Organización Dinámica Del Cerebro Emocional

The Neuroscientist
http://nro.sagepub.com Dynamic Organization of the Emotional Brain: Responsivity, Stability, and Instability
Leanne M. Williams and Evian Gordon Neuroscientist 2007; 13; 349 DOI: 10.1177/10738584070130040801 The online version of this article can be found at: http://nro.sagepub.com/cgi/content/abstract/13/4/349
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Dynamic Organization of the Emotional Brain: Responsivity, Stability, and Instability

LEANNE M. WILLIAMS and EVIAN GORDON
Models of emotion processing have commonly been formulated as dichotomies such as approach versus avoidance. These models and associated research on evolutionary adaptation, awareness, motivational arousal, and corticalsubcortical brain systems are reviewed. A continuum model of emotional-significance processing is proposed to integrate current dichotomies and reflect the highly interconnected nature of brain systems. This model highlights a spectrum from mismatches, signifying potential danger, to matches, signifying safety and the expectation of reward. Subcorticalcortical interactions and autonomic arousal modulation support mismatch and match processing across a temporal continuum from milliseconds (in which processing is automatic and arguably nonconscious) to tenths of a second (in which responses are facilitated and contextual evaluation commences) to minutes and hours (when memory consolidation and neural plasticity occur). Variations at distinct points along this continuum, with contributions from constitutional and genetic factors, may contribute to individual differences in emotional stability and instability in neuropsychiatric disorders. NEUROSCIENTIST 13(4): 349370, 2007. DOI: 10.1177/1073858407303429
KEY WORDS Emotion, Danger and reward, Arousal, Motivation, Neurobiology, Limbic, Prefrontal, Temporal continuum, Individual differences, Psychiatric disorder
Emotion theories have typically been formulated around dichomotous concepts. For instance, emotion theories grapple with the mechanisms for opposing systems of valence (positive and negativethe question of whether emotion processing can proceed automatically without sensory awareness or relies on conscious evaluation), the related question of whether emotion relies on cognitive appraisal or precedes it, and the role of subcortical versus cortical neural systems (Table 1). In the review of these theories, we show how a dichotomous concept of emotions might be integrated within a continuum. We first consider the evolutionary context of emotion, tied to our basic motivations to minimize danger and maximize reward. Drawing on the evolutionary context, it is proposed that the elemental properties of a stimulus linked to potential danger through evolution may be considered mismatches. These mismatches are generated by stimulus features with high arousability and
From the Brain Dynamics Center, Westmead Millennium Institute, Westmead, Australia (LMW, EG); Psychological Medicine, Western Clinical School, University of Sydney, Sydney, Australia (LMW, EG); Westmead Hospital, Westmead, Australia (LMW); and the Brain Resource International Database, Brain Resource Company, Sydney, Australia (EG). Leanne Williams is supported by a Pfizer Senior Research Fellowship. Thank you to Chris Rennie for comments on emotional arousal and biophysical modeling and to Rebecca Lloyd of Lloyd Graphics and Design (Beck.Lloyd@gmail.com) for figure production. The Brain Resource International Database is under the auspices of the Brain Resource Company (www.brainresource.com), with scientific decisions overseen by an independent network (BRAINnet; www.brainnet.org.au). Address correspondence to: Leanne Williams, Brain Dynamics Center, Acacia House, Westmead Hospital, Westmead, Sydney, NSW, 2145, Australia (e-mail: lea@psych.usyd.edu.au).
