association cortices receive and integrate information from a variety of sources, and that they influence a broad range of cortical and subcortical targets. Inputs to the association cortices include projections from the primary and secondary sensory and motorcortices, the thalamus, and the brainstem. Outputs from the association cortices reach the hippocampus, the basal ganglia and cerebellum, the thalamus, and other association cortices. Insight into how the association areas work has come primarily from observations of human patients with damage to one or another of these regions. Noninvasive brain imaging of normal subjects, functional mapping at neurosurgery, and electrophysiological analysis of comparable brain regions in nonhuman primates have generally confirmed these clinical impressions. Together, these studies indicate that, among other functions, the parietal association cortex is especially important for attending to complex stimuli in the external and internal environment, that the temporal association cortex is especially important for identifying the nature of such stimuli, and that the frontal association cortex is especially important for planning appropriate behavioral responses to the stimuli. The Association Cortices The preceding chapters have considered in some detail the parts of the brain responsible for encoding sensory information and commanding movements. But these regions account for only a fraction (perhaps a fifth) of the cerebral cortex (see  Figure 26.1 ). The consensus has long been that much of the remaining cortex is concerned with attending to complex stimuli, identifying the relevant features of such stimuli, recognizing the related objects, and planning appropriate responses (as well as storing aspects of this information). Collectively, these abilities are referred to as  cognition , and it is evidently theassociation cortices in the parietal, temporal, and frontal lobes that make cognition possible. (The association cortex of the occipital lobe is equally important in cognition; its functions, however, are largely concerned with vision, and much of what is known about these areas has been discussed in  Chapter 12 .) The primary sensory and motor cortices occupy a relatively limited portion of the cortical mantle, the majority of the cortex being devoted to more integrative functions. These other areas of the cerebral cortex are referred to collectively as the  association cortices  ( Figure 26.1 ) BY 1950 IT WAS WELL ESTABLISHED that different sensory modalities are mediated by distinct sensory systems and that different actions recruit distinct components of the motor system. But it was still unclear whether this specificity of neural action applied to higher cognitive functions. Indeed, many scientists thought that cognitive functions, because of their complexity, required the operation of the brain as a whole. Only in the last 40 years has strong support been obtained for the idea that all mental functions are localizable to specific areas of the brain (see Chapter 1). But it also has become clear that complex mental functions require integration of information from several cortical areas. This in turn has raised the question: How is this parallel and distributed processing of cognitive information brought together? In which cortical area does the integration occur? And how is the integration brought about? A prescient answer to these questions was provided in the 1870s by John Hughlings Jackson, the founder of modern British neurology. He proposed that the cortex is organized hierarchically and that some cortical areas serve higher-order integrative functions that are neither purely sensory nor purely motor, but associative. These higher-order areas of cortex, which we now call association areas , serve to associate sensory inputs to motor response and perform those mental processes that intervene between sensory inputs and motor outputs. The mental processes that Jackson attributed to these areas include interpretation of sensory information, association of perceptions with previous experience, focusing of attention, and exploration of the environment. Jackson supported his proposal with clinical evidence that certain cortical lesions, although limited in extent, produced surprisingly complex disturbances in behavior. How then do the association cortices achieve their integrative action? As we shall learn in this chapter, the association areas are capable of mediating complex cognitive processes because they receive information from different higher-order sensory areas and convey the information to higher-order motor areas that organize planned actions after appropriate processing and transformation. Three Multimodal Association Areas Are Concerned With Integrating Different Sensory Modalities and Linking Them to Action Jackson's view of the association areas has now been firmly established experimentally. We now know that each primary sensory cortex projects to nearby higher-order areas of sensory cortex, called unimodal association areas , that integrate afferent information for a single sensory modality. For example, the visual association cortex integrates information about form, color, and motion that arrives in the brain in separate pathways. The unimodal association areas in turn project to multimodal sensory association areas that integrate information about more than one sensory modality. Finally, the multimodal sensory association areas project to multimodal motor association areas located rostral to the primary motor cortex in the frontal lobe. The higher-order motor areas transform sensory information into planned movement and compute the programs for these movements, which are then conveyed to the premotor and primary motor cortex for implementation. The term primary cortex therefore has two different meanings: the primary sensory areas are the initial sites of cortical processing of sensory information, while the primary motor areas are the final sites for the cortical processing of motor commands. Because the multimodal association areas integrate sensory modalities and link sensory information to the planning of movement, they are thought to be the anatomical substrates of the highest brain functions—conscious thought, perception, and goal-directed action. Consistent with this idea, lesions to these association areas result in profound cognitive deficits. The major primary and higher-order sensory and motor cortical areas as well as the multimodal association areas of the cerebral cortex are listed in Table 19-1. Three multimodal association areas are particularly important (Figure 19-1): The posterior association area , at the margin of the parietal, temporal, and occipital lobes, links information from several sensory modalities for perception and language. The limbic association area , along the medial edge of the cerebral hemisphere, is concerned with emotion and memory storage. The anterior association area (prefrontal cortex), rostral to postcentral gyrus, is concerned with planning movement.
• #13: Figure 26.2. The structure of the human neocortex, including the association cortices. (A) A summary of the cellular composition of the six layers of the neocortex. (B) Based on variations in the thickness, cell density, and other histological features of the six neocortical laminae, the human brain can be divided into about 50 cytoarchitectonic areas, in this case those recognized by the neuroanatomist Korbinian Brodmann in his seminal monograph in 1909. (See  Box A  for additional detail.) An Overview of Cortical Structure Before delving into a more detailed account of the functions of these cortical regions, it is important to have a general understanding of cortical structure and the organization of its canonical circuitry. Most of the cortex that covers the cerebral hemispheres is  neocortex , defined as cortex that has six cellular layers, or laminae. Each layer comprises more or less distinctive populations of cells based on their different densities, sizes, shapes, inputs, and outputs. The laminar organization and basic connectivity of the human cerebral cortex are summarized in  Figure 26.2A  and  Table 26.1 . Despite an overall uniformity, regional differences based on these laminar features have long been apparent ( Box A ), allowing investigators to identify about 50 subdivisions of the cerebral cortex ( Figure 26.2B ). These histologically defined subdivisions are referred to as  cytoarchitectonic areas , and over the years, a zealous band of neuroanatomists has painstakingly mapped these areas in humans and some of the more widely used laboratory animals. Early in the twentieth century, cytoarchitectonically distinct regions were identified with little or no knowledge of their functional significance. Eventually, however, studies of patients in whom one or more of these cortical areas had been damaged, supplemented by electrophysiological mapping in both laboratory animals and neurosurgical patients, added to this knowledge. This work showed that many of the regions neuroanatomists had identified on histological grounds are also functionally distinct. Thus, cytoarchitectonic areas can also be distinguished by the physiological response properties of their constituent cells, and often by their patterns of local and long-distance connections. Despite significant variations among different cytoarchitectonic areas, the circuitry of all cortical regions has some common features ( Figure 26.3 ). First, eachcortical layer has a primary source of inputs and a primary output target. Second, each area has connections in the vertical axis (called  columnar  or  radial connections) and connections in the horizontal axis (called  lateral  connections ) . Third, cells with similar functions tend to be arrayed in radially aligned groups that span all of the cortical layers and receive inputs that are often segregated into radial or columnar bands. Finally, interneurons within specific corticallayers give rise to extensive local axons that extend horizontally in the cortex, often linking functionally similar groups of cells. The particular circuitry of anycortical region is a variation on this canonical pattern of inputs, outputs, and vertical and horizontal patterns of connectivity
• #14: Figure 26-2 Intracortical circuits. Note the loci of the synaptic connections (depicted with loops) of afferent fiber projections, the origins of the efferent projections, and the origins of intracortical connections within a given column. The specific region of cortex is not defined in this illustration. Abbreviations: G, granule cell; H, horizontal cell; M, Martinotti cel l; P, pyramidal cel l; S, stellate cell. Arrows indicate direction of information flow. (From Parent A: Carpenter's Human Neuroanatomy, 9th ed. Baltimore: Williams & Wilkins, 1996, p. 868.)
• #15: A More Detailed Look at Cortical Lamination Much knowledge about the cerebral cortex is based on descriptions of differences in cell number and density throughout the cortical mantle. Nerve cell bodies, because of their high metabolic rate, are rich in basophilic substances (RNA, for instance), and therefore tend to stain darkly with reagents such as cresyl violet acetate. These so-called Nissl stains (named after F. Nissl, who first described this technique when he was a medical student in nineteenth-century Germany) provide a dramatic picture of brain structure at the histological level. The most striking feature revealed in this way is the distinctive lamination of the cortex in humans and other mammals (see figure). In humans, there are three to six cortical layers, which are usually designated by Roman numerals, with letters for laminar subdivisions (layers IVa, b, and c in the visual cortex, for example). Each of the cortical laminae in the so-called  neocortex  (which covers the bulk of the cerebral hemispheres and is defined by six layers) has characteristic functional and anatomical features (see  Figures 26.2  and  26.3 ). For example, cortical layer IV is typically rich in stellate neurons with locally ramifying axons; in the primary sensory cortices, these neurons receive input from the thalamus, the major sensory relay from the periphery. Layer V, and to a lesser degree layer VI, contain pyramidal neurons whose axons typically leave the cortex. The generally smaller pyramidal neurons in layers II and III (which are not as distinct as their Roman numeral assignments suggest) have primarily corticocortical connections, and layer I contains mainly neuropil. Korbinian Brodmann, who early in the twentieth century devoted his career to an analysis of brain regions distinguished in this way, described about 50 distinct cortical regions, or cytoarchitectonic areas (see  Figure 26.2B ). These structural features of the cerebral cortex continue to figure importantly in discussions of the brain, particularly in structural/functional correlation of intensely studied regions such as the primary sensory and motor cortices. Not all of the cortical mantle is six-layered neocortex. The hippocampus, for example, which lies deep in the temporal lobe and has been implicated in acquisition of memories (see  Chapter 31 ), has only three or four laminae. The hippocampal cortex is regarded as evolutionarily more primitive, and is therefore called  archicortex  to distinguish it from the six-layered neocortex. Another type of cortex, called  paleocortex , generally has three layers and is found on the ventral surface of the cerebral hemispheres and along the parahippocampal gyrus in the medial temporal lobe. The functional significance of different numbers of laminae in neocortex, archicortex, and paleocortex is not known, although it seems likely that the greater number of layers in neocortex reflects more complex information processing than in archi- or paleocortex. The general similarity of neocortical structure across the entire cerebrum clearly suggests that there is a common denominator of cortical operation, but no one has yet deciphered what it is. Major types of cortex in the cerebral mantle, based primarily on the different numbers of laminae apparent in histological sections
• #16: Brodmann's cytoarchitectonic mapping of the human brain. (A) Lateral view; (B) medial view. The different regions are labeled with different symbols and numbers. Note the key regions that have been identified using Brodmann's numbering scheme. Several of these regions include: area 4: primary motor cortex; area 6: premotor area; areas 3, 1, and 2: primary somatosensory receiving areas; areas 5 and 7: posterior parietal cortex; area 17: primary visual cortex; and area 41: primary auditory receiving area. See text for further discussion of Brodmann's areas. (From Parent A: Carpenter's Human Neuroanatomy, 9th ed. Baltimore: Williams & Wilkins, 1996, p. 882.)
• #19: Figure 26.3.  Canonical neocortical circuitry. Green arrows indicate outputs to the major targets of each of the neocortical layers in humans; white arrow indicates thalamic input (primarily to layer IV); dark purple arrows indicate input from other cortical areas; and light purple arrows indicate input from the brainstem modulatory systems to each layer. Input-output relationships of cortex. Schematic diagram depicts the intrinsic organization and input-output relationships of the cerebral cortex. Excitatory connections are indicated by (+), and inhibitory synapse is indicated by (-). Note that thalamocortical and intracortical projections terminate mainly in layer IV, and monoaminergic projections are distributed mainly to more superficial layers. Cortical afferents terminating in layer IV can either excite or inhibit pyramidal cells in layer V, which contribute significantly to the outputs of the cerebral cortex. The major outputs to the spinal cord, cranial nerve motor nuclei, other brainstem structures, thalamus, and neo-striatum arise in layers V-VI, whereas projections to other regions of cortex either on the ipsilateral or contralateral side arise from layer III. (Adapted from Conn PM: Neuroscience in Medicine. Philadelphia: J.B. Lippincott, 1995, p. 316.) Excitability Characteristics of Neurons Within a Cortical Column Two factors that regulate cortical excitability should be noted. The first is that large cortical cells, such as pyramidal cells, integrate the activity of many neurons that impinge on these cells. Pyramidal cells also transmit signals to other layers of the cortex by virtue of their axon collaterals. Some connections are excitatory, whereby other neurons within a given cortical column are then excited. Other connections are inhibitory, especially with neurons in an adjacent column. The inhibitory neurons may then make synapse with additional neurons that are either inhibitory (producing cortical disinhibition) or excitatory. Thus, excitation of the pyramidal cell can lead to wide variations in the patterns of cortical excitability. For this reason, the nature of the functional patterns governing excitation within a cortical column still remains poorly understood. The second factor is that cortical afferents, such as those arising from the thalamus or from other regions of the cortex, have the capacity to activate large numbers of cortical neurons at any one given moment. These sources typically have fast excitatory synaptic actions. Other inputs that are mediated by acetylcholine, monoamines, or peptides appear to have a slow, modulatory-like action on these cel ls.
• #20: Thalamocortical relationships. (A) The relative positions of thalamic nuclei. (B) Lateral (left) and medial (right) views of the cerebral cortex that demonstrate the projection targets of thalamic nuclei. Color coding is to facilitate visualization of the projection targets of thalamic nuclei on the cerebral cortex. Abbreviations: VPM, ventral posteromedial nucleus; VPL, ventral posterolateral nucleus; VA, ventral anterior nucleus; VL, ventrolateral nucleus. Anatomical and Functional Relations of the Cerebral Cortex to the Thalamus and Other Lower Centers. All areas of the cerebral cortex have extensive to-and-fro efferent and afferent connections with deeper structures of the brain. It is especially important to emphasize the relation between the cerebral cortex and the thalamus. When the thalamus is damaged along with the cortex, the loss of cerebral function is far greater than when the cortex alone is damaged because thalamic excitation of the cortex is necessary for almost all cortical activity. Figure 57–2 shows the areas of the cerebral cortex that connect with specific parts of the thalamus. These connections act in two directions, both from the thalamus to the cortex and then from the cortex back to essentially the same area of the thalamus. Furthermore, when the thalamic connections are cut, the functions of the corresponding cortical area become almost entirely lost. Therefore, the cortex operates in close association with the thalamus and can almost be considered both anatomically and functionally a unit with the thalamus: for this reason, the thalamus and the cortex together are sometimes called the thalamocortical system . Almost all pathways from the sensory receptors and sensory organs to the cortex pass through the thalamus, with the principal exception of some sensory pathways of olfaction.
