Brain lesions and emotional disorders

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Brain lesions and emotional disorders Guido Gainotti Università Cattolica, Neuropsychology Service, Policlinico Gemelli, Largo A. Gemelli, 8 Rome, Italy Tel.: +39 063 550 1945; Fax: +39 063 550 1909; [email protected]

Many authors think that emotional disorders of brain-damaged patients result directly (as in the case of language, memory and other cognitive disorders) from the disruption of specific cortico–subcortical circuits. This claim, however, is only in part correct, as the homology between emotional and cognitive systems is partial and only some emotional disorders of brain-damaged patients are due to the disruption of specific brain structures. Other emotional disorders result from a more general mechanism, namely from the appraisal of the personal implications that physical and cognitive consequences of brain injury will have for the quality of life of the patient. The aim of this review is to stress the distinction between emotional and cognitive systems, the componential nature of emotions, the brain structures subtending the different components of emotion and the nature of the process of ‘emotional appraisal’. Starting from these theoretical premises, the author will attempt to distinguish the emotional disorders of brain-damaged patients that result from the disruption of specific brain structures from those that are due to more general appraisal and coping mechanisms.

Emotional & cognitive systems

componential nature and hierarchical organization of emotions; the brain structures that subtend the various components and levels of emotions; and the nature of the process of ‘emotional appraisal’. Starting from these theoretical premises, the author will try to distinguish the emotional disorders of brain-damaged patients that result from disruption of specific brain structures, from those that are due to more general appraisal and coping mechanisms.

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According to a current, but oversimplified, neurobiological model, emotional disorders should result directly from the disruption of specific brain structures, similar to disorders of language, memory and other cognitive functions. This model neglects theoretical differences between emotions and specific cognitive functions, and is inconsistent with important anatomo–clinical observations. From the theoretical point of view, language, visual-spatial cognition and memory are components of a general adaptive system that can be labelled the ‘cognitive system’, whereas emotions constitute an alternative general adaptive system, provided by an intrinsic componential structure. Furthermore, the cognitive system aims to understand the objective meaning of stimuli, whereas the ‘emotional system’ aims to appraise the subjective, personal significance of events or situations. From the clinical standpoint, the claim that emotional disorders of brain-damaged patients result directly from the lesion of specific brain mechanisms does not explain the results of recent well-controlled studies, which have shown that most emotional disturbances are not related to the lesion of specific brain structures [1]. In this discussion of emotional disorders of brain-damaged patients, the author will first take into account the theoretical background, namely: the main similarities and differences between emotional and cognitive system; the

Keywords: amygdala, brain lesions, emotional disorders, fronto-orbital cortex, hemispheric asymmetries, post-stroke depression

10.2217/14796708.1.3.xxx © 2006 Future Medicine Ltd ISSN 1479-6708

Distinction between emotional & cognitive systems

Most authors consider emotions as a complex, but phylogenetically primitive, adaptive system providing the organism with a limited set of innate, concerted and routinized response patterns devised to automatically solve some of the basic adaptive problems of the human species [2–5]. The emotional system is partly independent from (but strongly interconnected with) the phylogenetically more advanced cognitive system. According to Oatley and Johnson-Laird, the emotional system must be considered as an emergency system able to interrupt ongoing actions urgently to rapidly select a new operative scheme, whereas the cognitive system is more evolved, but needs more time to carry out its work [6]. Both structural similarities and functional differences exist between emotional and cognitive systems, as both systems base their activity on components that must: analyze Future Neurol. (2006) 1(3), xxx–xxx

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become increasingly interconnected and the complexity of emotions evolves accordingly. Several authors have proposed that complex emotions (such as guilt, vanity or envy) may derive from blends among the primary emotions and from increasing interactions between the emotional and cognitive systems [7–9]. Furthermore, in recent years, emotions have been viewed as having great influence on other important components of human behavior, such as guiding decisions [10]. All of these reasons have prompted the construction of hierarchically organized developmental models aiming to explain: a) how complex emotions can be formed starting from the simplest ones and b) how the highest components of this structure keep the expressive parts of the emotional system under control. In particular, the Leventhal’s developmental model proposes that human emotions may be based on three functional levels:

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the external stimuli; select the most appropriate response pattern; and put all these information into appropriate memory systems. However, each system deals with sensory information and selects specific action schemata according to the general logic of coping with emergencies and keeping complex, changing situations under control. Main components of the emotional system

• the sensorimotor level • the schematic level • the conceptual level [3]

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Different analyses of sensory data are made by the emotional and cognitive systems. An exhaustive analysis of highly processed data (devised to obtain objective information regarding the external situation) is accomplished by the cognitive system, whereas a quick computation of poorly processed sensory data is sufficient to appraise if the event is pleasant or dangerous for the individual. Equally different are the action schemata activated by the evaluation of external stimuli. The action schemata triggered by the process of emotional computation are immediately selected from a small number of innate operative patterns, corresponding to the basic emotions of joy, sadness, fear, anger, surprise and disgust [2], which are considered the most important interactive schemata of the human species. These innate action patterns are characterized by their concerted/organized/routinized nature and typically include expressive-communicative components and an important activation of the autonomic nervous system. On the other hand, actions selected by the cognitive system consist of controlled strategic plans, which can include intentional, but not automatic, communicative-expressive components and do not require a concomitant strong activation of the autonomic nervous system. The learning mechanisms used by the emotional and the cognitive systems differ, as emotional learning is based on unconscious conditioning mechanisms, whereas the cognitive system makes use of conscious and controlled mechanisms to store new information in declarative memory.

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The sensorimotor level consists of a set of innate expressive motor programs triggered automatically by well-defined stimuli and including components of motor and autonomic activation, as well as the corresponding subjective emotional feelings. These basic programs are linked, during development, to situations of the individual experience by mechanisms of conditioned learning, thus building the ‘emotional schemata’, which are the units of the second schematic level of automatic and spontaneous emotional processing. The last stage of this model is the conceptual level, which is based on mechanisms of conscious declarative memory and does not store concrete emotional experiences, but abstract notions regarding emotions and social rules concerning their expression. The activation of these representations is, therefore, not accompanied by the corresponding emotional feelings.