unexpectedness, such as abrupt sensory change, contrast, and rapid motion. Reward-related stimuli are more likely to involve a match, which is predictable and signifies safety, familiarity, or the prediction of reward. In the section An Evolutionary Context, we outline theories of emotion and motivation that focus on the dichotomy of valence and arousal, and we discuss the potential for a matchmismatch principle to unify these concepts. We also address the role of awareness in emotion processing as well as evidence that motivationally relevant emotional cues may be processed without awareness. We outline evidence from the major neurobiological theories of emotion, each of which has arisen from a distinct focus (such as the explanation of learned fear or the influence of emotions on decision making) and has relied on different sources of data (animal fear conditioning, lesions, human functional neuroimaging; e.g., Damasio 1996; Davidson and Irwin 1999; LeDoux 1996). Evidence from these theories has typically been interpreted in terms of a dichotomy of subcortical brain systems (for rapid, nonconscious appraisal of emotion) versus cortical systems (for conscious elaboration). This dichotomy is reformulated in terms of the parallel integration of evolutionary older subcortical systems, and more recently, evolved cortical ones. Theories of orienting and motivational arousal in the fields of psychophysiology and learning have also made important contributions to understanding the dynamics of emotion processing. Indeed, influential theories of motivational arousal implicate brain networks in common with emotion theories (Gray 1987; Pribram and McGuinness 1975; Sokolov 1990). Given the importance of brain and body interactions (e.g., Damasio 1996), we also incorporate the dynamics of sympathetic and parasympathetic
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THE NEUROSCIENTIST Volume 13, Number 4, 2007 Copyright 2007 Sage Publications Downloaded from http://nro.sagepub.com by Favio Vega on November 18, 2007 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution. ISSN 1073-8584
Table 1. Concept
Summary of the Dichotomous Concepts in the Formulation of Current Emotion Theories Dichotomy
Structure of mental space Types of emotion Emotional valence Appraisal of emotion Levels of awareness Motivational arousal Motivational arousal systems Brain systems Autonomic nervous system
Cognition Primary emotion Positive Precedes cognitive appraisal Unconscious Approach Behavioral activation Cortical Sympathetic
Emotion Secondary emotion Negative Results from cognitive appraisal Conscious Avoidance Behavioral inhibition Subcortical Parasympathetic
arousal in emotion processing (drawing on the basic physiology literature). This complementary content and context forms the basis of a continuum model in which emotion-related significance is key to the dynamical organization of information processing. The continuum model emphasizes the temporal continuum of information processing as well as the spatial dimension. Aspects of dichotomous concepts of emotion are reconciled as the extremes of the interacting dynamics that unfold across different time scales. There is a bias toward orienting to danger-related mismatch cues during short time scales; consistent with their greater immediate survival value, these cues do not necessarily rely on conscious awareness. Interactions between brainand body-arousal mechanisms across this temporal continuum create a multidimensional diversity of possible emotional reactions and associated behaviors. In the final sections, we consider how concepts from the continuum model may be applied to understanding individual differences that modulate emotion processing (such as age, gender, and genetic factors). We also apply this model to emotion-related instabilities that characterize major neuropsychiatric disorders. An Evolutionary Context An evolutionary context is key to understanding the role of emotion in organizing information processing. Darwin (1872/1998) argued that emotional responses are inherited patterns of behavior shaped by natural selection to maximize adaptation. He highlighted the primordial nature of facial expressions of emotion and suggested that they are evolutionary remnants of previous adaptive behavior, per1 sisting in a mild form. The seminal cross-cultural work of Ekman (1993) and Ekman and colleagues (1983) has provided support for Darwins claim of basic emotions (such as fear, anger, disgust, happiness, sadness, and surprise) that are universally recognized (see Fridland [1994] for detailed hypotheses on the evolutionary origins). There is also a broad crosscultural consensus on both the labeling and the meaning of these basic emotions (Ekman 1993). Other influential work has enumerated a greater number of basic emotions (Izard 1977; Plutchik 1962), but agreement remains that these emotions are signals for communicating potential
danger or reward and mobilizing associated action tendencies. Ethologists have drawn on evidence for the early emergence of basic expressions of emotion in human infants as evidence for the innate basis of these expressions (Eibl-Eibesfeldt 1989). Notably, these expressions emerge even in infants born deaf or blind (Darwin 1872/ 1998; Eibl-Eibesfeldt 1989; Izard 1977). Consistent with this evolutionary view, nonhuman primate homologues have also been identified for basic expressions of threat and happiness and associated behavior patterns. Expressions of fear, which signal the presence of potential dangers, are thought to have evolved from the fear grimace of nonhuman primates (Schmidt and Cohn 2001). In expressions of disgust, which signal potential threat from contamination, the wrinkling of the nose and contraction of the mouth may have come about from the gesture associated with expelling contaminated food. The smile in relation to an appeasement function may have arisen from the submissive gesture of silent bared teeth (Fig. 1), consistent with the ease with which smiles are recognized (e.g., by the enemy) even at a distance. Similarly, the expression of happiness in relation to pleasure may have evolved from the open-mouth primate play face (Fig. 1). Emotion and Motivation The evolutionary view of emotion highlights the integration of motivation and emotion, in contrast to cognitive models that have presumed that motivation precedes emotion and that emotional reactions are conscious reactions to the cognitive evaluation of the preceding stimulus (Toates 1986). Arguably, the most fundamental motivations are to avoid and minimize danger and to maximize reward. Danger-related stimuli would be expected to have the greatest immediate physical survival value, requiring mechanisms for rapid processing. Reward-related stimuli may be considered relatively more important to safety and survival at a longer time scale, thereby without quite the same urgency for processing. For instance, these stimuli are related to appetitive functions such as eating and affiliative (social) functions such as procreation, bonding, and belonging.