• #21: The noradrenaline pathways in the brain Many regions of the brain are supplied by the noradrenergic systems. The principal centres for noradrenergic neurones are the locus coeruleus and the caudal raphe nuclei. The ascending nerves of the locus coeruleus project to the frontal cortex, thalamus, hypothalamus and limbic system. Noradrenaline is also transmitted from the locus coeruleus to the cerebellum. Nerves projecting from the caudal raphe nuclei ascend to the amygdala and descend to the midbrain. Figure 45-2 Noradrenergic neurons in the pons. A. Noradrenergic neurons are spread across the pons in three more or less distinct groups: the locus ceruleus (A6 group) in the periaqueductal gray matter, the A7 group more ventrolaterally, and the A5 group along the ventrolateral margin of the pontine tegmentum. B. The A5 and A7 neurons mainly innervate the brain stem and spinal cord, whereas the locus ceruleus provides a major ascending output to the thalamus and cerebral cortex as well as descending projections to the brain stem, cerebellum, and spinal cord. A = amygdala; AO = anterior olfactory nucleus; BS = brain stem; C = cingulate bundle; CC = corpus callosum; CT = central tegmental tract; CTX = cerebral cortex; DT = dorsal tegmental bundle; EC = external capsule; F = fornix; H = hypothalamus; HF = hippocampal formation; LC = locus ceruleus; OB = olfactory bulb; PT = pretectal nuclei; RF = reticular formation; S = septum; T = tectum; Th = thalamus. The A6 cell group, the locus ceruleus , sits dorsally and laterally in the periaqueductal and periventricular gray matter (Figure 45-2). The locus ceruleus, which maintains vigilance and responsiveness to unexpected environmental stimuli, has extensive projections to the cerebral cortex and cerebellum, as well as descending projections to the brain stem and spinal cord. NOREPINEPHRINE (NORADRENALIN) Norepinephrine (along with acetylcholine) is one of the two neurotransmitters in the peripheral nervous system. Norepinephrine is synthesized from dopamine by means of the enzyme D opamine B eta- H ydroxylase (DBH), with oxygen, copper and Vitamin C as co-factors. Dopamine is synthesized in the cytoplasm, but norepinephrine is synthesized in the neurotransmitter storage vesicles. Cells that use norepinephrine for formation of epinephrine use SAMe (S-AdenylMethionine) as a methyl group donor. Levels of epinephrine in the CNS are only about 10% of the levels of norepinephrine. The most prominent noradrenergic (ie, norepinephrine-containing) nucleus is the locus ceruleus in the pons, which account for over 40% of noradrenergic neurons in the rat brain. Most of the other noradrenergic neurons are clustered in a region described as the lateral tegmental area . The neocortex, hippocampus, and cerebellum receive noradrenergic stimulation exclusively from the locus ceruleus. Most of the dopaminergic innervation of the hypothalamus comes from the lateral tegmental nuclei. Electrical stimulation of the locus ceruleus produces a state of heightened arousal. The noradrenergic system is most active in the awake state, and it seems to be important for focused attention, in contrast to the motor arousal of dopamine. Although the locus ceruleus has been identified as a pleasure center, it also seems to contribute to anxiety. Increased neuronal activity of the locus ceruleus is seen upon the occurrence of unexpected sensory events. Brain norepinephrine turnover is increased in conditions of stress. Benzodiazepines, the primary antianxiety drugs, decrease firing in the locus ceruleus, thus reducing distribution of noradrenalin to the forebrain and amygdala . This is part of the explanation for the use of benzodiazepines for inducing sleep . Active projection of norepinephrine from the locus coeruleus of the reticular activating system to the forebrain is a key feature of awakeness-arousal as distinguished from sleep. Norepineprhine projection to the basal nucleus of the forebrain is low in sleep -- virtually absent in REM (Rapid Eye-Movement) sleep. The basal nucleus when stimulated by norepinephrine from the locus coeruleus sends neuromodulating acetylcholine to the cerebral cortex, thereby promoting alertness. The beta-adrenergic blocking drug propranolol has also been used to treat anxiety. By blocking the adrenergic inputs to the amygdala, beta-blockers inhibit the formation of traumatic memories. Cortisol stimulation of the locus coeruleus due to chronic stress exacerbates norepinephrine stimulation of the amygdala. Beta-noradrenergic receptors also apparently inhibit feeding, whereas alpha-receptors seem to stimulate feeding. Although MAO inhibitors reduce metabolism of all catecholamines, it is believed that the anti-depressant effect is more related to norepinephrine than to dopamine. Most MAO in the brain is of type-B, but drugs selective for inhibiting MAO-A have proven to be better anti-depressants. MAO-A preferentially metabolizes norepinephrine & serotonin. MAO-A inhibiting drugs given for depression have critically elevated blood pressure in patients eating tyramine-containing foods (such as cheese) due to the failure to metabolize tyramine (which can act as a pressor agent). These drugs (eg, phenelzine & pargyline) inactivate MAO by forming irreversible covalent bonds. More modern MAO inhibitors are safer because they form reversible bonds. MAO-B inhibitors like deprenyl are also less likely to cause the "cheese effect". (Alcohol also selectively inhibits MAO-B.) Tricyclic Antidepressants Tricyclic anti-depressants derive their name from their 3-ring structure. Desipramine only inhibits norepinephrine re-uptake, with little effect on dopamine. Imipramine & amitriptyline are inhibitors of norepinephrine and serotonin re-uptake by the presynaptic terminals, but are more potent for serotonin. Cocaine is also a potent inhibitor of catecholamine re-uptake, but it does not act as an anti-depressant. Weight gain due to increased appetite is a frequent side effect of tricyclic anti-depressants, particularly of amitrip- tyline. By contrast, both cocaine & amphetamine reduce appetite. Both MAO inhibitors and tricyclic anti-depressants have immediate effects on brain monoamines, but clinically anti-depressants require several weeks of administration before they produce a therapeutic effect. It is therefore believed that it is not the immediate effects on neurotransmitters that is producing the antidepression, but the long-term effects on modification of receptors. Excessive cortisol secretion is seen in 40-60% of depressed patients, associated with diminished noradrenergic inhibition of corticotropin-releasing hormone secretion in the hypothalamus. Corticotropin-releasing hormone induces anxiety in experimental animals.
• #22: The dopamine pathways in the brain Dopamine is transmitted via three major pathways. The first extends from the substantia nigra to the caudate nucleus-putamen (neostriatum) and is concerned with sensory stimuli and movement. The second pathway projects from the ventral tegmentum to the mesolimbic forebrain and is thought to be associated with cognitive, reward and emotional behaviour. The third pathway, known as the tubero-infundibular system, is concerned with neuronal control of the hypothalmic-pituatory endocrine system Figure 45-3 Dopaminergic neurons in the brain stem and hypothalamus. A. Dopaminergic neurons in the substantia nigra (A9 group) and the adjacent retrorubral field (A8 group) and ventral tegmental area (A10 group) provide a major ascending pathway that terminates in the striatum, the frontotemporal cortex, and the limbic system, including the central nucleus of the amygdala and the lateral septum. B. Hypothalamic dopaminergic neurons in the A11 and A13 cell groups, in the zona incerta, provide long descending pathways to the autonomic areas of the lower brain stem and the spinal cord. Neurons in the A12 and A14 groups, located along the wall of the third ventricle, are involved with endocrine control. Some of them release dopamine as a prolactin release inhibiting factor in the hypophysial portal circulation. . Dopaminergic Cell Groups The dopaminergic cell groups in the midbrain and forebrain were originally numbered as if they were a rostral continuation of the noradrenergic system because identification was based on histofluorescence, which does not distinguish dopamine from norepinephrine very well. The A8-A10 cell groups include the substantia nigra pars compacta and the adjacent areas of the midbrain tegmentum (Figure 45-3). They send the major ascending dopaminergic inputs to the telencephalon, including the nigrostriatal pathway that innervates the striatum and is thought to be involved in initiating motor responses. Mesocortical and mesolimbic dopaminergic pathways arising from the A10 group innervate the frontal and temporal cortices and the limbic structures of the basal forebrain. These pathways have been implicated in emotion, thought, and memory storage. The A11 and A13 cell groups, in the dorsal hypothalamus, send major descending dopaminergic pathways to the spinal cord. These pathways are believed to regulate sympathetic preganglionic neurons. The A12 and A14 cell groups, along the wall of the third ventricle, are components of the tuberoinfundibular hypothalamic neuroendocrine system. Dopaminergic neurons are also found in the olfactory system (A15 cells in the olfactory tubercle and A16 in the olfactory bulb) and in the retina (A17 cells). Once in the brain, tyrosine can be converted to D ihydr O xy P henyl A lanine ( DOPA ) by the tyrosine hydroxylase enzyme using oxygen, iron and T etra H ydro B iopterin (THB) as co-factors. High concentrations of dopamine inhibit tyrosine hydroxylase activity through an influence on the THB co-factor. DOPA is converted to dopamine by A romatic A mino A cid D ecarboxylase (which is fairly nonspecific insofar as it will decarboxylate any aromatic amino acid) using P yridoxa L P hosphate (PLP) as a co-factor. This reaction is virtually instantaneous unless there is a Vitamin B6 deficiency. Dopamine & epinephrine are primarily inhibitory neurotransmitters that produce arousal. This may sound paradoxical, but the most likely explanation for this effect is that the postsynaptic cells for catecholamines themselves are inhibitory. There are 3-4 times more dopaminergic cells in the CNS than adrenergic cells. Dopamine in the caudate nucleus facilitates posture, whereas dopamine in the nucleus accumbens is associated with an animal's speed (and pleasure ). There are two primary dopamine receptor-types: D1 (stimulatory) and D2 (inhibitory), both of which act through G-proteins. D2 receptors often occur on the dopaminergic neurons, partially for the purpose of providing negative feedback . These so-called autoreceptors can inhibit both dopamine synthesis and release. The binding of dopamine to D1-receptors stimulates the activity of Adenylyl Cyclase (AC), which converts ATP to cyclic AMP (cAMP), a second messenger which binds to Protein Kinase A (PKA). PKA then modulates the activity of various proteins by the addition of phosphate. There are 4 main dopaminergic tracts in the brain: (1) the nigrostriatial tract from the substantia nigra to the striatum accounts for most of the brain's dopamine (2) the tuberoinfundibular tract from the arcuate nucleus of the hypothalamus to the pituitary stalk, which has a controlling effect on the release of the hormones prolactin through tonic inhibition via D2 receptors (3) the mesolimbic tract from the ventral tegmental area to many parts of the limbic system and (4) the mesocortical tract from the ventral tegmental area to the neocortex, particularly the prefrontal area. Dopamine cells project topographically to the areas they innervate.
• #23: The serotonin pathways in the brain The principal centres for serotonergic neurones are the rostral and caudal raphe nuclei. From the rostral raphe nuclei axons ascend to the cerebral cortex, limbic regions and specifically to the basal ganglia. Serotonergic nuclei in the brain stem give rise to descending axons, some of which terminate in the medulla, while others descend the spinal cord. Figure 45-4 Serotonergic neurons along the midline of the brain stem. Neurons in the B1-3 groups, corresponding to the raphe magnus, raphe pallidus, and raphe obscurus nuclei in the medulla, project to the lower brain stem and spinal cord. Neurons in the B4-9 groups, including the raphe pontis, median raphe, and dorsal raphe nuclei, project to the upper brain stem, hypothalamus, thalamus, and cerebral cortex. CD = caudate nucleus; HF = hippocampal formation; H = hypothalamus; Th = thalamus. Serotonergic Cell Groups Most serotonergic neurons are located along the midline of the brain stem in the raphe nuclei (from raphé , French for seam ). Raphe neurons in the B1-B3 cell groups along the midline of the caudal medulla (Figure 45-4) send descending projections to the motor and autonomic systems in the spinal cord. The raphe magnus nucleus (B4) at the level of the rostral medulla projects to the spinal dorsal horn and is thought to modulate the perception of pain. The serotonergic groups in the pons and midbrain (B5-B9) include the pontine, dorsal, and median raphe nuclei and project to virtually the whole of the forebrain. Serotonergic pathways play important regulatory roles in hypothalamic cardiovascular and thermoregulatory control and modulate the responsiveness of cortical neurons. Serotonin seems to have distinctive actions contributing to anxiety and impulsive behavior . Patients with evidence of low serotonin levels have attempted suicide by very dramatic means, such as cutting the throat . This may explain some of the therapeutic effects of fluoxetine (Prozac), which selectively prevents the re-uptake of serotonin. Fluoxetine is also distinctive because it has a half-life of about four days. Fluoxetine has been used therapeutically for panic, obsessive-compulsive and eating disorders (such as bulimia). Unlike the tricyclic anti-depressants, which often stimulate appetite, fluoxetine more often reduces appetite. Fluoxetine may even enhance learning [PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR 52:341-346 (1995)]. Depression patients treated with tryptophan as well as fluoxetine show less sleep disturbance at the outset of treatment than patients treated with fluoxetine alone [ JOURNAL OF PSYCHIATRY & NEUROSCIENCE; Levitan,RD ; 25(4):337-346 (2000) ]. Monkeys with high levels of testosterone & low levels of serotonin are both aggressive & lacking in restraints on impulsive/violent behavior. Arsonists who commit their crime for mercenary reasons show normal levels of serotonin, but those who commit the crime impulsively have low serotonin . Lead interferes with serotonin synapse formation. Monkeys experimentally exposed to lead became so dangerously aggressive that the study was halted early [ CHEMICAL & ENGINEERING NEWS 81(22):33-37 (2003) ]. Reserpine prevents the transport of all the monoamines (and acetylcholine) into storage vesicles in the presynaptic membrane -- leaving them vulnerable to destruction by monoamine oxidase. Reserpine (as extracts from the Rauwolfia plant) was used for centuries in India to treat "hysteria". Reserpine has been used as a potent tranquilizer, but it can produce serious depression that may lead to suicide attempts. LySergic acid Diethylamine (LSD) acts most strongly on the type-2 serotonin receptors, but it also has some effect on norepinephrine receptors. Serotonin seems to play a role in dreaming . During both dreaming and LSD intoxication, electrical activity in the visual cortex arises from the brain stem rather than from the eyes . LSD not only induces visual hallucinations, but it heightens sensory awareness while diminishing control of sensory input. The reduced ability to distinguish between sensory impressions can lead to feelings of being "in union with the universe". Artificial stimulation of the raphe simulates the actions of LSD, decreasing habituation to repetitive stimuli. Low doses of LSD & amphetamine, however, have been shown to enhance a form of associative learning. High-estrogen contraceptives may have contributed to depression by lowering serotonin levels in the brain. Low levels of growth hormone in depressed patients may be due either to low levels of norepinephrine, serotonin, or both.