Hierarchical organization of the emotional system

Emotional disorders directly due to brain lesions

As described previously, defining emotions as an emergency system, independent from and parallel to the cognitive system, mainly refers to the simplest forms and earliest stages of emotional development. During their development, emotional and cognitive systems

Brain structures subtending different components & levels of emotions & disorders resulting from brain-structure disruption

In order to distinguish emotional disorders due directly to brain lesions from those resulting from the process of appraisal of the personal Future Neurol. (2006) 1(3)

Brain lesions and emotional disorders – REVIEW

in terms of their emotional significance [4,10–13]. Furthermore, drawing on a suggestion originally advanced by Papez [14], several authors have proposed the existence of two different routes through which emotional stimuli can reach the amygdala [4,8]. The first (subcortical) route directly connects the thalamus with the amygdala, transmitting the crude sensory data that are needed to make a quick and raw computation of the possible personal meaning of incoming information. The amygdala could, in turn (through its feed-back connections with the cortical sensory areas), influence the further processing of incoming information through the second, more complex (cortical), route. LeDoux and colleagues have also shown that the subcortical route plays a critical role in processes of emotional conditioning [4,15,16], which allows the transition from the sensorimotor to the schematic level of the Leventhal’s model [3]. A lesion of the relay thalamic nuclei disrupts this form of conditioning, whereas ablation of the corresponding cortical sensory areas does not have the same effect. According to some clinical and neuroimaging studies, the role of the amygdala in emotional evaluation could be even more selective, concerning specifically the recognition of fearful facial expressions [11–13,17]. This claim, however, has been questioned by other studies, which have stressed the inconsistency of these data suggesting that the amygdala might be involved in processing biologically relevant stimuli, independent of their valence or category [18–20].

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significance of a brain lesion, it is necessary to start from an analysis of the brain structures that could subtend the main components and hierarchical levels of emotions. This problem is summarized in Table 1, with Figure 1 representing the structures reported and their main interconnections. The neuroanatomical, neurophysiological and neuroimaging data, which support the author’s statements are discussed further, in addition to disturbances observed in patients with lesions encroaching upon these structures. Some important points must be considered while consulting Table 1. First, the data reported in this table are a very reductive summary of the most important findings. Second, due to the intimate relationships existing among all the structures forming the emotional network, none of them plays an exclusive role in the corresponding component of the emotional processing. Finally, present knowledge regarding the activity of these regions during emotional processing and the effects of lesions of these structures is not always detailed enough to reveal subtle distinctions in the functions of various regions. Thus, the amygdala, which is crucially involved in evaluating the emotional significance of external stimuli, is also involved in the generation of expressive-motor and autonomic components of the emotional response and in functions of emotional learning. Analogous claims can be made with respect to the other structures reported in Table 1. Evaluation of emotional significance

Several authors have proposed that the amygdala could be the structure where conditioned associations are formed between information coming from the external world and internal emotional states, and where external stimuli are evaluated

Emotional response

The response programs triggered by emotionally laden stimuli include components of expressivemotor and of autonomic activation, but these

Table 1. Brain structures underlying the main components and levels of emotions. Components of emotion

Corresponding brain structures

Evaluation of emotional significance

Amygdala

Autonomic component

Insular cortex Hypothalamus

Emotional response

Anterior cingulate cortex

Expressive-motor component

Ventral striatum

Emotional levels Intrahemispheric Control/inhibition of the emotional response

Orbito-frontal cortex

Interhemispheric

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Schematic level

Right hemisphere

Conceptual level

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two components of the emotional response are probably subtended by different brain structures. The autonomic components might be generated by hypothalamic structures under the control of cortical structures, such as the insular (IC) and the anterior cingulate cortex (ACC), whereas the expressive-motor aspects might be subtended by the ventral striatum (VS) and the ACC.

patients with brain tumors selectively involving the H, autonomic and endocrinal disorders are frequent [22]; appetitive disorders (eating, drinking and sexual behavior) are rather common, whereas personality disturbances and disorders of social-emotional communication are very rare. At variance with this claim, some authors have described intermittent aggressive outbursts in patients with craniopharingioma [23], but similar disorders have not been confirmed in larger samples [24]. The regulatory role of the IC and ACC over the hypothalamic generation of the autonomic response is supported by neuroanatomical, experimental and clinical data. From the neuroanatomical point of view, the IC (which integrates nociceptive and visceral inputs) receives afferents from several major autonomic regions, has a viscerotopic sensory organization and sends efferents to the lateral H [25]. Its electrical stimulation produces changes in various autonomic parameters, both in animals and in humans [26], and its role in autonomic regulation might be lateralized [26,27]. From the clinical point of view, several neuroimaging and clinical data indicate a crucial role of the IC (and in particular, of the right insula) in cerebrogenic cardiovascular disturbances and sudden death [27–31]. The ACC is implicated in cognitive, motor and autonomic activities and seems necessary to adapt the autonomic state of arousal to concurrent cognitive and physical demands. The ventral, subgenual parts of the ACC have strong reciprocal connections with the ventral striatal, fronto-orbital (FO) and medial temporal regions [32], and ACC pyramidal neurons project directly to the H [33]. Furthermore, neuroimaging studies have shown that the ACC is part of a network systematically activated during emotional pain [34]. From the clinical point of view, abnormalities in autonomic cardiovascular responses during sympathetic stimulation [29] or during mental stress [35] have been observed recently in patients with focal damage involving the ACC.

Brain structures generating the vegetative components of the emotional response

Brain structures generating the expressive-motor components of the emotional response

The hypothalamus (H) is a brain structure whose major involvement in the generation of vegetative reactions has been known since the Karplus and Kreidl stimulation experiments [21], and whose role in autonomic functions is, to date, universally acknowledged [4,8,15]. From the clinical point of view, Weddel has shown that, in

Cortical and subcortical structures, namely the ACC and the VS are involved in the generation of the expressive-motor aspects of the emotional response. Having previously surveyed neuroanatomical and neuroimaging data suggesting inclusion of the ACC within the network of the emotion-related structures, clinical data pointing

Insula FO cortex

ACC

FO cortex

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Amygdala

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Figure 1. Locations of brain structures underlying the main components and levels of emotions and their interconnections.