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Fig. 1. Homologous displays in human and nonhuman primates. A, Rhesus macaque submissive display (photograph by Frans DeWaal, 1969; silent, bared-teeth display); B, human smile (from Kanade and others 2000; silent, bared-teeth display); C, Bonobo play face (photograph by Frans DeWaal, 1968; relaxed, open-mouth display); D, human play face (from Forbes and others 2000; relaxed, open-mouth display). Reproduced with permission from Figure 6 in Schmidt and Cohn (2001).
The integral link between motivations and emotion was highlighted nearly a century ago (Troland 1928). It was suggested that negative emotion is associated with nociception and avoidance of events that may have dangerous consequences, whereas reward and positive emotion are associated with beneception, the events that
facilitate survival and thus benefit the species from an evolutionary biological perspective. In the influential recent model of Lang and others (1990, 1993), emotions are driven by two diametrically opposed motivational systems: the appetitive approach system that mediates positive or pleasant events and the aversive (defensive)
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avoidance system that mediates negative or unpleasant events. Although this model introduces another dichotomy, Lang also emphasized a continuum of automaticity, spanning automatic, reflexive reactions to more detailed cognitive elaboration (Lang 1994). Are There Innate Cues for Emotional Significance? One might ask what cues have evolved to register emotional significance. Here, we consider a set of elemental primitives that define stimulus significance (Williams 2006).2 Danger has been associated through evolution with elemental cues that are highly arousing because of their unexpectedness (i.e., unpredictability or novelty) and intensity. For instance, loud noises, sudden sensory change or movement, and high contrast compose these properties (Robinson and others 2004). Experimentally, white-noiseburst startle stimuli are often used to represent unexpected and intense (loud) danger cues, which elicit reflexive fear responses (Lang and others 1990). Facial expressions may also comprise arousing primitive elements: for instance, the high contrast from the sclera, or whites of the eyes, when the eyes are widened in threatrelated expressions (Whalen and others 2004). The fear of other purportedly evolution-determined stimuli such as spiders and snakes has also been critically related to their unexpectedness (Merckelbach and others 1998). Natural rewards are associated more with predictability and familiarity and may be considered fundamental match cues. Positive cues signifying potential reward are defined by elements such as symmetry, rounded shapes, and smooth transitions in sound. Relatedly, symmetry is considered an essential feature of attractiveness (Perrett and others 1999). Because reward cues contain a lack of abruptness, they are likely to have moderate to low arousability. Facial expressions of happiness are also characterized by a reduction in contrast because the muscle configuration of smiling crinkles the eye region and minimizes the whites of the eyes. As noted above, the exposure of the teeth in a smile (also high contrast) may have evolved from a survival-related function that signals congruent emotion. Biological motion, even implicitly, may be part of the spectrum of motion cues for emotional significance (Senior and others 2000). Manipulation of just the angle of the eyebrows in schematic faces (e.g., upward to change an expression from neutral to threat) is sufficient to engage distinctive profiles of neural activity (Sokolov and Boucsein 2000). Subtle changes in the muscles of the mouth region also distinguish negative (e.g., downturned) from positive (e.g., up-turned) emotional expressions. Moreover, accuracy of recognition of facial emotion is reduced when motion perception is prevented (Ambadar and Cohn 2005). In influential motivational-arousal models, two orthogonal dimensions are seen to account for stimulus significance: arousal (or intensity) and valence (positive, negative; Lane and others 1999; Lang and others 1990;
Robinson and others 2004). Yet, highly valenced stimuli are also considered very arousing, and the most arousing stimuli are typically negative (Lang and others 1990; Merckelbach and others 1998; Robinson and others 2004). We propose that a principle of match and mismatch may capture the elemental cues of danger and reward and unify dimensions of arousal and valence. For instance, the intensity, unexpectedness, and high arousability of danger cues represent forms of mismatch. The elements of symmetry, lack of abrupt contrast, and moderate to low arousability in reward cues represent forms of match. Thus, the dichotomous concepts of valence and arousal may be unified in a continuum of mismatch to match in terms of the degree of predictability, from low predictability (typically high arousal, representing danger cues) to high predictability (typically low arousal, representing reward cues). In subsequent sections, we relate the matchmismatch principle to evidence