• #24: Distribution of acetylcholine receptors in the brain There are two main types of cholinergic receptors widely distributed throughout in the brain. These receptors are classified as muscarinic and nicotinic receptors. In certain regions of the brain only the muscarinic subtype is found eg midbrain, medulla, and pons while in other regions eg substantia nigra, locus coeruleus and septum only the nicotinic receptor subtype is found. Both sub-types are located in the corpus striatum, cerebral cortex, hippocampus, thalamus, hypothalamus and cerebellum. Figure 45-5 Cholinergic neurons in the upper pontine tegmentum and basal forebrain diffusely innervate much of the brain stem and forebrain. The basal forebrain cholinergic groups include the medial septum (MS) (Ch1 group), nuclei of the vertical and horizontal limbs of the diagonal band (DBv and DBh) (Ch2 and Ch3 groups), and the nucleus basalis of Meynert (BM) (Ch4 group), which topographically innervate the entire cerebral cortex, including the hippocampus (Hi) and the amygdala (Am). The pontine cholinergic neurons, in the laterodorsal (LDT) (Ch5 group), and pedunculopontine (PPT) (Ch6 group), tegmental nuclei, innervate the brain stem reticular formation (RF) as well as the thalamus (Th). Ha = habenular nucleus; IPN = interpeduncular nucleus; LH = lateral hypothalamus; MaPo = magnocellular preoptic nucleus; OB = olfactory bulb; VTA = ventral tegmental area. Cholinergic Cell Groups Acetylcholine is the transmitter used by both somatic and autonomic motor neurons. Certain populations of cholinergic interneurons are found in the brain stem and forebrain, and large cholinergic neurons in the mesopontine tegmentum and basal forebrain give rise to long ascending projections (Figure 45-5). The mesopontine cholinergic neurons are divided into a ventrolateral column (Ch6 cell group, or the pedunculopontine nucleus ), close to the lateral margin of the superior cerebellar peduncle, and a dorsomedial column (Ch5 cell group, or the laterodorsal tegmental nucleus ), a component of the periaqueductal gray matter just rostral to the locus ceruleus. These two cell groups send a major descending projection to the pontine and medullary reticular formation and provide extensive ascending cholinergic innervation of the thalamus. These projections are thought to play an important role in regulating wake-sleep cycles (Chapter 47).
• #31: Functions of Specific Cortical Areas Studies in human beings by neurosurgeons, neurologists, and neuropathologists have shown that different cerebral cortical areas have separate functions. Figure 57–3 is a map of some of these functions as determined by Penfield and Rasmussen from electrical stimulation of the cortex in awake patients or during neurological examination of patients after portions of the cortex had been removed. The electrically stimulated patients told their thoughts evoked by the stimulation, and sometimes they experienced movements. Occasionally they spontaneously emitted a sound or even a word or gave some other evidence of the stimulation. Putting large amounts of information together from many different sources gives a more general map, as shown in Figure 57–4. This figure shows the major primary and secondary premotor and supplementary motor areas of the cortex as well as the major primary and secondary sensory areas for somatic sensation, vision, and hearing, all of which are discussed in earlier chapters. The primary motor areas have direct connections with specific muscles for causing discrete muscle movements. The primary sensory areas detect specific sensations—visual, auditory, or somatic—transmitted directly to the brain from peripheral sensory organs. The secondary areas make sense out of the signals in the primary areas. For instance, the supplementary and premotor areas function along with the primary motor cortex and basal ganglia to provide “patterns” of motor activity. On the sensory side, the secondary sensory areas, located within a few centimeters of the primary areas, begin to analyze the meanings of the specific sensory signals, such as (1) interpretation of the shape or texture of an object in one’s hand; (2) interpretation of color, light intensity, directions of lines and angles, and other aspects of vision; and (3) interpretations of the meanings of sound tones and sequence of tones in the auditory signals.
• #32: Association Areas Figure 57–4 also shows several large areas of the cerebral cortex that do not fit into the rigid categories of primary and secondary motor and sensory areas. These areas are called association areas because they receive and analyze signals simultaneously from multiple regions of both the motor and sensory cortices as well as from subcortical structures. Yet even the association areas have their specializations. The most important association areas are (1) the parieto-occipitotemporal association area , (2) the prefrontal association area , and (3) the limbic association area . Following are explanations of the functions of these areas. Parieto-occipitotemporal Association Area. This association area lies in the large parietal and occipital cortical space bounded by the matosensory cortex anteriorly, the visual cortex posteriorly, and the auditory cortex laterally. As would be expected, it provides a high level of interpretative meaning for signals from all the surrounding sensory areas. However, even the parieto-occipitotemporal association area has its own functional subareas, which are shown in Figure 57–5. 1. Analysis of the Spatial Coordinates of the Body. An area beginning in the posterior parietal cortex and extending into the superior occipital cortex provides continuous analysis of the spatial coordinates of all parts of the body as well as of the surroundings of the body. This area receives visual sensory information from the posterior occipital cortex and simultaneous somatosensory information from the anterior parietal cortex. From all this information, it computes the coordinates of the visual, auditory, and body surroundings. 2. Area for Language Comprehension. The major area for language comprehension, called Wernicke ’ s area , lies behind the primary auditory cortex in the posterior part of the superior gyrus of the temporal lobe . We discuss this area much more fully later; it is the most important region of the entire brain for higher intellectual function because almost all such intellectual functions are language based. 3. Area for Initial Processing of Visual Language (Reading). Posterior to the language comprehension area, lying mainly in the anterolateral region of the occipital lobe, is a visual association area that feeds visual information conveyed by words read from a book into Wernicke’s area, the language comprehension area. This so-called angular gyrus area is needed to make meaning out of the visually perceived words. In its absence, a person can still have excellent language comprehension through hearing but not through reading. 4. Area for Naming Objects. In the most lateral portions of the anterior occipital lobe and posterior temporal lobe is an area for naming objects. The names are learned mainly through auditory input, whereas the physical natures of the objects are learned mainly through visual input. In turn, the names are essential for both auditory and visual language comprehension ( functions performed in Wernicke ’ s area located immediately superior to the auditory “names” region and anterior to the visual word processing area). Prefrontal Association Area. In Chapter 56, we learned that the prefrontal association area functions in close association with the motor cortex to plan complex patterns and sequences of motor movements. To aid in this function, it receives strong input through a massive subcortical bundle of nerve fibers connecting the parieto-occipitotemporal association area with the prefrontal association area. Through this bundle, the prefrontal cortex receives much preanalyzed sensory information, especially information on the spatial coordinates of the body that is necessary for planning effective movements. Much of the output from the prefrontal area into the motor control system passes through the caudate portion of the basal gangliathalamic feedback circuit for motor planning, which provides many of the sequential and parallel components of movement stimulation. The prefrontal association area is also essential to carrying out “ thought ” processes in the mind .This presumably results from some of the same capabilities of the prefrontal cortex that allow it to plan motor activities. It seems to be capable of processing non motor as well as motor information from widespread areas of the brain and therefore to achieve non motor types of thinking as well as motor types. In fact, the prefrontal association area is frequently described simply as important for elaboration of thoughts , and it is said to store on a short-term basis “working memories” that are used to combine new thoughts while they are entering the brain. Chapter 57 Cerebral Cortex, Intellectual Functions of the Brain, Learning and Memory 717 Broca’s Area. A special region in the frontal cortex, called Broca ’ s area , provides the neural circuitry for word formation . This area, shown in Figure 57–5, is located partly in the posterior lateral prefrontal cortex and partly in the premotor area. It is here that plans and motor patterns for expressing individual words or even short phrases are initiated and executed. This area also works in close association with Wernicke’s language comprehension center in the temporal association cortex, as we discuss more fully later in the chapter. An especially interesting discovery is the following: When a person has already learned one language and then learns a new language, the area in the brain where the new language is stored is slightly removed from the storage area for the first language. If both languages are learned simultaneously, they are stored together in the same area of the brain. Limbic Association Area. Figures 57–4 and 57–5 show still another association area called the limbic association area. This area is found in the anterior pole of the temporal lobe, in the ventral portion of the frontal lobe, and in the cingulate gyrus lying deep in the longitudinal fissure on the midsurface of each cerebral hemisphere. It is concerned primarily with behavior, emotions, and motivation. We will learn in Chapter 58 that the limbic cortex is part of a much more extensive system, the limbic system, that includes a complex set of neuronal structures in the midbasal regions of the brain. This limbic system provides most of the emotional drives for activating other areas of the brain and even provides motivational drive for the process of learning itself. Area for Recognition of Faces An interesting type of brain abnormality called prosophenosia is inability to recognize faces. This occurs in people who have extensive damage on the medial undersides of both occipital lobes and along the medioventral surfaces of the temporal lobes, as shown in Figure 57–6. Loss of these face recognition areas, strangely enough, results in little other abnormality of brain function. One wonders why so much of the cerebral cortex should be reserved for the simple task of face recognition. Most of our daily tasks involve associations Naming of objects Vision Visual processing of words Spatial coordinates of body and surroundings Somatosensory The occipital portion of this facial recognition area is contiguous with the visual cortex, and the temporal portion is closely associated with the limbic system that has to do with emotions, brain activation, and control of one’s behavioral response to the environment, as we see in Chapter 58. Word formation Broca‘s Area Limbic Association Area Wernicke‘s Area Auditory Behavior, emotions, motivation Language comprehension intelligence Motor Planning complex movements and elaboration of thoughts Figure 57–5 Map of specific functional areas in the cerebral cortex, showing especially Wernicke’s and Broca’s areas for language comprehension and speech production, which in 95 per cent of all people are located in the left hemisphere. 718 Unit XI The Nervous System: C. Motor and Integrative Neurophysiology
• #33: Figure 19-3 Pathways to the somatosensory, visual, and auditory association areas. Connections between cortical areas represent stages of information processing. At each stage progressively more abstract information is extracted from the sensory stimulus. Sensory information flows from the primary sensory areas (orange = primary somatosensory cortex; purple = primary visual cortex; yellow = primary auditory cortex) to adjacent unimodal association cortex. (From Jones EG, Powell TPS. 1970. Brain 93:793-820) Three Principles Govern the Function of the Association Areas Studies of afferent sensory pathways and association areas in the cortex have led to three important principles of sensory information processing: Sensory information is processed in a series of relays along several parallel pathways from peripheral receptors through primary sensory cortex and unimodal association cortex to the multimodal association cortex of the posterior part of the hemisphere: the posterior parietal and temporal cortices. Sensory information representing different modalities converges upon areas of cortex that integrate that information into a polysensory event. The posterior association areas that process sensory information are highly interconnected with the frontal association areas responsible for planning motor actions. These anterior association areas convert plans about future behaviors to concrete motor responses, such as satisfying hunger by eating. Sensory Information Is Processed Both Sequentially and in Parallel Cortical processing of sensory information has been studied most extensively in the visual and somatosensory systems, but the general principles derived from these studies apply to the other sensory modalities as well. In the chapters on the visual system (Chapters 25,26,27,28,29) we shall examine the cortical mechanisms that process incoming sensory signals into coherent information to construct visual perceptions. We shall learn how the axons of neurons in the primary visual cortex conveying simple sensory information converge on cells in adjacent secondary visual areas (Figure 19-3). The secondary visual areas are unimodal association areas. Even though neurons in these areas respond selectively to an array of inputs and are able to signal more complex aspects of the visual image, the information they process is entirely visual. In the monkey specific neurons in the visual association areas of the temporal lobe respond preferentially to a particular complex shape, such as a hand; some may respond selectively to specific faces. Damage to secondary sensory areas or to unimodal association cortex impairs the processing of specific types of sensory information, a condition called agnosia (Greek, “not knowing”). Injury to ventral areas of extra-striate cortex in humans may destroy the ability to recognize objects presented visually without affecting the ability to identify the same object by touch ( apperceptive agnosia ). Some patients can perceive an object and draw it accurately but cannot name it ( associative agnosia ).
• #34: Figure 19-4 Unimodal sensory inputs converge on multimodal association areas in the prefrontal, the parietotemporal, and limbic cortices. (The limbic cortices form an unbroken stretch along the medial edge of the hemisphere, surrounding the corpus callosum and the diencephalon.) Orange = somatosensory association cortex; purple = visual association cortex; yellow = auditory association cortex. Sensory Information From Unimodal Areas of Cortex Converges in Multimodal Areas Sensory pathways dedicated solely to visual, auditory, or somatic information converge in multimodal association areas in the prefrontal, parietotemporal, and limbic cortices (Figure 19-4). Neurons in these areas respond to combinations of signals representing different sensory modalities by constructing an internal representation of the sensory stimulus concerned with a specific aspect of behavior. For example, the multimodal sensory association cortex in the inferior parietal lobule is concerned with directing visual attention to objects in the contralateral visual field. Neurons in this area receive information about the position of a stimulus in the world as well as its spatial relationship to the individual's personal space. In monkeys, neurons in this area may respond to sight of a reward if the reward is within arm's reach (personal space) but not if it is across the room (extra-personal space). These neurons also receive highly specific information from the cingulate cortex (the limbic association area), such that emotional state is a factor in their firing. For example, if a monkey is presented with a syringe filled with juice, neurons in the inferior parietal lobule may respond more vigorously if the monkey is thirsty than if it is sated. As we shall see in Chapter 20, unilateral damage to the inferior parietal lobule results in sensory neglect of the contralateral world. Bilateral injury impairs the ability to explore the world on either side (Balint syndrome). Patients with Balint syndrome live as if they see only what is directly in front of them. They cannot locate objects in their visual world or construct an internal representation of the world around them ( amorpho-synthesis ). In Chapter 59, we shall learn about a region in the angular gyrus that is concerned with language and receives both visual input (reading) and somatosensory input (Braille). Injury to this area produces alexia (inability to read). Damage to the superior temporal lobe region (Wernicke's area), where the meaning of spoken words is analyzed, produces sensory aphasia. These difficulties in extracting language information from the ongoing sensory stream are also agnosias, but of a complex order.