ACC

IC

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IC VS

Amygdala

VS

Hypothalamus p al ala am

ACC: Anterior cingulated cortex; FO: Fronto-oribital; IC: Insular cortex; VS: Ventral striatum.

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extensively documented, whereas the hypothesis of a complementary role of the right and left hemispheres in different levels of emotional processing has been documented less so. It is worth noting, when considering the role of the FO areas in the regulation of emotions, that many patients with traumatic or degenerative lesions of these areas have shown a severely impaired ability to function in society, even if they obtain normal profiles on standard neuropsychological measures and are not impaired on cognitive tasks sensitive to frontal lobe damage. The inability of these patients to integrate the emotional response into an appropriate social and cognitive context has been considered by Damasio as resulting from a defect in the activation of the somatic markers [10], namely of the autonomic and proprioceptive afferences associated with a personal decision, which converge in the ventro-medial frontal cortex and allow us to anticipate the future consequences of our present actions. A lesion of these cortical areas could, therefore, disconnect the external stimuli from the corresponding internal somatic markers, leaving the subject insensitive to the consequences of their abnormal social behavior. Results supporting these views have been reported by Bechara and coworkers using a gambling task, in which choices that yield high immediate gains are followed by higher future losses [45,46]. Contrary to control subjects who rapidly realized the need for changing their initial options, patients with ventro-medial (FO) lesions were insensitive to future consequences and were primarily guided by immediate reward.

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to a major role of the ACC in the motor components of the emotional response will be discussed briefly. These data consist, on one hand, of the classical description of akinetic mutism with apathy and absence of spontaneous behavior after ACC lesions [36,37] and, on the other, of the more recent observation that circumscribed surgical lesions of the ACC are associated with reduced self-generated and spontaneous motor responses [38]. The involvement of the VS (and other parts of the basal ganglia) in the execution of stereotyped emotional action patterns is also suggested by anatomical and clinical data. Anatomically, these structures receive strong afferents from the amygdala, ACC and other limbic structures, and send projections to cortical, subcortical and brain-stem components of the motor system [39]. From the clinical point of view, patients with a degenerative disease of the basal ganglia, such as the Parkinson's disease show a marked reduction of spontaneous facial emotional expression [40] and analogous defects have been reported in stroke patients with lesions involving the basal ganglia [41,42]. Control & inhibition of socially unacceptable emotional responses

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As previously discussed, during ontogenetic development the emotional system becomes increasingly interconnected with the cognitive system, which takes emotions as a specific object of knowledge and learns social rules concerning the overt expression of emotions [2]. The action schemata activated automatically by external events can, indeed, often contrast with these social rules. To solve these conflicts, some cortical structures lying at the interface between the cognitive and emotional systems, exert a control over the expression of emotions inhibiting socially unacceptable emotional outbursts. Since the classical case of patient Pineas Gage, described by Harlow more than a century ago [43], many clinical and experimental data have convincingly shown that the FO areas play a critical role in these functions of social inhibition (see [4,8,44] for reviews). Furthermore, it has been more recently suggested that the right and left hemisphere might play a complementary role in emotional behavior [44], the right hemisphere being mainly involved in the schematic level of emotional processing and the left hemisphere in functions of control of the emotional output systems. The crucial role of the FO areas in the control of emotional and social behavior has been


Hemispheric asymmetries for emotional functions

The hypothesis of a right hemisphere dominance for emotions was originally based on personal observations showing that right hemisphere brain-damaged patients often show an abnormal emotional behavior, labelled ‘indifference reaction’, whereas left hemisphere brain-damaged patients show a dramatic, but psychologically appropriate, ‘catastrophic reaction’ [47,48]. In more recent years, a large body of clinical and experimental evidence has extended this hypothesis, showing that the right hemisphere plays a crucial role in emotional communication [49–51], autonomic functions [52,53] and in the subjective experience of emotions [54,55]. An alternative model assumes a different hemispheric specialization for positive and negative emotions, with a major role of the left hemisphere for the former 5

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emotional event. In other words, if one is not aware of one’s disability, emotional appraisal will be inappropriate. If this preliminary process is not impaired, one’s appraisal of the personal consequences of a brain lesion will be mainly related to psychological variables, namely to the representation that one would have of these consequences, with respect to social roles, goals and quality of life. Figure 2 summarizes this distinction between emotional disorders of brain-damaged patients due to the lesion of specific brain structures, and those resulting from the outcome of the process of appraisal. Furthermore, two lines of research concerning the anatomical and psychological interpretations of post-stroke depression (PSD) respectively [61–68], and the neuroanatomical correlates of behavioral disorders in dementia [1] will be used to illustrate instances of the appraisal mechanism.

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and the right hemisphere for the latter [56,57]. This model is based on the observation that the right hemisphere dominance is more obvious for negative emotions than for positive emotions, such as smiling, but is at variance with many data of the literature (see [5,8,51] for reviews). Therefore, it is possible that the stronger dominance of the right hemisphere for negative emotions may be better explained: a) by assuming that the right hemisphere may be mainly involved in the automatic (schematic) level of emotional processing, and the left in functions of emotional control; b) by considering that smiling and other positive emotions can be intentionally used for functions of approach and of social communication, whereas negative emotions are not intentionally used with this purpose. Positive expressions could, therefore, be generated by both hemispheres, whereas negative expressions could be generated only by the right hemisphere. However, from the clinical point of view, it is worth noting that, in patients with fronto-temporal degeneration, disinhibition, loss of social awareness and other emotional and social disturbances prevail in patients with right fronto-temporal atrophy [58,59].

Neuroanatomical & psychological interpretations of post-stroke depression

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This line of research was raised by the suggestion by Robinson and coworkers that the major forms of PSD may be due to a specific neuroanatomical mechanism, namely the interruption, by lesions encroaching upon the left hemisphere frontal cortex of monoaminergic pathways running from the brain stem to the neocortex [61,62]. Unfortunately, several investigations have failed to confirm the validity of this model. In particular, studies conducted on large groups of unselected stroke patients have failed to confirm the relation between PSD and left frontal lesions [63–64], and two systematic reviews have offered no support to Robinson’s hypothesis [65,66]. On the other hand, epidemiological studies have shown that psycho–social factors, such as a lack of social support, divorce, institutionalization, living alone or having few social contacts, are strongly associated with PSD (reviewed in [67]). This observation is consistent with data obtained by Gainotti and colleagues who studied the qualitative aspects of PSD to test some predictions based on Robinson’s model [68]. Results of this study have shown that: the symptomatological profiles of patients with major PSD are more similar to those of patients with minor PSD, than to those of subjects with a major endogenous depression; and unmotivated (biological) aspects of depression are only on the foreground in patients with endogenous depression, whereas motivated (reactive) aspects prevail in patients with both major and minor forms of PSD.