concerning the role of awareness in emotion processing, the neurobiological basis, and theories of orienting and arousal. This principle forms the basis of a continuum model that draws on an integration of these lines of evidence in proposing neural and body-arousal dynamics for processing match and mismatch cues (Fig. 2, Fig. 3). Emotion and Awareness In traditional cognitive models of emotion, it has been presumed that emotion processing must be preceded by conscious appraisal of the stimulus. This view of emotion is akin to a concept of feeling, generated by reactions to the stimulus. It has historical roots in James (1884) theory that emotion is the interpretation of feedback from the body, a theory that emphasizes subjective feelings, rather than the concept of emotion as a fundamental, motivationally determined action tendency. A related debate concerns the question of whether emotional valence is distinguished before conscious awareness or relies on feedback from conscious appraisal. The distinction between motivationally determined emotion and feeling has previously been formulated as a dichotomy between primary and secondary emotion (Damasio 1994; Freeman 1999). Primary emotion involves innately wired and preorganized responses, including body reactions, to stimulus features such as size, motion, and sound. This concept is equivalent to the concept of elemental match and mismatch primitives outlined above. All that is needed to elicit a primary emotion is a rough, quick, and dirty detection of these features, feasibly without any reliance on consciousness. Secondary emotion, on the other hand, involves learned associations and occurs once we have conscious thought about the stimulus and begin experiencing feelings and forming systematic connections between categories of objects and situations (Damasio 1994). Contrary to the traditional view, numerous lines of evidence have demonstrated that motivationally significant emotions may be processed without conscious awareness, but nonetheless, they substantially influence
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Fig. 2. A summary of the proposed continuum model for processing mismatch cues of potential danger (A) and match cues for potential reward (B). Mismatch cues (A) may be detected without conscious awareness within 100 ms, via brainstem sensory nuclei (superior colliculus in the visual domain, 1). Direct sensory input facilitates defensive-type activation, with engagement of periaqueductal gray (PAG, 3.) and amygdala (4), and arousal modulation from locus coeruleus (2), and its direct projections to ventral prefrontal cortex (PFC; including medial sector and anterior cingulate cortex (ACC, 5). Defensive-type responses are facilitated during the subsequent period 100 to 250 ms, with ongoing engagement of amygdala (4) and activation in early visual association areas (6), somatosensory areas (including insula, providing central representations of arousal, 8), and medial PFC (MPFC, including dorsal portions) for monitoring of arousal changes (7). In the period 250 to 500 ms, the hippocampus (10), lateral PFC (LPFC, particularly dorsal portions, 9), and parietal cortex (11) support contextual evaluation and working-memory updating of danger-related mismatch cues. During the later period of 500 ms to seconds, hippocampal-LPFC activation (9,10), with ongoing amygdala-MPFC (4,7) modulation, supports the transition of significant danger-related cues from working to short-term memory. During the long-term scales of minutes to hours, accumulated outcomes from danger-related processing, interacting with arousal systems, modulate neural plasticity. Match cues (B) have a partially separable trajectory within the first 300 ms. These cues may be detected within 150 ms (slightly later than mismatch cues, allowing for initial appraisal of potential danger and assurance of safety). Match detection (B) may still occur, without conscious awareness, via sensory input from brainstem sensory nuclei (1). Input from match cues facilitates approach-type activation involving hypothalamus (lateral hypothalamic area, LHA, and ventromedial hypothalamus, VMH; 12), ventral tegmental area (VTA, 13), medial forebrain bundle (MFB, including nucleus accumbens and ventral striatum, 14), and direct links to orbitofrontal cortex (OFC, 15). These responses are facilitated during the subsequent 150 to 300 ms period, with ongoing activation of MFB (14), and engagement of early visual association (6) somatosensory-related areas (8), and OFC (15) for monitoring predictability. The later period 300 to 500 ms involve networks in common with mismatch cues: hippocampus (10), LPFC (9), and parietal cortex (11) to support contextual evaluation and working-memory updating of reward-related match cues. Over the subsequent period 500 ms to seconds, hippocampal-LPFC (9,10) networks support the transition of significant reward-related cues from working to short-term memory, with ongoing modulation from MFB (14) and OFC (15) circuits. During long-term scales of minutes to hours, accumulated outcomes from reward-related processing interact with arousal systems to modulate neural plasticity.