• #35: Figure 19-5 The flow of information in the frontal lobe motor control system is essentially the reverse of that in the sensory systems. Information is processed in polymodal prefrontal areas (A) that are involved in motor planning and project to the premotor cortex. The premotor cortex generates motor programs (B) that it actuates by means of its projections to the motor cortex. Neurons in the motor cortex primarily fire to produce movements in particular directions around specific joints. The Sequence of Information Processing Is Reversed in the Motor System The posterior association areas are heavily interconnected with the association cortex of the frontal lobe. To understand these relationships we must first recognize that information processing in the motor system is essentially the reverse of the sequence in the sensory systems (Figure 19-5). Motor planning begins with a general outline of behavior and is translated into concrete motor responses through processing in the motor pathways. Within the frontal cortex individual neurons are not hard-wired to specific motor responses. Rather, individual cells fire during a range of related behaviors. Individual movements as well as complex motor actions derive from the patterns of firing of large networks of neurons in the frontal lobe. The final motor pathways leaving the cerebral cortex originate primarily from the primary motor cortex, which occupies the precentral gyrus. As we shall learn in Chapter 38, individual neurons in the primary motor cortex of normal, active monkeys fire just before a group of muscles contract to move a specific joint in a particular direction. The premotor cortex is a set of interconnected areas in the frontal lobe just rostral to the motor cortex. Premotor cortex includes areas 6 and 8 and the supplementary motor cortex on the medial surface of the hemisphere. Neurons there are active during preparation for movement. For example, some neurons fire while the animal is planning for movement, far in advance of the actual motor response. Whereas lesions of the primary motor cortex in humans produce contralateral hemiplegia—the complete absence of voluntary movement, although some postural and stereotyped involuntary movements may persist—lesions of the premotor cortex result in the inability to use the contralateral limbs (even though the strength of elemental movements such as grip and pulling may be largely preserved). The patient behaves as if the motor programs for moving the contralateral limbs have been lost, a condition known as limb kinetic apraxia. If the lesion is in the dominant hemisphere, even movement of the ipsilateral limbs, which depend upon the learned motor programs in the dominant hemisphere, will be impaired ( sympathetic apraxia ). The premotor cortex receives inputs mainly from three sources: (1) the motor nuclei in the ventroanterior and ventrolateral thalamus (which receive input from the basal ganglia and the cerebellum); (2) the primary somatosensory cortex and parietal association cortex (which provide information about the ongoing motor response); and (3) the prefrontal association cortex. In the next section we discuss the prefrontal association cortex in detail to illustrate how a multimodal association area functions. The posterior parietal association areas are considered in Chapter 20 and the posterior, temporal, and occipital areas in Chapter 28 in the context of visual perception. The limbic association areas are discussed in Chapter 50 in connection with emotion and again in Chapter 62 in connection with learning and memory.
• #37: "In our study, we've shown that the frontal lobes were the most critical region for visual perspective taking, and the inferior medial prefrontal region, particularly for the right, for detecting deception," says Dr. Stuss. Visual perspective taking is the ability to empathize or identify with the experience of another person. personalities. What is important about the study is that it helps families, friends and caregivers of the patient to appreciate and understand a very important reason why this occurs. This deficit in mentalizing can affect social cognition which is important in everyday human interactions. For example, patients with damage in the specific frontal area are often less empathetic and sympathetic, and they miss socialcues which lead to inappropriate judgements
• #39: C. A drawing of a computer reconstruction of the passage of a tamping iron through the brain of Phineas Gage over a century ago. This injury resulted in severe personality changes that illuminated our understanding of the function of the frontal lobes. (Adapted from Damasio et al. 1994) Phineas Gage and frontal lobe damage This year is the 150th anniversary of one of the world's most important on-the-job accidents. The accident injured only one worker, but it made medical history-and it taught us volumes about how the brain controls emotions and behavior. On September 13, 1848, railroad worker Phineas Gage was tamping blasting powder into a hole, using a three-and-a-half foot iron rod, when the powder exploded. The rod shot through Gage's skull, entering his left cheek and exiting through the top of his head. Amazingly, Gage survived this massive injury. In fact, one observer reported that Gage was able to walk away from the accident, "talking with composure and equanimity of the hole in his head." The long-term effects of Gage's accident, however, were devastating. Previously a polite and sociable gentleman, Gage became an antisocial, foul-mouthed, irresponsible, bad-mannered lout and unrepentant liar. According to his friends, he was "no longer Gage." He drifted from job to job, finally dying penniless. While Gage's life was ruined, his unfortunate accident taught researchers about the critical role of the brain's frontal lobes-the area of Gage's brain injured by the iron bar that penetrated his skull-in controlling behavior, emotions, and judgment. La a ater studies proved that injuries to the frontal lobes, or diseases that damage this brain area, can cause disinhibited behavior, poor judgment, and even antisocial or criminal behavior. Antonio Damasio and colleagues, who have studied a dozen patients with frontal lobe damage similar to Gage's, say that the patients are incapable of planning for the future, and are deficient in judgment, reasoning ability, and "moral insight." Other re e esearch links frontal lobe dysfunction to aggression, alcoholism, and psychopathic criminality, and suggests that the deviant behavior seen in many children with Fetal Alcohol Syndrome may stem from damage to this brain area. Problem #1 Phineas Gage is a hard-working, diligent, reliable, responsible, Intelligent. good-humored, deeply religious, family-oriented man until he is involved in an accident at which time an explosion occurs and a crowbar is driven into his brain. It transacts the orbit and pierces the frontal lobes. Amazingly, he has only a brief loss of consciousness and although he is rendered blind due to optic nerve damage, he has no other motor, sensory, language, or memory impairment. Over the course of time, several subtle and unfortunate changes in personality and behavior are noted. These include: 1. He becomes unreliable and fails to come to work and when present he is "lazy." 2. He has no interest in going to church, constantly drinks alcohol, gambles, and "whores about." 3. He is accused of sexually molesting young children. 4. He ignores his wife and children and falfls to meet his financial and family obligations. 5. He becomes "lazy" and fails to complete any task at work or at home. He has lost his sense of humor. 6. He curses constantly and does so in inappropriate circumstances. Questions 1. What portion of the brain ig most likely affected? 2. What is the function of this region? 3. Why are there no other cortical disturbances detected? Answers This case represents a classic example of frontal lobe injury. Located on the medial and undersurfaceof the frontal lobes is the limbic system. Dysfunction to the frontal lobe may result in profound behavioral abnormalities. In patients with "functional" psychiatric disorders (depression, anxiety, schizophrenia), metabolic abnormalities have been detected in the frontal lobes-"lobectomy" was performed in patients with severe mental illness. (A relic of one of the early neurosurgical instruments is on display in the pharmacy museum in the french quarter. Modern neurosurgery is more advanced. Somewhat.) 2. In addition to the personality and behavioral features, the frontal lobes play a role in these mental tasks: sustaining attention shifting attention initiating mental and motor activity inhibiting socially unaccepatable behavior (words or actions) 3. Because the injury spared the language, memory, motor, sensory, and visual cortex regions, there are no other neurological impairments. It is truly amazing the Phineas Gage survived his injury and that there were no other neurological impairments except that "Phineas Gage was no longer Phineas Gage."
• #43: SCHIZOPHRENIA That neurologic abnormalities underlie the clinical condition schizophrenia is now secure knowledge (see Hyde and Weinberger in this issue of Seminars). However, the precise pathologic lesions and the localization of the abnormalities continue to arouse interest and controversy. Much recent work has highlighted abnormalities of frontal lobe function in this condition. Several authors have drawn attention to the likeness of some schizophrenic symptoms to frontal lobe disorder, in particular that involving dorsolateral prefrontal cortex. Symptoms included are those of the affective changes, impaired motivation, poor insight. and other "defect symptoms." Evidence for frontal lobe dysfunction in schizophrenic patients has been noted in neuropathologic studies, (23) in EEG studies, (24) in radiologic studies using CT measures, (25) with MRI, (26) and in cerebral blood flow (CBF) studies. (27) The last have been replicated by findings of hypofrontality in several studies using positron emission tomography (PET). (28) These findings emphasize the importance of neurologic and neuropsychologic investigation of patients with schizophrenia, using methods that may uncover underlying frontal lobe disturbances, and the important role that frontal lobe dysfunction may play in the development of schizophrenic symptoms. (23)
• #50: Figure 26.12. Activation of neurons near the principal sulcus of the frontal lobe during delayed response task. (A) Illustration of task. The experimenter randomly varies the well in which the food is placed. The monkey watches the morsel being covered, and then the screen is lowered for a standard time. When the screen is raised, the monkey is allowed to uncover only one well to retrieve the food. Normal monkeys learn this task quickly, usually performing at a level of 90% correct after less than 500 training trials. (B) Region of recording. (C) Activity of a delay-specific neuron in the prefrontal cortex of a rhesus monkey recorded during the delayed response task shown in (A). The histograms show the number of action potentials during the cue, delay, and response periods. The neuron begins firing when the screen is lowered and remains active throughout the delay period. (D) When no food is presented, but the screen is still lowered and raised, the same neuron is relatively silent. (After  Goldman- Rakic , 1987 .) “ Planning Neurons” in the Monkey Frontal Cortex In further confirmation of the human clinical evidence about the function of the frontal association cortices, neurons that appear to be specifically involved in planning have been identified in the frontal cortices of rhesus monkeys. The behavioral test used to study cells in the monkey frontal cortex is called the  delayed response task  ( Figure 26.12A ). Variants of this task are used to assess frontal lobe function in a variety of situations, including the clinical evaluation of frontal lobe function in humans ( Box C ). In the delayed response task, the monkey watches an experimenter place a food morsel in one of two wells; both wells are then covered. Subsequently, a screen is lowered for an interval of a few seconds to several minutes (the delay). When the screen is raised, the monkey gets only one chance to uncover the well containing food and receive the reward. Thus, the animal must decide that he wants the food, remember where it is placed, recall that the cover must be removed to obtain the food, and keep all this information available during the delay so that it can be used to get the reward. The monkey's ability to carry out this task is diminished or abolished if the area anterior to the motor region of the frontal cortex—called the prefrontal cortex—is destroyed bilaterally (in accord with clinical findings in human patients). Some neurons in the prefrontal cortex, particularly those in and around the principal sulcus ( Figure 26.12B ), generate a response that is correlated with the delayed response task; that is, they are maximally active during the period of the delay, as if their firing represented the information maintained from the presentation part of the trial (i.e., the cognitive information needed to guide behavior when the screen is raised;  Figure 26.12C , D ). Such neurons return to a low level of activity during the actual motor phase of the behavior, suggesting that they represent working memory and planning rather than the actual movement itself. Delay-specific neurons in the prefrontal cortex are also active in monkeys that have been trained to perform a variant of the delayed response task in which the response is to internally generated memories. Evidently, these neurons are equally capable of using stored information to guide behavior. Thus, if a monkey is trained to associate eye movements to a particular target with a delayed reward, the delay-associated neurons in the prefrontal cortex will fire during the delay, even if the monkey moves his eyes to the appropriate region of the visual field in the absence of the target. The existence of delay-specific neurons in the frontal cortex of rhesus monkeys, as well as attention-specific cells in the parietal cortex and recognition-specific cells in the temporal cortex, generally supports the functions of these cortical areas inferred from clinical evidence in humans . Nonetheless, functional localization, whether inferred by examining human patients or by recording single neurons in monkeys, is an imprecise business. The observations summarized here are only a rudimentary guide to thinking about how complex cognitive information is represented and processed in the brain, and how the relevant brain areas and their constituent neurons contribute to such important but still ill-defined qualities as personality, intelligence ( Box D ), or other cognitive functions that define what it means to be a human being. Lesions of the Prefrontal Association Area in Monkeys Interfere With Motor Planning In the 1930s Carlyle Jacobsen showed that the prefrontal association area is concerned with the memory and planning of motor actions. He removed the prefrontal association area in two monkeys and studied their behavior using a variety of tasks that involved delayed action. In a delayed alternation task the monkey had to choose between two containers, one on the right and one on the left, with a time delay between each choice. In a delayed-response task the experimenter showed food to a hungry animal and, while the animal watched, the food was placed randomly under one of two identical opaque containers, one on the left, the other on the right. After a delay of 5 s or longer the monkey was permitted to select one of the containers (Figure 19-8). Normal animals quickly learned to perform the two tasks correctly, but the animals with frontal damage did poorly on both. Most important, the lesioned animals performed well only when there was no delay. Jacobsen's experiments suggested that the frontal association area is needed for executing complex motor tasks when the essential cues are not present in the environment at the time of the response and must be recalled by short-term memory. Therefore the prefrontal association cortex is involved in short-term memory. Later research showed, however, that the lesions do not produce a generalized deficit involving all aspects of short-term memory. Rather, the deficit is specific for working memory , a temporary storing of information used to guide future actions. Working memory is a form of motor planning, and it refers to the active maintenance of information relevant to an ongoing behavior. The idea of working memory was introduced in 1974 by the cognitive psychologist Alan Baddeley. He suggested that apparently simple aspects of everyday life—carrying on a conversation, adding a list of numbers, driving a car—depend on a short-term memory mechanism that integrates moment-to-moment perceptions across time, rehearses them, and combines them with simultaneous access to archival information about past experience, actions, or knowledge. According to Baddeley, working memory has three distinct components: one for verbal memories; a parallel component for visual memories; and a third component that functions as a central executive, coordinating the flow of attention from one component of working memory to another. Neuropsychologists have developed several tests of working memory and have used them to activate the frontal lobe in imaging studies in order to demonstrate aspects of working memory that are impaired by lesions of the frontal lobe (Box 19-2). Lesions of the Frontal Association Cortex: Deficits of Planning The functional deficits that result from damage to the human frontal lobe are diverse and devastating, particularly if both hemispheres are involved. This broad range of clinical effects stems from the fact that the frontal cortex has a wider repertoire of functions than any other neocortical region (consistent with the fact that the frontal lobe in humans and other primates is the largest of the brain's lobes and comprises a greater number of cytoarchitectonic areas). The particularly devastating nature of the behavioral deficits after frontal lobe damage reflects the role of this part of the brain in maintaining what is normally thought of as an individual's “personality.” The frontal cortex integrates complex perceptual information from sensory and motor cortices, as well as from the parietal and temporal association cortices. The result is an appreciation of self in relation to the world that allows behaviors to be planned and executed normally. When this ability is compromised, the afflicted individual often has difficulty carrying out complex behaviors that are appropriate to the circumstances. These deficiencies in the normal ability to match ongoing behavior to present or future demands are, not surprisingly, interpreted as a change in the patient's “character.” The case that first called attention to the consequences of frontal lobe damage was Phineas Gage, a worker on the Rutland and Burlington Railroad in mid-nineteenth-century Vermont. A conventional way of blasting a rock in that era was to tamp powder into a hole with a heavy metal rod. Gage, the popular and respected foreman of the crew, was undertaking this procedure one day in 1848 when his tamping rod sparked the powder, setting off an explosion that drove the rod, which was about a meter long and 4 or 5 centimeters in diameter, through his left orbit (eye socket), destroying much of the frontal part of his brain in the process (see the illustration on the page introducing this Unit). Gage, who never lost consciousness, was promptly taken to a local doctor, who treated his wound. An infection set in, presumably destroying additional frontal lobe tissue, and Gage was an invalid for several months. Eventually, he recovered and was—to outward appearances—well again. Those who knew Gage, however, were profoundly aware that he was not the “same” individual that he had been before. A temperate, hardworking, and altogether decent person had, by virtue of this accident, been turned into an inconsiderate, intemperate lout who could no longer cope with normal social intercourse or the kind of practical planning that had allowed Gage the social and economic success he enjoyed before. The physician who had looked after Gage until his death in 1863 summarized his impressions of Gage's personality as follows: [Gage was] 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 with his desires, at times pertinaciously obstinate, yet capricious and vacillating, devising many plans of future operations, which are no sooner arranged than they are abandoned in turn for others appearing more feasible. A child in his intellectual capacity and manifestations, he has the animal passions of a strong man. Previous to his injury, although untrained in the schools, he possessed a well-balanced mind, and was looked upon by those who knew him as a shrewd, smart businessman, very energetic and persistent in executing all his plans of operation. In this regard his mind was radically changed, so decidedly that his friends and acquaintances said he was ‘no longer Gage'. J. M. Harlow, 1868  (Publications of the Massachusetts Medical Society  2: pp. 339–340) Another classical case of frontal lobe deficits was a patient followed for many years by the neurologist R. M. Brickner during the 1920s and '30s. Joe A., as Brickner referred to his patient, was a stockbroker who underwent bilateral frontal lobe resection because of a large tumor at age 39. After the operation, Joe A. had no obvious sensory or motor deficits; he could speak and understand verbal communication and was aware of people, objects, and temporal order in his environment. He acknowledged his illness and retained a high degree of intellectual power, as judged from an ongoing ability to play an expert game of checkers. Nonetheless, Joe A.'s personality had undergone a dramatic change. A restrained, modest man, he became boastful of professional, physical, and sexual prowess, showed little restraint in conversation, and was unable to match the appropriateness of what he said to his audience. Like Gage, his ability to plan for the future was largely lost, as was much of his earlier initiative and creativity. Even though he retained the ability to learn complex procedures, he was unable to return to work and had to rely on his family for support and care. Sadly, these effects of damage to the frontal lobes have also been documented by the many thousands of frontal lobotomies (or “leukotomies”) performed in the 1930s and '40s as a means of treating mental illness. The rise and fall of this “psychosurgery” provides a compelling example of the frailty of human judgment in medical practice, and of the conflicting approaches of neurologists, neurosurgeons, and psychiatrists in that era to the treatment of mental disease (Box B).