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Emotional disorders possibly due more to the outcome of the appraisal process than neuroanatomical reasons

The main goal of this review consists of showing that only some emotional disorders of braindamaged patients are due to the lesion of specific brain structures, whereas others result from the appraisal that the subject makes of the consequences of the brain lesion. An objection that could be addressed to this hypothesis consists in arguing that control mechanisms subtending high-level appraisal also depend on rather specific brain networks. For example, Drevets and Raichle have reported the reciprocal relation between dorsal and ventral parts of the midline system in the control of cognition and emotion [60]. Therefore, it could be misleading to consider emotional disorders resulting from the outcome of emotional appraisal as different from those resulting from disruption of specific brain structures, as appraisal also involves specific brain mechanisms. This objection is only in part correct as emotional appraisal requires a series of control mechanisms (such as disease awareness), which are related to specific brain networks but cannot be reduced to these control mechanisms. These are simply a preliminary condition necessary to properly evaluate the

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Figure 2. Neurobiological and psychological models of emotional disorders after brain damage.

Neurobiological model

Psychological model

Disruption of brain mechanism subtending specific components of emotions

Disrupted brain structure

Amygdala Hypothalamus

Outcome of the process of appraisal of the personal consequences of the brain lesion

Emotional (and associated nonemotional disorders)

Defect of emotional evaluation

Depression

Loss of sympathetic activation

Imbalance in autonomic parameters

Anger

Anterior cingulate cortex

Apathy Loss of spontaneous motor activity

Apathy

Ventral striatum

Reduction of emotional expression

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Insular cortex

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Orbito-frontal cortex

Right hemisphere

Abnormal social and emotional behavior Dominance of immediate reward, with insensitivity to future consequences Abnormal ‘indifference reaction’ Reduction of emotional communication Disorders of autonomic functions

Taken together, these data suggest that PSD is due more to the personal appraisal that each subject makes of the consequences of the brain lesion, than to the brain structures damaged by stroke. This statement obviously does not only hold for depression observed in stroke patients. Several authors have shown, for example, that depression observed in patients suffering from traumatic brain injury [69] or in the early stages of the Alzheimer’s disease can be caused by psychological factors (reviewed in [70]). Furthermore, other instances of diseases with lesions restricted to specific brain structures in which appraisal processes most likely influences the patient’s emotional state can easily be found. For example, Brand and coworkers have recently discussed psychogenic and organic factors that potentially caused emotional dysfunction in a patient with removal of a foramen Monro cyst [71], or, more generally, in patients suffering from tumor removal. www.futuremedicine.com

Neuroanatomical correlates of behavioral disorders in dementia

Rosen and colleagues have recently examined, using voxel-based morphometry, the neuroanatomical correlates of 12 major emotional and behavioral disorders [1], assessed by the Neuropsychiatric Inventory [72]. Only four of these major behavioral disorders (namely apathy, disinhibition, eating disorders and aberrant motor behavior) correlated with tissue loss in specific brain regions, whereas none of the other eight emotional/behavioral disorders (which included delusions, hallucinations, aggression/agitation, depression, anxiety, elation/euphoria, irritability/lability and sleep disturbances) correlated with atrophy of specific brain structures. Furthermore, a large overlap was found in the neuroanatomical correlates of the previously mentioned four major behavioral disorders, as these behavioral defects were associated with right frontal atrophy involving the orbito-frontal 7

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Conclusions

with the results of electrical stimulation and of recording of event-related potentials from depth electrodes have, indeed, consistently suggested that amydgala, anterior insula and VS could, respectively, subtend the basic emotions of fear [10–12,16,77] disgust [78,80] and anger [81–82]. These data must be considered with great caution for several reasons. Some authors have shown that the amygdala might be activated more by the biological relevance of stimuli than by their valence or category [18–20,83]. The insula has strong visceral afferences and a viscerotopic organization [25]. Feelings of disgust resulting from its lesion have not been noticed in a well-controlled clinical study [84] and could, in any case, be due to a defect of information coming from its visceral afferences to the insula. Finally, outbursts of anger have been described in patients with lesions specifically involving the H [23], amygdala or other limbic structures, whereas data suggesting an involvement of the VS in anger come from more animal than clinical investigations. Furthermore, various studies, conducted both in animals and in humans [85–87], emphasize the important role of the VS in reward processing and motivated behavior (e.g., in substancedependent individuals) rather than in anger. Despite these cautions, the possibility that specific components of the limbic system may subtend specific categories of emotions is of great interest and will certainly be investigated extensively in the next few years. As for the brain structures implementing the emotional discharge, they could receive some light from the development of high-frequency, deep brain stimulation (DBS) studies [88,89], and of emotional outbursts resulting from cerebellar lesions [90]. As for the first point, DBS of the subthalamic nucleus [88] and the nucleus accumbens region [89] has induced transient or persistent affective emotional states, such as depression [88], hypomania [89], episodes of involuntary laughter or contralateral smile [91]. Pathological laughter and crying have also been observed in patients with lesions involving the ponto–cerebellar pathways [90]. It is possible that the mechanisms underlying these emotional disorders may be better explained by highly controlled quasiexperimental procedures, such as DBS, than by the study of spontaneous brain pathology. On the other hand, a better understanding of the mechanisms subtending the most complex emotional and social disorders of braindamaged patients could be obtained by new

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cortex, ACC and anterior insula, namely regions that have already been described as subtending various aspects of emotional processing. These results, on one hand, strongly support the involvements of the medial wall and of the orbito-frontal regions of the right hemisphere in mediating aspects of social and emotional behavior but, on the other hand, do not support the hypothesis that depression and irritability/aggression, often observed since the early stages of a dementing disease, are due to specific neural mechanisms [73,74]. Even if more complex neurobiological explanations cannot be excluded, it seems more likely to assume that, in the early stages of dementia the patient becomes aware that a devastating event is progressively invading him, and that depression, frustration and irritability are the consequences of this appraisal process.