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Fig. 3. A summary of the orienting and arousal dynamics that modulate processing of danger and reward. This figure summarizes the dynamics of sympathetic and parasympathetic arousal (excitatory and inhibitory divisions of the autonomic nervous system, respectively) that modulate central processing of matchmismatch cues. Sympathetic arousal is indicated by red and the degree of sympathetic arousal by the number of red + symbols. On the other hand, parasympathetic arousal is indicated by green and the degree of parasympathetic arousal by the number of green symbols. The detection of mismatches (indicated by the filled line) that signify potential danger will substantially increase sympathetic arousal underlying orienting, which will be reflected in changes such as heart-rate acceleration to facilitate defensive tendencies. Some degree of parasympathetic control may subsequently be required to regulate these responses. Detection of matches (indicated by the dotted line) will also elicit some degree of initial sympathetic orienting but less than that elicited by mismatches, given the lower arousability of matches. Once safety is assured, however, relatively greater parasympathetic arousal will be involved in bringing the body back from alert and facilitating approach tendencies. With accumulation of outcomes from match and mismatch processing, there will be a change in the set point at which the nervous system responds to these cues, reflected in changes in tonic arousal. These changes are not depicted in this figure but would be reflected in variations in the baseline from which increases and decreases in phasic arousal are elicited.
the organization of information processing and responses. Emotions have been shown to affect alerting evaluations, even when stimuli are presented subliminally (Bargh and others 1992; Dijksterhuis and Aarts 2003; Greenwald and others 1998; Murphy and Zajonc 1993). This evidence provides support for the view that primary emotions (or in the present terminology, match and mismatch cues) do not require conscious appraisal. Other studies have been put forward as evidence for nonconscious appraisal of valence: the apparent precedence of threat-related faces in subliminal presentation of facial emotion stimuli in binocular rivalry and backward masking tasks and the increased positive appraisal of a stimulus following mere (subliminal) exposure (Pasley and others 2004; Whalen and others 1998; Williams MA and others 2004). From a matchmismatch account, the apparent nonconscious appraisal of valence could reflect the precedence of unpredictable cues and the rewarding effects of predictable or familiar cues. Convergent neurobiological evidence for this view is outlined in the section Neurobiology of Emotion.