• #51: Figure 19-10 Neurons in the cortex around the principal sulcus track working memory. The records show the firing of a neuron in the right principal sulcus of a monkey during an oculomotor delayed-response task. While the animal fixated at the center of the visual field a visual cue was presented in the left visual hemifield for 0.5 s (indicated by the letter C). The animal was required to continue to stare at the center of the visual field during the delay period (D) following the presentation of the cue. At the end of the delay period a signal was given for the animal to turn its eyes to where the cue had been (response, R). On trials in which the monkey correctly turned its eyes to the left (upper traces), the neuron fired throughout the delay period. On the trial in which the animal incorrectly turned its eyes to the right (lower trace), the neuron began to fire but then almost completely stopped firing after 3 s. Some neurons failed to show any increase in firing during the delay when the animal made an incorrect response. (Adapted from Funahashi et al. 1989.)
• #52: Elaboration of Thought, Prognostication, and Performance of Higher Intellectual Functions by the Prefrontal Areas—Concept of a “Working Memory.” Another function that has been ascribed to the prefrontal areas by psychologists and neurologists is elaboration of thought . This means simply an increase in depth and abstractness of the different thoughts put together from multiple sources of information. Psychological tests have shown that prefrontal lobectomized lower animals presented with successive bits of sensory information fail to keep track of these bits even in temporary memory, probably because they are distracted so easily that they cannot hold thoughts long enough for memory storage to take place. This ability of the prefrontal areas to keep track of many bits of information simultaneously and to cause recall of this information instantaneously as it is needed for subsequent thoughts is called the brain’s “working memory.” This could well explain the many functions of the brain that we associate with higher intelligence. In fact, studies have shown that the prefrontal areas are divided into separate segments for storing different types of temporary memory, such as one area for storing shape and form of an object or a part of the body and another for storing movement. By combining all these temporary bits of working memory, we have the abilities to (1) prognosticate; (2) plan for the future; (3) delay action in response to incoming sensory signals so that the sensory information can be weighed until the best course of response is decided; (4) consider the consequences of motor actions before they are performed; (5) solve complicated mathematical, legal, or philosophical problems; (6) correlate all avenues of information in diagnosing rare diseases; and (7) control our activities in accord with moral laws. Working Memory -Most of our memories are fleeting because few of the many experiences we have in the course of an average day are remembered for very long, nor do they need to be. Transient memories are absolutely essential to the process of understanding the meaning of events as they occur in the present. This type of very short-term memory for things being experienced now is known as working memory; it allows you to comprehend what you are reading or to figure out the meaning of what has just been said to your in a conversation. Working memory can be thought of as a low capacity information reservoir that is always full, sensations flowing into it continuously at about the same rate that they are forgotten. Some of the information held in short-term storage may be important enough to be remembered for a long time and must therefore be transferred to a more stable form of storage, which is represented by far more robust alterations in the brain's chemical and physical make-up in the form of synaptic connections. It is not necessarily for an important experience to trigger the formation of long-term memories, other factors such emotion, practice, and rehearsal also facilitate the transformation. Experiments show that in all cases the most important underlying distinction between the short- and long-term memory formation is that the latter requires a dialogue between synapses and genes and the former does not. The working memory itself is located in the prefrontal cortex. As experimental techniques became refined, it has become clear that there is no rigid dividing line between a memory and a thought. A model of working memory has been developed to combine perceptions, memories and concepts together, and consists of three parts: Phonological loop - Memory in this area (see Figure 25) enables us to remember sequences of approximately seven digits, letter, or words. The language areas of the brain are mainly in the left hemisphere, around and above the ear. The language loop start with hearing words in the auditory cortex and/or reading words in the visual cortex. Perception of language results from the convergence of auditory and visual information in Wernicke's area. Expression of language is controlled by Broca's area; while the angular gyrus is concerned with meaning. Visual-spatial scratch pad - It is like a sort of inner eye, which receives and codes data into visual or spatial images. For example, it comes into play when we need to remember where we were on a page when we start reading a book again. Functional imaging suggests that this complex structure represents the "what" and "where" in short-term memory (see Figure 25). Central executive - This most important yet least well understood component of the working memory model, is postulated to be responsible for the selection, initiation, and termination of processing routines (e.g., encoding, storing, retrieving). It is believed that this component coordinates information from a number of sources, directs the ability to focus and switch attention, organizes incoming material and the retrieval of old memories and combines information arriving via the other two temporary storage systems. It performs various tasks such as reasoning or doing mental arithmetic - rather like the RAM (Radom Access Memory) of a computer.
• #53: Figure 19-9 Imaging of working memory. Statistical parametric maps (SPMs) rendered onto the lateral brain surface (green) demonstrate the functional anatomy of the verbal and visuospatial short-term working-memory systems. Areas of significant changes in blood flow associated with a comparison of experimental and control blood-flow distributions are shown as yellow, red, or white areas. The blue lines indicate sulci. (Courtesy of E. Paulesu.) A. Scans were recorded during a short-term verbal memory task for letters and compared with scans from a similar nonverbal task. The “phonological loop” localizes to Broca's area and the left inferior parietal cortex. B. Comparison of scans from a short-term memory task with those from a rhyming task with no memory demands enables identification of the inferior parietal lobule as the anatomical site of the “phonological store.” C. Comparison of scans from a task in which a series of line drawings were remembered with those from a control task reveal that the “visuospatial sketchpad” localizes to the right occipital, parietal, and prefrontal cortices. 1. The visuospatial “buffer” in this experiment localized to the inferior parietal lobe in the region of the angular gyrus on the right (2). Verbal Working Memory People are capable of keeping a small amount of verbal information in mind for almost indefinite periods. We commonly use working memory to remember telephone numbers for short periods of time until we can write them down or consign them to long-term memory. Alan Baddeley proposed a model of working memory based on observations in normal subjects carrying out specific tasks that interfere with components of this system. This model conceives of an “articulatory loop” with two components: (1) a silent speech or subvocal rehearsal system the phonological logs that can be accessed by reading words or numbers, and (2) a short-term memory store activated directly by speech (the phonological store). This theoretical model now has a biological basis in neuroanatomy, supported by imaging studies. Areas of brain activation are indexed by changes of cerebral blood flow observed when subjects perform tasks known to isolate these two components of verbal working memory. In one task subjects were told to rehearse silently a list of consonants presented on a screen and then indicate if a probe letter had been seen previously. This task engaged both components of the articulatory loop. In a second task subjects were required to make rhyming judgments. Letters again appeared on the screen, and the subjects were required to indicate when a letter that rhymed with the letter B appeared. This task is known to engage the subvocal rehearsal system but not the phonological store. The results show that the phonological store involves the left supramarginal gyrus whereas the subvocal rehearsal system involves Broca's area (Figure 19-9A, B). Nonverbal working memory has a similar dichotomy between a visuospatial scratch pad and short-term visuospatial memory system (Figure 19-9C). Baddeley stressed that the various components of verbal and nonverbal memory are controlled through a central executive function. The frontal lobes play a crucial role in this process, which ensures that complex behavior can be planned and remains flexible in the face of changing circumstances. One marked feature of central executive function is the ability to remember what one has done recently. The region ventral to the principal sulcus stores information in working memory about what the object is—the object's shape and color. The region dorsal to the sulcus holds information about where the object is—its location in space. In addition, some neurons in the prefrontal cortex respond to both object shape and object location, suggesting that they may integrate information about an object and spatial information, which is necessary to guide behavior. These neurons presumably receive input from both dorsolateral and ventrolateral regions of the prefrontal cortex. Moreover, in addition to these regions concerned with visuospatial memory, positron emission tomography (PET) studies have demonstrated that the human brain has a separate locus for verbal memory, as predicted by the earlier cognitive experiments. As we shall learn in the next chapter and in Chapter 25, the posterior parietal association cortex, which is concerned with spatial perception, projects to the prefrontal cortex and makes connections with the regions involved in working memory and with the motor regions concerned with motor planning and execution of eye and hand movements. To plan and execute complex behavior under everyday conditions, the frontal association areas must in turn call upon the posterior parietal and limbic association areas. Indeed, anatomical studies suggest that the prefrontal association areas work reciprocally with the posterior parietal association areas.
• #54: Figure 19-12 Common output targets of parietal and prefrontal association areas in cortical and subcortical areas. The connections of the posterior parietal (intraparietal sulcus) and caudal principal sulcus are based on double-label studies in which one anterograde tracer was injected into the prefrontal cortex and another into the parietal cortex of the same animal. Superimposition of adjacent sections shows these areas projecting to common target areas including (1) limbic areas on the medial surface, (2) opercular and superior temporal cortices on the lateral surface, and (3) a range of subcortical sites. (Adapted from Goldman-Rakic 1987.) Interaction Among Association Areas Leads to Comprehension, Cognition, and Consciousness The dorsolateral prefrontal association cortex and parietal association cortex are among the most densely interconnected regions of association cortex, and both project to numerous common cortical and subcortical structures (Figure 19-12). The interactions between the posterior and anterior association areas are critical in guiding behaviors. Neurons in the posterior association areas often also continue firing after the stimulus has ceased. They may also respond to a particular stimulus only when the stimulus is involved in a behavior, and not when the stimulus is not involved. For example, they might fire in response to a light if it is a cue to explore the nearby space (to obtain a reward). These neurons fire regardless of the type of behavioral response required, such as an eye or hand movement, and may even fire when the animal is prevented from making any exploratory movement but merely required to attend to a part of space from the periphery of its vision to obtain a reward. Hence, neurons in the posterior association area are most tightly linked to the sensory rather than motor aspects of a complex behavior. Neurons in the premotor cortex may have similarly selective responses to sensory stimuli, but they fire only if action (motor output) is required. The interactions between the posterior and anterior association areas determine whether an action will occur and what the temporal pattern of motor responses will be. More than a century ago John Hughlings Jackson expressed the view that the conscious sense of a coherent self is not the outcome of a distinct system in the brain. Rather, he argued, consciousness emerges from the operation of the association cortices. Patients with focal lesions of association areas have selective and quite restricted loss of self-awareness for certain classes of stimuli while maintaining awareness for others. For example, a patient with a large lesion in the right (nondominant) parietal lobe may be unaware of the contralateral world. Lacking the concept of “left,” the patient will eat only the food on the right side of the tray and, if still hungry, will learn to rotate to the right in order to position the remaining food on the right side. Similarly, a patient with language disturbance resulting from damage to Wernicke's area will be unaware of the symbolic content of language. The patient will prattle on in response to a question, without understanding the question. Because the patient's “speech” is inflected normally with emotional tone, it appears from the patient's behavior as if words are merely an adornment to gestural communication. Similar dissociation is found in the so-called split-brain patient, in whom the cerebral hemispheres have been separated (by surgically sectioning the corpus callosum and anterior commissure) in order to control chronic epileptic seizures. Split-brain patients seem to have two independent conscious selves. Because the nondominant (usually right) hemisphere is “mute,” some might assume that only the dominant (left) hemisphere, which “talks,” is conscious. However, as we shall see next, by forcing behavioral choices that rely upon information available only to the right hemisphere, it is possible to identify a broad range of cognitive functions that are mediated by the right hemisphere alone.
• #61: CONFABULATION (DELUSIONAL & FALSE MEMORIES) When secondary to right (or bilateral) frontal damage, speech may become exceedingly bizarre, delusional, and fantastical, as loosely associated ideas become organized and anchored around fragments of current experience. For example, one patient, when asked as to why he had been hospitalized, denied that there was anything wrong, but instead claimed he was there to do some work. When asked what kind of work, he pointed to the air conditioning unit, and stated: "I'm a repair man. I'm here to fix the air conditioner. Now, if you'd please excuse me. I've got work to do." A 24 year old store cleark who received a gunshot wound (during the course of a robbery) which resulted in destruction of the right inferior convexity and orbital areas, attributed his hospitalization to a plot by the government to steal his inventions (Joseph 1986a). He claimed he was a famous inventor, had earned millions of dollars and had even been on TV. When it was pointed out that he had undergone surgery for removal of bone fragments and the bullet, he pointed to his head and replied, "that's how they are stealing my ideas." Another patient, formerly a janitor, who suffered a large right frontal subdural hematoma (which required evacuation) soon began claiming to be the owner of the business where he formerly worked (Joseph 1988a). He also alternatively claimed to be a congressman and fabulously wealthy. When asked about his work as a janitor he reported that as a congressman he had been working under cover for the C.I.A. Interestingly, this patient, also stated he realized what he was saying was probably not true. "And yet I feel it and believe it though I know it's not right." Frontal lobe confabulation seems to be due to disinhibition, difficulties monitoring responses, withholding answers, utilizing external or internal cues to make corrections, accessing appropriate memories, maintaining a coherent line of reasoning, or suppressing the flow of tangential and circumstantial ideas (Fischer et al. 1995; Joseph 1986a,1988a, 1999a; Johnson, O'Connor and Cantor 1997; Kapur and Coughlan 1980; Shapiro et al.1981; Stuss et al. 1978; Stuss and Benson 1986). That is, since the right frontal lobe can no longer regulate information processing and the flow of perceptual and ideational activity, information that is normally filtered out and suppressed is instead expressed. In consequence, the Language Axis of the left hemisphere becomes overwhelmed and flooded by irrelevant, bizarre associations, leading sometimes to the expression of false memories, which the patient (that is, Broca's area) repeats (Joseph, 1982, 1986ab, 1988ab). As noted, in some respects injuries involving the orbital frontal lobes can result in symptoms similar to those with right frontal injuries, including the production of confabulatory ideation. However, in contrast to right (or bilateral) frontal injuries which may result in the production of fantastical spontaneous confabulations where contradictory facts are ignored or simply incorporated, confabulatory responses associated with orbital injuries tend to be more restricted, transitory, and in some cases must be provoked (Fischer et al. 1995).