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The meaning of emotional disorders observed in patients with various kinds of brain damage remains highly controversial. Most authors view these disturbances as being directly linked to the disruption of specific neural mechanisms, whereas other authors underline the importance of the cognitive appraisal that each patient makes of the consequences of brain damage for his future quality of life. Both a reductionistic approach and a generic psychological interpretation fail to explain the complexity and the heterogeneous nature of this problem. A multidimensional approach is certainly difficult as it requires integration of neuroanatomical, neurophysiological, neuropsychological, neuroimaging and psychodynamic data. Recent attempts to integrate psychoanalysis and neuroscience [75,76] could perhaps contribute to this stimulating enterprise. Future perspective

During the next few years, investigations into the brain organization of emotions will probably concern several levels of the brain network involved in: a) the schematic level of emotional processing, b) the implementation of the emotional discharge and c) the control of emotions. Considering first point, several data gathered in recent years seem to suggest that some of the structures listed in Table 1 as involved in specific components of emotions could also play a selective role in processing a specific basic emotion. Neuroimaging data and studies conducted in brain-damaged patients, combined 8



Executive summary

inter-hemispheric factors may have on the complex interactions between emotional and cognitive systems. Finally, it is important to note that the founders of the International Society for Neuro-Psychoanalysis have recently proposed an account of emotional disorders of brain-damaged patients framed in psychoanalytic terms [95–97]. This new approach could contribute to re-equilibrate the imbalance between neurobiological and psychological interpretations of emotional disorders of brain-damaged patients that have been repeatedly stressed in this review.

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conceptual models, such as the theory of mind (ToM) and by the development of closer relationships between psychoanalysis and cognitive neuroscience. Studies conducted considering various aspects of the ToM have confirmed that the orbito-frontal cortex [92] and the right hemisphere [93] play a crucial role in the emotional components of ToM tasks. Furthermore, the right frontal cortex might be critical for tasks involving self-awareness and ToM [94]. It is, therefore, likely that a more extensive application of this theory may contribute to clarifying the different contributions that intra- and

The meaning of emotional disorders of brain-damaged patients

• Emotional disorders in patients with brain damage can be the result of neurobiological and psychological reasons. The former stems from the disruption of structures playing a critical role in various aspects of emotions and the latter from the evaluation/appraisal that the patient makes of the personal consequences of the brain damage. At variance with the ‘cognitive system’, which aims to detect the objective meaning of stimuli, the ‘emotional system’ aims to appraise the subjective, personal significance of events and, therefore, evaluate the personal consequences of a brain lesion. Emotions as a multicomponent adaptive emergency system

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• The emotional system can be considered as a primitive adaptive system devised to: rapidly detect stimuli relevant to the needs of the individual; respond quickly with a limited number of operative schemata, including motor, expressive and autonomic components; and learn the emotional meaning of stimuli. During an individual’s development, the emotional system becomes increasingly interconnected with the cognitive system, which learns the rules concerning the social expression of emotions and inhibits socially inappropriate emotional responses.

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Brain structures underlying the main components of emotions & disorders resulting from disruption of these structures • The amygdala is the structure where conditioned associations are formed between external situations and internal emotional schemata and where external stimuli are evaluated in terms of their emotional value. Bilateral amygdala lesions provoke emotion recognition disorders. • The hypothalamus is the brain structure where the autonomic components of emotions are generated, usually under the control of cortical areas, such as the anterior cingulated cortex (ACC) and the insula. Lesions of all of these structures produce vegetative disturbances, but not necessarily clear emotional disorders. • Cortical and subcortical structures, namely the ACC and the ventral striatum, are involved in the generation of the expressivemotor aspects of the emotional response. Lesion of the striatum leads to a reduction of emotional expression, whereas ACC damage is associated with a reduction of self-generated and spontaneous motor responses. • The fronto-orbital areas play a critical role in the inhibition of socially unacceptable emotional behaviors and patients with lesions involving these areas usually show striking emotional and social disorders. • Important hemispheric asymmetries have also been consistently reported with the right hemisphere playing a crucial role in emotional communication, autonomic functions and the subjective experience of emotions. Emotional disorders resulting from the appraisal that the subject makes of the consequences of a brain lesion • Some emotional disorders of brain-damaged patients seem to be due more to the appraisal that the subject makes of the personal consequences of the brain damage, than to specific neuroanatomical lesions. Thus, in patients with focal brain lesions, post-stroke depression, which is observed in a high proportion of patients and hampers the process of functional recovery, seems due more to psychological or psycho–social reasons than to a left frontal lesion, as previously suggested. Furthermore, only few emotional and behavioral disorders of patients with dementia correlate with atrophy of specific brain structures. Conclusion • The meaning of emotional disorders observed in patients with various kinds of brain damage cannot be fully explained by purely neurobiological or psychological models. A multidimensional approach, trying to integrate neurobiological factors with psychodynamic and psycho–social models could contribute to this difficult but stimulating enterprise.


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13.

14.

15.

16.

17.

18.