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Neurobiology of Emotion Converging evidence regarding the neural correlates of emotion processing comes from animal-conditioning, human-lesion, and neuroimaging studies. Consistent with their evolutionary significance, many of these studies have focused on facial expressions as experimental stimuli. For reasons of clarity (rather than reality), we have organized the review of evidence according to the spatial brain structures most consistently implicated in emotion processing, and we follow this with an overview of the temporal dimension of emotion processing. Spatial Brain Networks: Danger and Reward Emotional brain systems may be considered in relation to their roles in sensory input, appraisal of emotional significance (in terms of the mismatchmatch principle), and contextual processing and memory (Williams 2006). Brainstem Regions Brainstem structures have typically been given less emphasis than other subcortical structures, which may
be partly because of a lack of integration in physiological and neuroimaging research. Superior colliculus. Brainstem sensory nuclei such as the superior colliculus (in the visual domain) respond rapidly (within 100 ms) to low-level, magnocellular cues related to the spectrum of match and mismatch (Dean and others 1989; Fig. 2). The superior colliculus responds to cues that may be considered mismatches as well as to expected salient reward (Dean and others 1989). It is part of a direct posterior thalamic pathway to the amygdala, thought to facilitate defense-related responses (Linke and others 1999). A corresponding short latency dopamine pathway from the superior colliculus to the substantia nigra for direct facilitation of reward-related processing has also been identified (Comoli and others 2003).3 Notably, this latter pathway has both excitatory and inhibitory properties, which may enhance approach responses via dopamine circuits or suppress these responses if danger is detected. A similar suppression may occur if an expected reward is omitted. It remains unknown how (or whether) neurons in the superior colliculus identify unpredictable reward cues. We propose that these cues may be first detected as potential threat and that reward processing will only proceed once stimulus details are appraised. Corresponding brainstem sensory nuclei, such as the inferior colliculus for auditory cues, may perform a similar function in other modalities. Ascending reticular activating system (ARAS). The ARAS comprises the periaqueductal gray (PAG) area, which is implicated in defensive responses. The PAG is adjacent to the superior colliculus, which may be a direct source of sensory signals. Pain also has strong influence on the PAG (Willis and Westlund 1997), consistent with a role in processing aversive stimuli. Noradrenergic activation of the ARAS mediates body changes associated with defensive responses (such as heart-rate acceleration; Aston-Jones and others 1991). As a key part of the ARAS, the locus coeruleus projects widely throughout the cortex and interacts with the anterior cingulate and ventral prefrontal cortex in automatic emotion processing (Aston-Jones and others 1991; Liddell and others 2005). The P3 potential (particularly the early P3a subcomponent) has been associated with locus coeruleusmediated noradrenergic responses to unexpected stimuli and involves anterior cingulate generators (Ranganath and Rainer 2003). Hypothalamus. Both the lateral hypothalamic areas (LHA) and the ventromedial hypothalamus (VMH) have been implicated in consumptive behaviors related to 4 appetitive reward signals (Nakamura and Ono 1986). LHA lesions will cause animals to stop eating and drinking and lose activation, whereas VMH stimulation causes a cessation of eating as well as docile behavior and aversive reactions. The fundamental nature of these responses suggests that these hypothalamic nuclei are involved in relatively automatic processing of reward (Fig. 1). These areas are also closely linked to autonomic circuits.
Amygdala The amygdala has been consistently implicated in perception and responses to danger (Adolphs and others 1994; LeDoux 1996; Morris and others 1996; Williams and others 2001). Evolution has ensured that the amygdala is a site of polysensory integration with dense neurotransmitter receptors and projections to both subcortical and cortical circuits, making it well suited as an alarm center for automatic generation of multiple response options in the face of threat cues (Davis and Whalen 2001; Zald 2003). Behaviorally, amygdala lesions impair recognition of basic expressions of emotion, particularly fear (Adolphs and others 1994). Elemental mismatch cues may be relayed directly to the amygdala along brainstemposterior thalamic pathways, bypassing the primary sensory cortices (Linke and others 1999). Evidence for a short latency thalamoamygdala pathway for auditory fear cues was provided by the seminal fear-conditioning work of LeDoux (1996). Neuroimaging studies of blind-sight patients (with damage to the striate visual cortex) and masked (nonconscious) stimuli in healthy individuals have provided convergent evidence for colliculus-pulvinar and amygdala activation in response to fearful expressions (Morris and others 2001; Whalen and others 1998; Liddell and others 2005; Williams, Liddell, and others 2006; Williams, Das, and others 2006). The amygdala also has a direct white-matter connection with inferotemporal early visual association areas, which may support rapid visual processing of fear signals (Catani and