• #62: THE RIGHT FRONTAL LOBE AND THE REGULATION OF AROUSAL The right cerebral hemisphere is clearly dominant in regard to the mediation and control over most aspects of social-emotional functioning (chapter 10). There is also a variety of findings which strongly suggest that the so called alerting/arousal vigilance network is localized to the right frontal lobe (Posner & Raichle, 1994), and that the right frontal lobe exerts bilateral influences on arousal (DeRenzi & Faglioni, 1965; Heilman & Van Den Abell, 1979, 1980; Joseph, 1982, 1986a, 1988a, 1999a; Konishi, et al., 1999; Tucker, 1981). For example, the intact, normal right hemisphere is quicker to react to external stimuli, and has a greater attentional capacity compared to the left (Dimond, 1976, 1979; Heilman & Van Den Abell, 1979; Jeeves & Dixon, 1970; Joseph, 1988ab). In split brain studies the isolated left hemisphere tends to become occasionally unresponsive, suffers lapses of attention, and is more limited in attentional capacity as compared to the right which attends to both the left and right half of visual, auditory, and tactile space (Dimond 1976, 1979; Joseph 1986a, 1988ab). Indeed, visual and somesthetic stimuli, or active touch exploration with either the right or left hand, elicits evoked EEG responses preferentially and of greater magnitude over the right hemisphere and right frontal lobe (Desmedt 1977). The right hemisphere also becomes desynchronized (aroused) following left or right sided stimulation (indicating it is bilaterally responsive), whereas the left brain is activated only with unilateral (right side) stimulation (Heilman & Van Dell Abell, 1980). In fact, the right frontal lobe and hemisphere responds more quickly even to stimuli appearing on the right side (Dimond 1976 1979; Heilman and Van Den Abell 1979, 1980; Jeeves and Dixon 1970). In consequence, if the right frontal lobe (or hemisphere) is injured, the left frontal lobe is unable to attend to events occurring on the left side of the body, which results in unilateral left-side neglect. The right frontal lobe is also larger than the left suggesting a greater degree of interconnections with other brain tissue, and it appears to exert bilateral inhibitory influences on attention and arousal (Cabeza and Nyberg 1997; DeRenzi and Faglioni 1965; Dimond 1976 1979; Heilman and Van Den Abell 1979, 1980; Jeeves and Dixon 1970; Joseph 1986a, 1988ab; Konishi et al., 1999; Pardo et al. 1991; Tucker 1981). For example, as based on functional imaging, it has been found that when performing a "go/no-go task" and the Wisconsin Card Sort--tasks requiring the inhibition of irrelevant or erroneous responses, activity significantly increases in the right inferior frontal lobe, and that this was the case irrespective of if the human subjects used the right or left hand (Konishi et al., 1999). By contrast, the left frontal region appears to exert unilateral excitatory influences which promotes right sided motor control and speech expression. However, because the right frontal lobe appears to exert bilateral inhibitory influences, whereas the influences of the left are unilateral and excitatory, when the left frontal region is damaged, the right may act unopposed and there may be excessive left cerebral inhibition or reduced activity (e.g., Bench et al., 1995); for example, as manifested by speech arrest, depression, and/or apathy. Nevertheless, because left cerebral excitatory influences are predominantly unilateral, with massive right cerebral damage, although the left hemisphere is aroused, the left is unable to activate the right half of the brain. This may result in unilateral inattention and neglect of the left half of the body and space (Heilman & Valenstein, 1972; Joseph, 1986a, 1988a; Na et al., 1999). That is, the patient's (undamaged) left hemisphere may ignore his of her left arm or leg, and if their neglected extremities are shown to them, may claim they belong to the doctor or a person in the next room. That such disturbances occur only rarely with left frontal or left hemisphere damage further suggests that the right hemisphere is able to continue to monitor events ocurring on either side of the body. Thus although the damaged left hemishere is hypoaroused (or inhibited by the right), there is little or no neglect. However, with lesions involving the right frontal lobe, not only is there a loss of inhibitory control, but the left may act unopposed such that there is excessive excitement. The patient becomes disinhibited as manifested by speech release, confabulation, lability, and a host of impulsive disturbances which may wax and wane in severity. As detailed below, mania, confabulation, hypersexuality, tagentiality, and impulsive, labile, disinhibited and inappropriate social and emotional behaviors are predominately associated with right frontal dysfunction (Bogousslavsky et al. 1988; Clark and Davison 1987; Cohen and Niska 1980; Cummings and Mendez 1984; Fischer et al. 1995; Forrest 1982; Girgis 1971; Jack et al. 1983; Jamieson and Wells 1979; Joseph 1986a, 1988a, 1999a; Kapur and Coughlan 1980; Lishman 1973; Miller et al. 1986; Oppler 1950; Rosenbaum and Berry 1975; Shapiro et al.1981; Starkstein et al. 1987; Stern and Dancy 1942; Stuss and Benson 1986); a function of loss of inhibitory control as well as its role in all aspects of emotion. In fact, and as originally pointed out by Lisman (1968, 1973), injuries to the right frontal lobe are clearly associated with what has been described as the "frontal lobe personality," including, in the extreme, the development of a full blown manic psychosis coupled with disinhibited sexuality.
• #63: THE FRONTAL LOBE PERSONALITY by Rhawn Joseph, Ph.D. The frontal lobes serve as the "Senior Executive" of the brain and personality, acting to process, integrate, inhibit, assimilate, and remember perceptions and impulses received from the limbic system, striatum, temporal lobes, and neocortical sensory receiving areas (Fuster 1997; Joseph 1986a; Koechlin et al., 1999; Milner and Petrides 1984; Passingham 1993; Selemon et al. 1995; Shallice and Burgess 1991; Stuss 1992; Stuss and Benson 1986; Strub and Black 1993; Van Hosen et al., 1996). Through the assimilation and fusion of perceptual, volitional, cognitive, and emotional processes, the frontal lobes engages in decision making and goal formation, modulates and shapes character and personality and directs attention, maintains concentration, and participates in information storage and memory retrieval (Dolan et al., 1997; Joseph, 1986a, 1988a, 1999a; Kapur et al., 1995; Passingham, 1997; Posner & Raichle, 1994; Tulving et al., 1994). The frontal neocortex is "interlocked" with the limbic system, striatum, and the primary and secondary receiving areas via converging and reciprocal connections, and receives verbal and ideational impulses transmitted from the multi-modality associational areas including Wernicke's area and the inferior parietal lobule (Cavada 1984; Fuster 1997; Jones and Powell 1970; Goldman-Rakic 1995, 1996; Passingham, 1993, 1997; Pandya & Yeterian 1990; Petrides & Pandya 1988). It is thus able to act at all levels of information analysis. THE FRONTAL LOBE PERSONALITY With unilateral, bilateral, or even seemingly mild frontal lobe dysfunction patients may initially display an array of waxing and waning abnormalities including the "frontal lobe personality," i.e. tangentiality, childishness, impulsiveness, jocularity, grandiosity, irritability, increased sexuality, and manic excitement (Joseph, 1988a, 1999a; Lishman, 1973). Over fifty years of research and numerous case studies have consistently indicated that with significant frontal lobe pathology attentional functioning may become grossly comprised, behavior may become fragmented, and initiative, goal seeking, concern for consequences, planning skills, fantasy and imagination, and the general attitude toward the future may be lost. The patient's range of interests may shrink, they may be unable to adapt to new situations or carry out complex, purposive, and goal directed activities, and lack insight, judgement, and common sense (Fuster 1997; Freeman and Watts 1942; Girgis 1971; Hacaen 1964; Joseph 1986a, 1988a, 1999a; Luria 1980; Passingham 1993; Petrie 1952; Stuss 1991; Stuss and Benson 1986). Conversely, when engaging in memory, planning, decision making, goal formation, and tasks requiring imagination, the frontal lobes become highly active--as demonstrated by functional imaging (Brewer et al., 1998; Passingham, 1997; Wagner et al., 1998; Dolan et al., 1997; Squire, et al,. 1992; Tulving et al., 1994; Kapur et al., 1995). With massive trauma, stroke, neoplasm or surgical destruction (i.e. frontal lobotomy), patients may show a reduction in activity and take very long to achieve very little. They may be unconcerned about their appearance, their disabilities, and demonstrate little or no interest in self-care or the manner in which they dress, or even if their clothes are soiled or inappropriate (Bradford 1950; Broffman 1950; Freeman and Watts 1942; Petrie 1952; Strom-Olsen 1946; Stuss 1991; Stuss and Benson 1986; Tow 1955). Although some patients demonstrate restlessness, impulsiveness, and flight of ideas, they may also tire easily, show careless work habits and a desire to get things over with quickly. As repeatedly documented following frontal lobotomy, they may immediately develop a tendency to lie in bed unless forcibly removed (Broffman 1950; Freeman and Watts 1942 1943; Rylander 1948; Tow 1955). Even with mild and subtle frontal lobe damage, patients may seem to take hours to get dressed, to finish their business in the bathroom, or to shop and purchase simple items. For example, patients may spend hours in the bathtub playing with the bubbles. A curious mixture of obsessive compulsiveness and passive aggressiveness may be suggested by their behavior. In severe cases, compulsive utilization of utensils and tools may occur, as well as distractability and perserveration. For example, following frontal lobotomy, "sometimes a pencil and a piece of paper will be enough to start an endless letter that may end up with the mechanical repitition of a certain phrase, line after line and even page after page" (Freeman and Watts 1943, p. 801). Even with "mild" to moderate frontal lobe injuries patients may initially demonstrate periods of tangentiality, grandiosity, irresponsibility, laziness, hyperexcitability, promiscuity, silliness, childishness, lability, personal untidiness and dirtiness, poor judgment, irritability, fatuous jocularity, and tendencies to spend funds extravagantly. Unconcern about consequences, tactlessness, and changes in sex drive and even hunger and appetite (usually accompanied by weight gain) may occur, coupled with a reduction in the ability to produce original or imaginative thinking. DISINHIBITION AND IMPULSIVENESS Following lobotomy or massive or even mild frontal injuries patients may become emotionally labile, irritable, euphoric, aggressive, and quick to anger, and yet be unable to maintain a grudge or a stable mood state as they rapidly oscillate between emotions (Bradford 1950; Greenblatt 1950; Joseph 1986a, 1999a; Rylander 1939; Strom-Olsen 1946; Stuss 1991; Stuss and Benson 1986). Depending on the degree of damage, they may become unrestrained, overtalkative, and tactless, saying whatever "pops into their head", with little or no concern as to the effect their behavior has on others or what personal consequences may result (Broffman 1950; Bogousslavasky et al. 1988; Freeman and Watts 1943; Joseph 1986a, 1999a; Luria 1980; Miller et al. 1986; Partridge 1950; Rylander 1939, 1948; Strom-Olsen 1946). With severe injuries patients may seem inordinantly disinhibited and influenced by the immediacy of a situation, buying things they cannot afford, lending money when they themselves are in need, and acting and speaking "without thinking." Seeing someone who is obese they may call out in a friendly manner, "Hey, fatty", and comment on their presumed eating habits. If they enter a room and detect a faint odor, its: "Hey, who farted?" Following severe injuries there may be periods of gross disinhibition which may consist of loud, boisterous, and grandiose speech, singing, yelling, and beating on trays. The destruction of furniture and the tearing of clothes is not uncommon. Some patients may impulsively strike doctors, nurses, or relatives and thus behave in a thoroughly labile, aggressive, callous and irresponsible manner (Benson and Geschwind 1971; Freeman and Watts 1942, 1943; Joseph 1986a, 1999a; Strom-Olsen 1946; Stuss and Benson 1986). One patient, with a tumor involving the right frontal area, following resection, attempted to throw a fellow patient's radio through the window because he did not like the music. He also loudly sang opera in the halls. Indeed, during the course of his examination he would frequently sing his answers to various questions (Joseph 1986a). Impulsiveness can also be quite subtle. Luria (1980, p. 294), describes one patient with a slowly growing frontal tumor "whose first manifestation of illness occurred when, on going to the train station, he got into the train which happened to arrive first, although it was going in the opposite direction." UNCONTROLLED LAUGHTER AND MIRTH Frontal lobe patients can act in a very childish and puerile manner, laughing at the most trivial of things, making inappropriate jokes, teasing, and engaging total strangers in hillarious conversation (Ackerley 1935; Freeman and Watts 1942, 1943; Kramer 1954; Luria 1980; Petrie 1952; Rylander 1939, 1948; Stuss and Benson 1986). Pathological laughter, joking, and punning may occur superimposed upon a labile effect. Many are vastly amused by their own jokes (Ironside 1956; Kramer 1954; Martin 1950). They can be quite funny, but often they are not! In part, frontal lobe humor is a function of tangentiality and disinhibition. Loosely connected ideas are strung together in an unusual fashion. The tendency to exaggerate and to impulsively comment upon whatever draws their attention is also contributory, and their humor and laughter may have a contagious quality. Nevertheless, rather than funny, frontal patients may seem crude and inappropriate. They may laugh without reason and with no accompanying feelings of mirth. These disturbances were in fact documented over 50 years ago. Kramer (1954) for example, describes 4 cases of uncontrollable laughter after lobotomy. They were unable to stop their laughter on command or upon their own volition. The laughter would come on like spells, occurring up to a dozen times a day, and/or continue into the night, requiring sedation in some cases. In these instances, however, the laughter had no contagious aspects but seemed shrill and "frozen." When questioned about the laughter the patients either confabulated a reason for their mirth, or seemed completely perplexed as to the cause. THE ORBITAL FRONTAL PERSONALITY Focal tumors of the orbital regions have also been reported to give rise to gelastic seizures (Chen and Foster 1973; Daly and Moulder 1957; Loiseau, Cohandon, and Cohandon 1971); that is, seizures which induce uncontrolled laughter. In fact, with lesions localized to the orbital frontal lobes patients may become disinhibited, hyperactive, euphoric, extroverted, labile, overtalkative, and develop perseveratory tendencies (Butter 1969; Butter et al. 1970; Greenblatt 1950; Joseph 1999a; Kennard et al. 1941; Kolb et al. 1974; Malloy, Birhlr, and Duffy 1993; Reitman 1946 1947; Ruch and Shenkin 1943). Proneness to criminal behavior, promiscuity, gradiosity, and paranoia have also been observed (Blumer and Benson 1975; Lishman 1973; Luria 1980; Raine et al. 1994; Stuss and Benson 1986). In general, right orbital damage seems to result in the most severe alterations in mood and emotional functioning (Grafman et al. 1986), which in turn is likely a function of the greater role of the right frontal lobe and the right hemisphere including the right inferior frontal lobe, in the regulation of emotion and arousal (Joseph, 1986a, 1988a, 1999a; Konishi et al., 1999; Tucker, 1981). In addition to laughter, punning and "Witzelsucht" (puerility), language might become excessively and inappropriately profane, and the patient may seem inordinately inconsiderate, outspoken, and obstinant (Broffman 1950; Partridge 1950; Strom-Olsen 1944; Stuss 1991; Stuss and Benson 1986). However, although they may easily swear, laugh, joke, and make threats, they may also become inordinately apathetic and listless, spending much of their time doing nothing. Alteration of Behavior and Personality A lack of initiative and spontaneity is the most common effect of frontal lobe disease and much easier to observe than to quantitative. With relatively mild form of this disorder, patient exhibit and idleness of thought, speech and action and they lapse into this state without complaints. They are tolerant to most condition in which they are placed, though they may may act unreasonably for brief period if irritated, seemingly being unable to think through the consequence of their remonstrance. They let member of the family answer questions and do the talking interjecting a remark only rarely. Question directed to such patients may evoke only a brief, unqualified answer.. Once started on a task they may persist in it (“stimulus bound”) I.e. thy tend to perseverate. Fluster emphasize the failure over time to maintain events in serial order and to integrate new events and information with previously learned data. Placidity: worry, anxiety, self concern, hypochondriasis, and pain reduces Psychomotor retardation: number of movements, spoken words and thought per unit of time diminish. Mild form abulia and severe akinetic mutism. Poorly localized to bilateral ventromedial frontal and fronto-diencephalic connections. INTELLECTUAL DEFICITS AND LACK OF CONCERN FOR LONG TERM CONSEQUENCES It has frequently been claimed that intelligence is not effected even with massive injuries to the frontal lobes. However, this