Adolph R, Tranel D, Damasio AR: Neural systems subserving emotion: lesion studies of the amygdala, somatosensory cortices and ventromedial prefrontal cortices. In: Handbook of Neuropsychology, Second Edition (Volume 5): Emotional Behaviour and its Disorders. Gainotti G (Ed.). Elsevier, Amsterdam, The Netherlands, 89–110 (2001). Papez JW: A proposed mechanism of emotion. Arch. Neurol. Psychiatry 79, 217–224 (1937). LeDoux JE: Cognitive-emotional interactions in the brain. Cogn. Emotion 3, 267–289 (1986). LeDoux JE, Sakaguchi A, Iwata J et al.: Interruption of projections from the medial geniculate body to an archi-neostriatal field disrupts the classical conditioning of emotional responses to acoustic stimuli in the rat. NeuroScience 17, 615–627 (1986). Morris JS, Frith CD, Perrett DI, et al.: A differential neural response in the human amygdala to fearful and happy facial expressions. Nature 383, 812–815 (1996). Rapcsak SZ, Galper SR, Camer JF et al.: Fear recognition deficits after focal brain damage. A cautionary note. Neurology 54, 575–581 (2000). Adolphs R, Tranel D, Hamann S et al.: Recognition of facial emotion in nine subjects with bilateral amygdala damage. Neuropsychologia 37, 1111–1117 (1999). Siebert M, Markowitsch HJ, Bartel P: Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease. Brain 126, 2627–2637 (2003). Demonstrates that the amygdala is not specifically involved in fear recognition but in processing biologically relevant stimuli, independently of their valence. Karplus JP, Kreidl A: Gehirn und sympathicus. VII. Uber beziehungen der hypothalamuszentren zu blutdruck und innerer sekretion. Pf. Arch. Gesam. Physiol. Men. Thiere 215, 667–670 (1927). Weddel RA: Effects of subcortical lesion site on human emotional behavior. Brain Cogn. 25, 161–193 (1994). Tonkonogy JM, Geller JL: Hypothalamic lesions and intermittent explosive disorders. J. Neuropsychiatry Clin. Neurosci. 4, 45–50 (1992). Shirane R, Ching-Chan S, Kusaka Y et al.: Surgical outcomes in 31 patients with craniopharingiomas extending ouside the suprasellar cistern: an evaluation of the frontobasal interhemispheric approach. J. Neurosurg. 96, 704–712 (2002).

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Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. Rosen HJ, Allison SC, Shaucher GF et al.: Neuroanatomical correlates of behavioural disorders in dementia. Brain 128, 2612–2625 (2005). •• Demonstrates that only some emotional disorders of patients with dementia correlate with tissue loss in specific brain regions. 2. Ekman P: Expression and the nature of emotions. In: Approaches to Emotion. Scherer K, Ekman P (Eds). Erlbaum, Hillsdale, NJ, USA, 319–344 (1984). 3. Leventhal H: A perceptual motor theory of emotion. In: Advances in Experimental Social Psychology. Vol. 17. Berkowitz L (Ed.). Academic Press, New York, NY, USA, 117–182 (1987). 4. LeDoux JE: The Emotional Brain. Simon & Schuster, New York, NY, USA (1996). 5. Gainotti G: Neuropsychological theories of emotions. In: The Neuropsychology of Emotions. Borod J (Ed.). Oxford University Press, New York, NY, USA, 214–238 (2000). 6. Oatley K, Johnson-Laird P: Toward a cognitive theory of emotions. Cogn. Emotion 1, 29–50 (1987). 7. Russel JA: Is there universal recognition of emotion from facial expressions? A review of cross-cultural studies. Psychol. Bull. 115, 102–141 (1994). 8. Gainotti G: Emotions as a biologically adaptive system: an introduction. In: Handbook of Neuropsychology, Second Edition (Volume 5): Emotional Behaviour and its Disorders. Gainotti G (Ed.). Elsevier, Amsterdam, The Netherlands, 1–15 (2001). 9. Scherer KR, Peper M: Psychological theories of emotion and psychological research. In: Handbook of Neuropsychology, Second Edition (Volume 5): Emotional Behaviour and its Disorders. Gainotti G (Ed.). Elsevier, Amsterdam, The Netherlands, 17–48 (2001). 10. Damasio AR: Descartes' Error: Emotion, Research and the Human Brain. Grosset/Putnam, New York, NY, USA (1994). 11. Adolph R, Tranel D, Damasio H et al.: Fear and the human amygdala. J. Neurosci. 15, 5879–5881 (1995). 12. Calder AJ, Young AW, Rowland D et al.: Facial emotion recognition after bilateral amygdala damage: differentially severe impairment of fear. Cogn. Neuropsychol. 13, 699–745 (1996).

A

19.

10

20.

••

21.

22.

23.

24.

25.

Cecchetto DF, Saper CB: Role of the cerebral cortex in autonomic function. In: Central Regulation of Autonomic Functions. Loewy AD, Spyer KM (Eds). Oxford University Press, New York, NY, USA, 208–223 (1990). Oppenheimer SM, Gelb A, Girvin JP et al.: Cardiovascular effects of human insular cortex stimulation. Neurology 42, 1727–1732 (1992). Oppenheimer SM: The anatomy and physiology of cortical mechanisms of cardiac control. Stroke 24(Suppl. 12) 13–15 (1993). Cheung RTF, Hachinski V: The insula and cerebrogenic sudden death. Arch. Neurol. 57, 1685–1688 (2000). Woo MA, Macay PM, Keens PT et al.: Functional abnormalities in brain areas that mediate autonomic nervous system control in advanced heart failure. J. Card. Fail. 11, 437–446 (2005). Colivicchi F, Bassi A, Santini M et al.: Cardiac autonomic derangement and arrhythmias in right-sided stroke with insular involvement. Stroke 35, 2094–2098 (2004). Indicates that a hemispheric lateralization in autonomic activity is mediated by the right-sided insular cortex. Meyer S, Strittmatter M, Fischer C et al.: Lateralization in autonomic dysfunction in ischemic stroke involving the insular cortex. Neuroreport 15, 357–361 (2004). Bush G, Luu P, Poster MI: Cognitive and emotional influences in anterior cingolate cortex. Trends Cogn. Sci. 4, 215–222 (2000). Ongur D, An X, Price JL: Prefrontal cortical projections to the hypothalamus in macaque monkeys. J. Comp. Neurol. 401, 480–505 (1998). Rainville P: Brain mechanisms of pain affect and pain modulation. Curr. Opin. Neurobiol. 12, 195–204 (2002). Critchley HD, Mathias CJ, Josephs O et al.: Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain 126, 2139–2152 (2003). Nielsen JM, Jacobs LL: Bilateral lesions of the anterior cingulate gyri. Report of case. Bull. Los Angeles Neurol. Soc. 16, 231–234 (1951). Barris RW, Schuman HR: Bilateral anterior cingulated gyrus lesions: syndrome of the anterior cingulate gyri. Neurology 3, 44–52 (1953). Cohen RA, Kaplan RF, Moser DJ et al.: Impairments of attention after cingulotomy. Neurology 53, 819–824 (1999).

ho rP ro

Bibliography

26.