view is completely erroneous for even in mild cases, although intelligence per se may not seem to be reduced as based on IQ testing, the ability to effectively employ one's intelligence is almost always compromised. Frontal lobe damage and lobotomy reduces one's ability to profit from experience, to anticipate consequences, or to learn from errors (Bianchi 1922; Drewe 1974; Goldstein1944; Halstead 1947; Milner 1964 1971; Nichols and Hunt 1940; Joseph 1986a, 1999a; Petrie 1952, Porteus and Peters 1947; Rylander 1939; Shallice and Burgess 1991; Stuss and Benson 1986; Tow 1955). There is a reduction in creativity, fantasy, dreaming, and abstract reasoning. The capacity to synthesize ideas into concepts or to grasp situations in their entirety is lost, and interests of an intellectual nature are diminished, or sometimes abolished. As described by Freeman and Watts (1943, p. 803) "patients who were great readers of good literature will be interested only in comic books or movie magazines. Men of considerable intellectual achievement... when discussion turns on the great events of the day will pass off some cliches as their own opinions". In mild or severe cases thinking may be contaminated by perseverative intrusions of irrelevant and tangential ideas, randomly formed associations, and illogical intellectual activity. These patient are also often effected by the immediacy of their environment and have difficulty making plans or adequately meeting long term goals. Even if highly intelligent, they may no longer be able to use that intelligence affectively, and they may undergo a complete personality change. In 1981, following his graduation from Stanford University, D.F., and three friends, founded their own electronics/computer company, which immediately became a modest success, and began to rapidly grow and expand. D.F., tall, lanky, clumsy, already losing his hair, and only 27 years old, was an electronics genius and in all respects the classic "nerd." He had never dated, and never had a social life, and throughout his younger years had been treated like a "retard" by his school mates. Although he was "vice president" of his company, and a co-owner, and worth over seven figures, he simply lacked the self-confidence to mingle or socialize with the opposite sex, and didn't feel comfortable interacting with anyone who did not share his enthusiasm for computers. Neverthless, D.F. was lonely. He needed a girlfriend. In 1985 his company "went public" (made a public offering of stock) and D.F. was suddenly a multi-millionaire without a girlfriend. It was soon thereafter that a "new girl" was hired to work as an assistant and secretary, just outside his office. "She was beautiful! An angel! Long blond hair. Green eyes. She must have weighed only 100 pounds. Everytime I walked out side my office I felt shocked to see her. And she wasn't married. She was only 23. I started thinking about her all the time. I coudn't concentrate. I dreamed about her. I wanted to marry her. I loved her. Love her!" he gushed, his words racing. But D.F. didn't have the nerve to approach her, or talk to her, except to say hi. "She always smiled at me, when I said hi. A big smile. I knew she liked me." But he still didn't ask her out. Instead, he began to fantasize, about being married, having children. And then after several tortured months, D.F. came to a decision. "I bought her a huge diamond ring. Ten thousand dollars. And I asked her to marry me." According to D.F., he simply approacher her, offered her the ring, which she took and put on her finger. And then he asked her to marry him. Apparently she was stunned. Apparently she even laughed. Apparently she even thanked him for the ring. But she said no. D.F. was mortified and became massively depressed. He couldn't function. Couldn't think."I just wanted to die." D.F. purchased a handgun. Took it home. Placed the barrel in his mouth. But then aimed it incorrectly. He pointed it directly into the roof of his mouth, pulled the trigger, and then blew out his right frontal lobe. Approximately six months later, D.F. arrived for his appointment to see me, with a toothbrush, toothpaste, hair brush, and wash rag sticking out of his shirt pocket (Joseph 1988a). When I asked, pointing at his pocket, "What's all that for?" he replied with a laugh, "That's just in case I want to brush my teeth," and in so saying he quickly drew the toothbrush from his pocket and began to demonstrate. During the course of the exam he laughingly demonstrated how the skin flap which covered the hole in his head (from the craniotomy and bullet wound) could bulge in or out when he held his breath or held his head upside down. He even climbed up and stood on this examiner's desk and bent over so as to offer a better view of the hole in his head. Throughout the exam he behaved in a silly, pueril manner, often joking and laughing inappropriately. Even when discussing the blond secretary and the aftermath, he laughed, becoming serious for only a few moment when I asked him if she had given him back the ring. She hadn't. Nevertheless, despite his bizarre and inappropriate behavior, D.F.'s overall WAIS-R IQ was above 130 (98% rank: "Very Superior"). Unfortunately, although he had a high IQ, he could no longer employ that intelligence, intelligently. On the other hand, he was no longer depressed, which is one of the many reasons that frontal lobotomies became such a popular in-office psychiatric procedure during the 1940s and 1950s. Frontal lobe patients also may have difficulty thinking up or considering alternative problem solving strategies and thus developing alternative lines of reasoning. For example, Nichols and Hunt (1940) dealt a patient five cards down including the ace of spades which always fell to the right on two successive deals and then to the left for two trials. The patients task was to learn this pattern and turn up the ace. The patient failed to master this after 200 trials. Some frontal lobe patients may also have extreme difficulty sorting even common everyday objects according to category (Rylander, 1939; Tow, 1955), for example, sorting and grouping drinking containers (glasses) with other drinking containers (mugs), tools with tools, etc. Similarily, they may have difficulty performing the Wisconsin Card Sorting Task (Crockett et al., 1986; Drewe, 1974; Milner, 1964, 1971) which involves sorting geometric figures according to similarity in color, shape, or number. However, the manner in which a patient fails on this task is dependent on the locus and laterality of the damage. For example, patients with orbital damage seem to have relatively little difficulty performing this category sorting task (Drewe, 1974; Milner, 1971). Similarly, patients with right frontal damage, although they show a tendency to make perseverative type errors (i.e. persisting in a choice pattern which is clearly indicated as incorrect), perform significantly better than those with left frontal damage (Drewe, 1974; Milner, 1964, 1971). Thus overall, patients with left medial and convexity lesions perform most poorly, and have the greatest degree of difficulty thinking in a flexible manner or developing alternative response strategies. I.Q. Testing A number of studies of conceptual functioning have been performed before and after surgical destruction of the frontal lobes. Although in some cases, such as D.F., described above, the IQ remains high, performance is so uneven and there is so much intertest variability that it is apparent that patients have suffered significant declines (Petrie, 1952; Smith, 1966). In studies in which patients undergoing frontal leucotomy for intractable pain were administered the Wechsler Intelligence Scales both pre- and post surgery, a 20 point drop in the IQ was reported (Koskoff, 1948, cited by Tow, 1955). Likewise, in cases where the Raven's Progressive Matrices or Porteus Mazes were administered both before and after lobotomy, significant declines in intellectual functioning have been documented (Petrie, 1952; Porteus & Peters, 1947; Tow, 1955). As with most tests, the usual pattern is to improve with practice. Hence, these results (and those mentioned above) indicate that frontal lobe damage disrupts abstract reasoning skills, verbal-nonverbal pattern analysis, learning and intellectual ability, as well as the capacity to anticipate the consequences of one's actions or to profit from experience. However, the effects of frontal damage on IQ is dependent on the locus of the damage. For example, left frontal patients show lower Wechsler IQs than those with right frontal lesions (Petrie, 1952; Smith, 1966). In fact, 17 of 18 patients with left frontal damage reported by Smith (1966) scored lower across all subtests compared to those with right frontal lesions. Indeed, patients with left sided destruction perform as poorly as those with bilateral damage (Petrie, 1952). In analyzing subtest performance, Smith (1966) notes that left frontal lobotomy patients scored particularly poorly on Picture Completion (which requires identification of missing details). This is presumably a consequence of the left cerebral hemisphere being more conerned with the perception of details (or parts, segments) vs wholes (chapters 10, 11). Petrie (1952), however, reports that performance on the Comprehension subtests (i.e. judgment, common sense) was most significantly impaired among left frontals. In contrast, individuals with severe right frontal damage have difficulty performing Picture Arrangement--often leaving the cards in the same order in which they are laid (McFie & Thompson, 1972). This may be a consequence of deficiencies in the capacity to discern social-emotional nuances, a function at which the right hemisphere excels (chapter 10). Nevertheless, since so few studies have been conducted it is probably not reasonable to assume that lesions lateralized to the right or left frontal lobe will always effect performance on certain subtests, particularly if there is a mild injury. It is also important to consider in what manner lateralized effects on IQ may be contributing to or secondary to reduced motivation and apathy since bilateral and left frontal damage often give rise to this constellation of symptoms. If the patient is apathetic they are not going to be motivated to perform at the best of their ability. The frontal lobes serve as the "Senior Executive" of the brain and personality, acting to process, integrate, inhibit, assimilate, and remember perceptions and impulses received from the limbic system, striatum, temporal lobes, and neocortical sensory receiving areas (Fuster 1997; Joseph 1986a; Koechlin et al., 1999; Milner and Petrides 1984; Passingham 1993; Selemon et al. 1995; Shallice and Burgess 1991; Stuss 1992; Stuss and Benson 1986; Strub and Black 1993; Van Hosen et al., 1996). Through the assimilation and fusion of perceptual, volitional, cognitive, and emotional processes, the frontal lobes engages in decision making and goal formation, modulates and shapes character and personality and directs attention, maintains concentration, and participates in information storage and memory retrieval (Dolan et al., 1997; Joseph, 1986a, 1988a, 1999a; Kapur et al., 1995; Passingham, 1997; Posner & Raichle, 1994; Tulving et al., 1994). The frontal lobes are not a homologous tissue, and each frontal region is concerned with somewhat different as well as overlapping functions. However, the frontal lobes are clearly functionally laterlized, with a specific spectrum of disorders and functions classically associated with and mediated by the right hemisphere and right frontal lobes, and a different spectrum associated with the left frontal regions. For example, reduced speech output, Broca's aphasia, apathy, "blunted" schizophrenia and major depression are often associated with left lateral (and bilateral) frontal injuries (Bench et al., 1995; Benes, McSparren, and Bird, 1991; Buchsbaum et al. 1998; Carpenter et al. 1993; Casanova et al. 1992; Curtis et al. 1998; d'Elia and Perris 1973, Goodglass & Kaplan, 1999; Hillbom 1951; Perris 1974; Robinson and Downhill 1995; Sarno, 1998). By contrast, impulsiveness, confabulatory verbosity, grandiosity, and mania are often produced by right frontal (as well as bilateral) lesions (Bogousslavsky et al. 1988; Clark and Davison 1987; Cohen and Niska 1980; Cummings and Mendez 1984; Forrest 1982; Girgis 1971; Jack et al. 1983; Jamieson and Wells 1979; Joseph 1986a, 1988a, 1999a; Lishman 1973; Miller et al. 1986; Oppler 1950; Robinson and Downhill 1995; Rosenbaum and Berry 1975; Starkstein et al. 1987; Stern and Dancy 1942; Stuss and Benson 1986). Moreover, as the right frontal lobe is associated with the expression of emotional melodic speech injuries to this area can also produce pressured and/or confabulatory speech that may be melodically distorted. Thus, where with left frontal injuries patients may seem apathetic, indifferent, and/or severely depressed and psychotic if not schizophrenic, right frontal injuries are associated with manic-like disinhibited states, including waxing and waning abnormalities associated with manic-depression. Patient's may become so disinhibited they develop the classic "frontal lobe personality," and become disinhibited, hyperactive, euphoric, extroverted, labile, overtalkative, and may develop perseveratory tendencies (Butter 1969; Butter et al. 1970; Greenblatt 1950; Joseph 1999a; Kennard et al. 1941; Kolb et al. 1974; Malloy, Birhlr, and Duffy 1993; Reitman 1946 1947; Ruch and Shenkin 1943). Patients may become so disinhibited, delusional, grandiose, and emotionally labile that they develop what has classically been described as mania. By contrast, with a left frontal lesion, rather than a loss of emotional control, there is a loss of emotion, and the patient will become severely apathetic, indifferent, and with massive lesions unresponsive, though classically left frontal injuries are associated with depression. These right and left frontal differences are a function of lateralized differences in the control over arousal. Whereas the orbital frontal lobes contraol limbic arousal, the right and left frontal lobes contraol neocortical arousal, with the right frontal lobe exerting bilateral inhibitory and excitatory influences, whereas the left frontal lobe exerts unilateral excitatory influences. MANIA When the right orbital and/or right lateral convexity are damaged, behavior often becomes inappropriate, labile, and disinhibited. Individuals may become hyperactive, distractable, hypersexual, tangential, delusional, and confabulatory (Bogousslavsky et al. 1988; Clark and Davison 1987; Cohen and Niska 1980; Cummings and Mendez 1984; Joseph,1986a, 1988a, 1999a; Lishman 1973; Robinson and Downhill 1995; Starkstein et al. 1987). Although laughing and joking one moment, these same patients can quickly become irritated, angered, enraged, destructive, or conversely tearful and depressed with slight provocation. That is, the patient may present with manic-depressive symptoms, with mania predominating. Hence, manic-depression (bipolar affective disturbances) may be due to waxing and waning abnormalities involving the right and left frontal lobes. Mania and manic-like features have been reported in many patients with injuries, tumors, and even seizures involving predominantly the frontal lobe and/or the right hemisphere (Bogousslavsky et al. 1988; Clark and Davison 1987; Cohen and Niska 1980; Cummings and Mendez 1984; Forrest 1982; Girgis 1971; Jack et al. 1983; Jamieson and Wells 1979; Joseph 1986a, 1988a, 1999a; Lishman 1973; Miller et al. 1986; Oppler 1950; Robinson and Downhill 1995; Rosenbaum and Berry 1975; Starkstein et al. 1987; Stern and Dancy 1942). One frontal patient described as formerly very stable, and a happily married family man, became excessively talkative, restless, grossly disinhibited, sexually preoccupied, extravagantly spent money and recklessly purchased a business which soon went bankrupt (Lishman 1973). In another case, a 46-year old woman was admitted to the hospital and observed to be careless about her person and room, and incontinent of urine and feces. She slept very little and acted in a hypersexual manner. Her symptoms had developed several months earlier when she began accusing a neighbor of taking things she had misplaced. She also would confront him and strip off her clothes. She began going about in just a slip and bra, and informed people she was descended from queens, was fabulously wealthy, and that many men wanted to divorce their wives and marry her. During her hospitalization she was frequently quite loud, disoriented to time and place, and extremely tangential, jumping from subject to subject. After several years she died and a meningioma involving the orbital surface of the right frontal lobes was discovered (Girgis 1971). I have examined 19 male and five female patients who developed mania after suffering a right frontal stroke or trauma to the right frontal lobe. All but four of the males had good premorbid histories and had worked steadily at the same job for over 3-5 years (e.g. Joseph, 1986a, 1988a). Following their injuries all developed delusions of grandeur, pressured speech, flight of ideas, decreased need for sleep, indiscriminant financial activity or irresponsibility, emotional lability, and increased libido, including, in one case, persistent sexual overtures coupled with genital exposure, to the patient's sisters and mother. One formerly very conservative engineer with over 20 patents to his name suffered a right frontal injury when he fell from a ladder. He became sexually indiscriminate and reportedly patronized up to 3 prostitutes a day, whereas before his injury his sexual activity was limited to once weekly with his wife. He also spent money lavishly, suffered delusions of grandeur, camped out at Disney Land and attempted to convince personnel to fund his ideas for a theme park on top of a mountain, and at night had dreams where the Kennedy's would appear and offer him advice --and he was a republican!