27.

28.

29.

30.

•

31.

32.

33.

34.

35.

36.

37.

38.



42.

43.

44.

45.

••

46.

47.

48.

49.

50.

51.

52.

54.

55.

56.

57.

58.


59.

•

60.

61.

62.

63.

64.

65.

J. Intern. Neuropsychol. Soc. 9, 429–439 (2003). Singh A, Herrmann N, Black SE: The importance of lesion location in poststroke depression: a critical review. Can. J. Psychiatry 4, 921–927 (1998). Carson AJ, MacHale S, Allen K et al.: Depression after stroke and lesion location: a systematic review. Lancet 356, 122–126 (2000). Gainotti G, Marra C: Controversies on post-stroke depression. In: Focus on Stroke Research. Brown SP (Ed.). Lancet Publishers, New York, NY, USA, 191–206 (2005). A review of data showing that post-stroke depression is due more to psychological than to neuroanatomical factors. Gainotti G, Azzoni A, Razzano C et al.: The post-stroke depression rating scale: a test specifically devised to investigate affective disorders of stroke patients. J. Clin. Exp. Neuropsychol. 19, 340–356 (1997). Vickery CD, Gontkovsky ST, Caroselli JS: Self-concept and quality of life following acquired brain injury: a pilot investigation. Brain Inj. 19, 657–665 (2005). Gainotti G: Assessment and treatment of emotional disorders. In: Handbook of Clinical Neuropsychology. Halligan PW, Kischka U, Marshall JC (Eds). Oxford University Press, Oxford, UK, 368–386 (2003). Brand M, Kalbe E, Lutz W et al.: Organic and psychogenic factors leading to executive dysfunction in a patient suffering from surgery of a colloid cyst of the Foramen of Monro. Neurocase 10, 420–425 (2004). Cummings JL, Mega M, Gray K et al.: The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 44, 308–314 (1994). Starkstein SE, Manes F: Neural mechanisms of anxiety, depression and disinhibition. In: Handbook of Neuropsychology, Second Edition (Volume 5). Emotional Behaviour and its Disorders. Gainotti G (Ed.). Elsevier, Amsterdam, 263–286 (2001). Tekin S, Mega MS, Masterman DM et al.: Orbitofrontal and anterior cingulated cortex neurofibrillary tangle burden is associated with Alzheimer’s disease. Ann. Neurol. 49, 355–361 (2001). Kandel ER: Biology and the future of psychoanalysis: a new intellectual framework for psychiatry revisited. Am. J. Psychiatry 156, 505–524 (1999). Influential attempt to integrate psychoanalysis and neuroscience.

ho rP ro

41.

53.

damaged patients. Neuropsychologia 32, 847–856 (1994). Wittling W: Brain asymmetry in the control of autonomic-physiologic activity. In: Brain Asymmetry. Davidson RJ, Hugdahl K (Eds). MIT Press, Cambridge, MA, USA, 305–357 (1995). Mammucari A, Caltagirone C, Ekman P et al.: Spontaneous facial expression of emotions in brain-damaged patients. Cortex 24, 521–533 (1988). Wittling W, Roschmann R: Emotionrelated hemispheric asymmetry: subjective emotional response to laterally presented films. Cortex 29, 431–448 (1993). Davidson RJ: Affective style and affective disorders: perspectives from affective neurosciences. Cogn. Emotion 12, 307–330 (1998). Davidson RJ: Prefrontal and amygdala contributions to emotion and affective style. In: Handbook of Neuropsychology, Second Edition (Volume 5): Emotional Behaviour and its Disorders. Gainotti G (Ed.). Elsevier, Amsterdam,The Netherlands, 111–124 (2001). Perry RJ, Rosen HR, Kramer JH et al.: Hemispheric dominance for emotions, empathy and social behaviour: evidence from right and left handers with frontotemporal dementia. Neurocase 7, 145–160 (2001). Rankin KP, Kramer JH, Mychack P, Miller BL: Double dissociation of social functioning in frontotemporal dementia. Neurology 60, 266–271 (2003). Demonstrates that, in patients with fronto-temporal degeneration, emotional and social disturbances prevail in patients with right fronto-temporal atrophy. Drevets WC, Raichle ME: Reciprocal suppression of regional cerebral blood flow during emotional versus higher cognitive processes: implications for interactions between emotion and cognition. Cogn. Emotion 12, 353–385 (1998). Robinson RG, Starr LB, Kubos KL et al.: A two-year longitudinal study of post-stroke mood disorders: Findings during the initial evaluation. Stroke 14, 736–741 (1983). Robinson RG, Kubos KL, Starr LB et al.: Mood disorders in stroke patients: importance of lesion location. Brain 107, 81–93 (1984). Gainotti G, Azzoni A, Gasparini F et al.: Relation of lesion location to verbal and nonverbal mood measures in stroke patients. Stroke 2, 2145–2149 (1997). Desmond DW, Remien RH, Moroney JT et al.: Ischemic stroke and depression.

ut

40.

Nauta WJH, Domesick VB: Afferent relationships of the basal ganglia. Ciba Found. Symp. 107, 3–23 (1984). Smith MC, Smith MK, Ellgring H: Spontaneous and posed facial expression in Parkinson's disease. J. Int. Neuropsychol. Soc. 2, 383–391 (1996). Cancelliere AEB, Kertesz A: Lesion localization in acquired deficits of emotional expression and comprehension. Brain Cogn. 13, 133–147 (1990). Cohen MJ, Riccio CA, Falnnery AM: Expressive aprosodia following stroke to the right basal ganglia: a case report. Neuropsychology 8, 242–245 (1994). Harlow JM: Recovery from the passage of an iron bar through the head. Publ. Mass. Med. Soc. 2, 237–246 (1868). Gainotti G, Caltagirone C, Zoccolotti PL: Left/right and cortical/subcortical dichotomies in the neuropsychological study of human emotions. Cogn. Emotion 7, 71–93 (1993). Bechara A, Damasio H, Tranel D et al.: Deciding advantageously before knowing the advantageous strategy. Science 275, 1293–1295 (1997). Demonstrates, with a task that simulates daily decisions, that patients with ventromedial (fronto-orbital) lesions are primarily guided by immediate reward and are insensitive to future consequences of their actions. Bechara A, Tranel D, Damasio H: Characterization of decision-making deficit of patients with ventromedial prefrontal cortex. Brain 123, 2189–2202 (2000). Gainotti G: Réaction "catastrophiques" et manifestations d'indifferénce au cours des atteintes cérébrales. Neuropsychologia 7, 195–204 (1969). Gainotti G: Emotional behavior and hemispheric side of the lesion. Cortex 8, 41–55, (1972). Ross ED: Right hemisphere's role in language, affective behavior and emotion. Trends Neurosci. 7, 342–346 (1984). Blonder LX, Burns A, Bowers D et al.: Right hemisphere facial expressivity during natural conversation. Brain Cogn. 21, 44–56 (1993). Borod JC, Haywood CS, Koff E: Neuropsychological aspects of facial asymmetry during emotional expression: a review of the normal adult literature. Neuropsychol. Rev. 7, 41–60 (1997). Meadows ME, Kaplan RF: Dissociation of autonomic and subjective responses to emotional slides in right hemisphere

A

39.

66.

67.

•

68.

69.

70.

71.

72.

73.

74.

75.

••

11

REVIEW – Gainotti

78.

79.

••

80.

81.

82.

83.

84.

12

86.

87.

88.

••

89.

Carelli RM: Activation of accumbens cell firing by stimuli associated with cocaine delivery during self-administration. Synapse 35, 238–242 (2000). Peoples LL, Lynch KG, Lesnock J et al.: Accumbal neural responses during the initiation and maintenance of intravenous cocaine self-administration. J. Neurophysiol. 91, 314–323 (2004). Ghitza UE, Propopenko VF, West MO et al.: Higher magnitude accumbal phasic changes among core neurons exhibiting tonic firing increases during cocaine self-administration. NeuroScience 137, 1075–1085 (2005). Bejjani BP, Damier P, Arnulf I et al.: Transient acute depression induced by highfrequency deep-brain stimulation. N. Engl. J. Med. 340, 1476–1480 (1999). First description of transient or persistent affective emotional states induced by highfrequency deep-brain stimulation. Romito LM, Raja MD, Daniele A et al.: Transient mania with hypersexuality after surgery for high-frequency stimulation of the subthalamic nucleus in Parkinson’s disease. Mov. Disord. 17, 1371–1374 (2002). Parvizi J, Anderson SW, Martin CO et al.: Pathological laughter and crying. A link to the cerebellum. Brain 124, 1708–1719 (2001). Interesting paper proposing that the cerebellum may convey important signals to the emotion-effector sites regulating emotional expression. Okun MS, Bowers D, Springer U et al.: What’s in a smile? Intra-operative observations of contralateral smiles induced by deep brain stimulation. Neurocase 10, 271–279 (2004). Hynes CA, Baird AA, Grafton ST: Differential role of the orbital frontal lobe in emotional versus cognitive perspectivetaking. Neuropsychologia 44, 374–383 (2006).

90.

•

91.

92.

93.

Tsamay-Tsoory SG, Tomer R, Goldsher D et al.: Impairment in cognitive and affective empathy in patients with brain lesions: anatomical and cognitive correlates. J. Clin. Exp. Neuropsychol. 26, 1113–1127 (2004). Keenan JP, Rubio J, Racioppi C et al.: The right hemisphere and the dark side of consciousness. Cortex 41, 695–704 (2005). Stimulating paper regarding the relationships between the right frontal cortex, self-awareness and positive (empathy) or negative (deception) aspects of thinking about another person’s thinking. Kaplan-Solms K, Solms M: Clinical Studies in Neuro-Psychoanalysis: Introduction to a Deep Neuropsychology. Karnac, London, UK, (2000). Turnbull OH, Jones K, Reed-Screen J: Implicit awareness of deficit in anosognosia: an emotion-based account of denial of deficit. Neuro-Psychoanalysis 4, 69–86 (2002). Proposes an interpretation of anosognosia and other emotional disorders of brain-damaged patients framed in psychoanalytic terms. Turnbull OH, Evans CEY, Owen V: Negative emotions and anosognosia. Cortex 41, 65–75 (2005).

ho rP ro

••

85.

ut

77.

Gainotti G: Emotions, unconscious processes and the right hemisphere. NeuroPsychoanalysis, 7, 71–81 (2005). Krolak-Salmon P, Henaff MA, Vighetto A et al.: Early amygdala reaction to fear spreading in occipital, temporal and frontal cortex: a depth electrode ERP study in human. Neuron 42, 665–676 (2004). Intracranial event-related potentials to fear facial expression were first observed in the amygdala and subsequently spread to occipital, temporal and frontal cortical areas. Calder AJ, Keane J, Manes F et al.: Impaired recognition and experience of disgust following brain injury. Nature Neurosci. 3, 1077–1078 (2000). Wicker B, Keysers C, Plailly J et al.: Both of us disgusted in my insula: the common neural basis of seeing and feeling disgust. Neuron 40, 655–664 (2003). Demonstrates that observing a facial expression of disgust activates the same sites in the anterior insula involved in disgust feelings. Krolak-Salmon P, Henaff MA, Isnard J et al.: An attention modulated response to disgust in human ventral anterior insula. Ann. Neurol. 53, 446–453 (2003). Lawrence AD, Calder AJ, McGowan SW et al.: Selective disruption of the recognition of facial expression of anger. Neuroreport 13, 881–884 (2002). Calder AJ, Keane J, Lawrence AD et al.: Impaired recognition of anger following damage to the ventral striatum. Brain 127, 1958–1969 (2004). Fitzgerald DA, Angstadt M, Jeldone LM et al.: Beyond threat: amygdala reactivity across multiple expressions of facial affect. Neuroimage (2005) [Epub ahead of print]. Manes F, Paradiso S, Robinson RG: Neuropsychiatric effects of insular stroke. J. Nerv. Ment. Dis. 187, 707–712 (1999).

A

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94.

••

95.

96.

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Affiliation • Guido Gainotti Università Cattolica, Neuropsychology Service, Policlinico Gemelli, Largo A. Gemelli, 8 Rome, Italy Tel.: +39 063 550 1945; Fax: +39 063 550 1909; [email protected]