• #64: DISINHIBITED SEXUALITY In some cases following frontal lobe damage patients may engage in inappropriate sexual activity (Benson and Geschwind 1971; Brutkowski 1965; Freeman and Watts 1942, 1943; Girgis 1971; Leutmezer et al., 1999; Lishman 1973; Miller et al. 1986; Strom-Olsen 1946; Stuss and Benson 1986). One patient, after a right frontal injury began patronizing up to 4 prostitutes a day, whereas his premorbid sexual activity had been limited to Tuesday evenings with his wife of 20 years (Joseph 1988a). Another patient with a right frontal stroke propositioned nurses and would spontaneously reach out and fondle large breasted women (Joseph 1988a). It is not unusual for a hypersexual, disinhibited frontal lobe injured individual to employ force. One individual who was described as quite gentle and sensitive prior to his injury, subsequently raped and brutalized several women. Similar behavior has been described following lobotomy. As stated by Freeman and Watts (1943, p. 805): "Sometimes the wife has to put up with some exaggerated attention on the part of her husband, even at inconvenient times and under circumstances which she may find embarrassing. Refusal, however, has led to one savage beating that we know of, and to an additional separation or two" (p. 805). Curiously, in these situations Freeman and Watts (1943, p. 805) have suggested that "spirited physical self-defense is probably the best strategy of the woman. Her husband may have regressed to the cave-man level, and she owes it to him to be responsive at the cave-women level. It may not be agreeable at first, but she will soon find it exhilarating if unconventional." Seizure activity arising from the deep frontal regions have also been associated with increased sexual behavior, including sexual automatisms, exhibitionism, gential manipulation, and masturbation (Leutmezer et al., 1999; Spencer, Spencer, Williamson, & Mattson 1983; Williamson, et al., 1985). One young man that I evaluated and who was subsequently found, with depth electrode recording, to have seizures emitting from the right frontal lobe, had been arrested over 7 times for exposing himself in public. His parents complained that he would sometimes walk around the house grabbing and exposing his genitals, and would sometimes even pee on the floor. In fact, while I was evaluating him as he lay in bed at the Yale Seizure Unit (VAMC) he suffered a seizure which involved the following sequence. He grunted loudly and his left arm shot out in a lateral arc. His left hand then returned to his body and he began to fiddle with the buttons of his pajamas continuing in a downward motion until he reached his penis which he then took in his hand and began to squeeze. As I looked on, he suddenly began to urinate and with such force that I was nearly sprayed with urine. Fortunately, I deftly escaped by leaping to the side and against the wall which put me well out of his range. By contrast, a young woman I examined with right frontal-temporal seizures would spread her legs and engage in pelvic thrusting, coupled with grunting, lip licking and tongue protrusion. Currier et al., (1971), have also reported pelvic thrusting and moaning, and sex appropriate vocalizations, with temporal lobe seizures. However, according to Leutmezer et al., (1999) and as based on prolonged scalp-EEG monitoring, sexual automatisms, such as "sexual hypermotoric pelvic or truncal movements are common in frontal lobe seizures," whereas "discrete genital automatisms, like fondling and grabbing the genitals are more common in seizures involving the temporal lobe." Presumably, the results of Leutmezer et al., (1999) differ from that of Currier, et al., (1971), Joseph (1988a, 1999a), Spencer et al., (1983), and Williams et al., (1985), due to their use of scalp rather depth electrodes which are more sensitive and exacting. On the other hand, temporal lobe/hippocampal sclerosis and atrophy were also documented in the Leutmezer et al. (1999) study. Nevertheless, given the close functional association between the frontal and temporal lobes, and the fact that even a frontal seizure can propagate to the amygdala and thus involve the temporal lobe, perhaps the dysfunctional differences in abnormal sexual behavior are due to seizure origin and the subsequent spread of seizure activity. Indeed, insofar as the behavior involves fondling and grabbing, the hands are being employed, and the hands are generally represented along the medial walls, within the SMA, cingulate, and along the lateral surface of the frontal lobe (see below), whereas truncal movements are more the province of the striatum with which the amygdala is intimately interconnected. Indeed, even with complete destruction of the anterior temporal lobe human and non-human primates may fondle their genitals and masturbate--a common components of the Kluver-Bucy syndrome (see chapter 13). However, as the amygdala has been removed bilaterally, then this part of the brain cannot be directing hand-movements toward the genitals, which thus implicates the frontal lobes. Although this issue cannot be resolved here, it is nevertheless rather obvious than frontal-temporal seizures can produce abnormal and/or inappropriate sexual behavior. There is also some evidence for functional laterality in regard to sexual automatisms and abnormal sexual behavior. In most instances, "sexual" seizures are associated with right frontal seizure foci (Joseph 1988a; Spencer et al. 1983). However, patients may also become hyposexual (Greenblatt 1950; Miller et al. 1986), especially with left frontal injuries, and/or experience genital pain with left temporal seizures (Leutmezer et al., 1999).
• #65: Frontal Lobe Syndrome Frontal lobe syndrome is a disorder affecting the prefrontal areas of the frontal lobe. The prefrontal lobe comprises the vast area of the frontal lobe anterior to the motor cortex and includes the undersurface of the frontal lobe, or the orbital region. The frontal lobe syndrome is said to be present when an individual who is previously capable of judgment and sustained application and organization of his life becomes aimless and improvident, and may lose tact, sensitivity, and self-control. Additionally, the individual affected by pathology in the prefrontal cortex may demonstrate impulsiveness and a failure to appreciate the consequences of his or her reckless behavior.1 Frontal lobe syndrome can be caused by head trauma or may be the consequence of brain tumor, cerebrovascular accident, infection, or a degenerative cortical disease such as Pick's disease.2 This syndrome represents an organic explanation for psychologically-based symptoms the patient may demonstrate. Due to the anterior location of the prefrontal region, lesions to this region may be missed on a standard neurological examination or on a cursory mental status examination. The mental changes produced by lesions in the prefrontal region have led to the recognition of the "frontal lobe personality," as the patient tends to demonstrate specific personality changes which are more often revealed by a qualitative analysis of the patient's attitudes and types of errors produced rather than by a crude quantitative analysis of performance.3 The behavioral changes associated with bilateral prefrontal lesions may be difficult to measure, but family, friends, and employers may tell you that the patient is "no longer the same."4 Following a head injury, personality change in the injured patient is frequently reported and is often cited by family members as the most difficult and persistant problem that they face. Spouses of patients with frontal lobe syndrome relate that "it is like living with a different person," or that the patient "is not the person I married." Post-traumatic personality changes seen with injuries to the prefrontal region may result in marital break-up, social isolation, or unemployment, as some are fired from their jobs because of inadequate performance or because of offending their co-workers.1,2,4,5,6 Compounding the problem in the identification of prefrontal involvement is the dissociation between how well a patient with a bifrontal lesion can appear during the initial office visit and how poorly they actually perform in real life.4 The consequences of damage to the prefrontal region include: alterations of attention concrete thinking perseveration reduced activity disturbed affect The frontal lobe syndrome patient may demonstrate an attention deficit. The patient may appear slow, uninterested, may lack spontaneity, may be easily distracted by irrelevant environmental stimuli, and may be unable to sustain attention. The patient's disinterest and easy distractibility may contribute to an apparent poor memory. The frontal lobe syndrome patient's memory is normal, but absentmindedness may lead to the appearance of a memory deficit as the patient literally "forgets to remember" and has the inability to focus attention long enough to form the rudiments of memory. These patients may fill in memory gaps with confabulation, or the elaboration of imaginary facts and experiences to fill in their gaps of knowledge or memory.2,3,4,5,6 These patients may also engage in concrete thinking, which is an impairment of abstract thought. This trend may be identified during a basic mental status evaluation by the patient's inability to properly interpret proverbs.2,4 Closely linked to concrete thinking is the demonstration of "utilization behavior" in which the patient has the tendency to manually grasp and use objects presented within reach.2,3 Perseveration is common in frontal lobe syndrome patients and is the tendency to maintain a previously established motor pattern without modifying the activity according to the demands of the changing environment because of an inability to shift from one line of thinking to another.2,3,4 When faced with a series of different motor tasks, the patient may end up performing one component of the series of tasks over and over again and may demonstrate great difficulty, or an inability to change motor patterns. Perseveration is one of the reasons for poor job performance in the frontal lobe syndrome patient. These patients may demonstrate a diminution of spontaneous activity, a lack of drive, an inability to plan ahead, a lack of concern, and possible bouts of restlessness and aimless, uncoordinated behavior.1-6 These findings may also contribute to poor job performance and family relations. Lastly, the frontal lobe syndrome patient may demonstrate a disturbance of affect ranging from complete apathy to disinhibition depending upon the location of the lesion. A lesion to the dorsolateral aspect of the prefrontal region may produce apathy, emotional blunting, and an indifference to the surrounding world. Their apathy may be noted during examination and may extend toward work and family. These patients may become incontinent, not because of a lesion affecting bladder function, but because of a disregard for their surroundings and the consequences of their actions. Conversely, a patient with a lesion to the orbital region of the prefrontal lobe, or the underside, may exhibit disinhibition, a failure to appreciate the consequences of one's actions, and euphoria with a tendency to jocularity. These patients may exhibit moria (childish excitement), joking and pathological punning, sexual indiscretions, and exhibitionism.1-6 Thus, in the presence of an unremarkable neurological examination, these specific findings may be the only indication of an injury or an underlying pathology in the affected patient. Next month's column will stress simple testing procedures for frontal lobe syndrome. References Walton J. Brain Diseases of the Nervous System, 10th Edition, Oxford Medical Publishers, New York, 1993. Trimble MR. Behavior and personality disturbances, In: Bradley WG, Daroff RB, Fenichel GM, and Marsden CD, Neurology in Clinical Practice, Vol. I, Butterworth-Heinemann, Boston, 1991. Gainotti G. Frontal lobe damage and disorders of affect and personality, In: Swash M and Oxbury J, Clinical Neurology, Churchill-Livingstone, New York, 1991. Devinsky O. Behavioral Neurology, Mosby, St. Louis, 1992. Greenwood R, Barnes MP, McMillan TM, and Ward CD. Neurological Rehabilitation, Churchill-Livingstone, New York 1993. Strub RL and Black FW. The Mental Status Examination in Neurology, 3rd Ed. F.A. Davis, Philadelphia, 1991. The Frontal Lobe is the most anterior, right under the forehead. Functions: How we know what we are doing within our environment ( Consciousness ). How we initiate activity in response to our environment. Judgments we make about what occurs in our daily activities. Controls our emotional response. Controls our expressive language. Assigns meaning to the words we choose. Involves word associations. Memory for habits and motor activities. Observed Problems: Loss of simple movement of various body parts ( Paralysis ). Inability to plan a sequence of complex movements needed to complete multi-stepped tasks, such as making coffee ( Sequencing ). Loss of spontaneity in interacting with others. Loss of flexibility in thinking. Persistence of a single thought ( Perseveration ). Inability to focus on task ( Attending ). Mood changes ( Emotionally Labile ). Changes in social behavior. Changes in personality. Difficulty with problem solving. Inablility to express language ( Broca's Aphasia ). The frontal lobes are responsible for voluntary motor activity, speaking ability and elaboration   of thought.  The primary motor cortex, which is located in between the left hemisphere and somato sensory cortex, confers voluntary control over the movement produced by the skeletal muscles.  As in sensory processing, the motor cortex on each side of the brain primarily controls muscles on the opposite side of the body.  Damage to the motor cortex on the left side of the brain produces paralysis on the right side of the body and vice versa.  The frontal lobe extends from the central sulcus to the anterior limit of the brain.  The posterior portion of the frontal lobe is precentral gyrus, which is specialized for the control of fine movements, such as the movement of fingers one at a time.  The prefrontal cortex, the most anterior portion of the frontal lobe, is the only cortical area known to receive input from all sensory modalities.  This region was also the target of prefrontal lobotomies, a type of  brain surgery conducted in attempts to control certain types of psychological disorders.  As a result  of the surgery, patients showed impairments in certain aspects of memory and in their facial expressions of emotion. The frontal lobe can be divided into three functional zones: Motor cortex: Responsible for initiating voluntary movements Premotor cortex: Selects movements based on external cues. Prefrontal cortex: Ensures that the right movements are made at the time and place.