others 2003; Fig. 2). Depth recordings in blind-sight patients have revealed early activity in these visual association areas for fearful expressions, consistent with the notion that these areas support appraisal of fear cues in the absence of conscious attention (de Gelder and others 1999). Convergent evidence from animal fear conditioning and human neuroimaging studies has highlighted a parallel, slower cortical pathway to the amygdala for more detailed and conscious processing of fear stimuli (Das and others 2005; LeDoux 1996; Williams, Das, and others 2006). This slower, indirect pathway relies on the elaboration of stimuli via sensory cortices. Amygdala activation from both direct and indirect pathways has been associated with increases in arousal (indexed by skin-conductance responses [SCRs]; Williams and others 2001; Williams, Liddell, and others 2006). These findings accord with the influential somaticmarker hypothesis (Damasio 1996), which proposes that arousal feedback to the amygdala may occur with conscious elaboration of stimuli as well as in the absence of awareness. As noted below, we have observed corresponding medial prefrontal cortex (MPFC) activation with increases in amygdala and SCRs. Medial Forebrain Bundle (Ventral Tegmentum, Septal Area, Basal Ganglia) The medial forebrain bundle (MFB), first described by Olds (1969), comprises the ventral tegmental area
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(VTA) of the midbrain, the septal area, and the basal ganglia (which itself constitutes the striato-pallido-nigral bundle, formed by the caudate nucleus and putamen of the striatum and its primary connections with the globus pallidus, substantia nigra, and nucleus accumbens). Whereas danger processing is supported by the noradrenergic ARAS system, the MFB circuits contain more than 80% of the brains reward-related neurotransmitter, dopamine, and are often referred to as the mesolimbic dopamine pathway (Bozarth 1991). Research into reward processing has focused in particular on the ventral tegmentum and nucleus accumbens (also termed the ventral striatum). Ventral striatal activation is observed even for implicit (subliminal) omissions of expected stimuli (Berns and others 1997), consistent with the presence of a direct pathway to the substantia nigra. Functional neuroimaging studies also demonstrate activation in the nucleus accumbens and related areas for explicit presentation of natural reward cues, including food and drink, attractive faces, facial expressions of happiness, and stimuli related to pleasant sexual arousal and successful competition (Critchley and others 2000; ODoherty and others 2002; Phan and others 2002). Moreover, these areas are activated by learned associative rewards such as money (Knutson and others 2001). Hippocampus The hippocampus is also a site of polysensory integration and has many neurotransmitter receptors. Convergent evidence points to the role of the hippocampus in contextual evaluation of emotionally significant cues (for both potential danger and reward), which may be supported by its anatomical connections to both the amygdala and the striatal pathways. In learning and orienting theory, the hippocampus subserves comparison of match and mismatch signals with stored information and associated updating of significant new information in working memory (Gray 1987; Sokolov 1960, 1990). Similarly, conditioning and functional neuroimaging studies have implicated the hippocampus in both implicit and explicit context processing of stimulus characteristics such as probability (Harrison and others 2006; Phillips and LeDoux 1995). Hippocampal activation to both negative and positive facial emotions (Canli and others 2002; Phillips and others 1998) may reflect this context-processing function. Unlike the amygdala, these hippocampal functions may not rely on stimulus arousability. A dissociation of the amygdala (with SCRs) and hippocampus (absence of phasic SCRs) has been observed in lesion studies and concurrent functional MRISCR recording with fearful face and oddball mismatch stimuli (Bechara and others 1995; Williams and others 2001; Williams, Felmingham, and others 2007). The hippocampus may also contribute to the longer term persistence of emotionally significant information on the basis of accumulated contextual information. Hippocampal structures interact with the amygdala to facilitate memory that is enhanced by emotional significance
(Phelps 2004) as well as the prefrontal cortices outlined below. Prefrontal Cortices The prefrontal cortex may be divided anatomically into the MPFC, the lateral prefrontal cortex (LPFC), and the orbitofrontal cortex (OFC). In turn, the MPFC may be subdivided into the medial frontal gyrus, the anterior cingulate cortex (ACC), and the ventral areas (including the infralimbic and prelimbic areas). Both the LPFC and MPFC (including the ACC) may also be considered in terms of their dorsal versus ventral portions. According to the somatic-marker hypothesis, ventral, medial, and orbital sectors have a key role in emotionrelated decision making by incorporating changes in body arousal (visceral and central representations; Damasio 1994, 1996). This process may occur explicitly as a conscious signal (i.e., gut feeling) or implicitly as a nonconscious bias (Damasio 1994, 1996). In support of this hypothesis, MPFC lesions lead to attenuated SCRs and poor winloss decisions (Damasio 1996). We have found that both nonconscious and conscious fearful faces elicit SCRs with concomitant MPFC activation (preferentially greater in ventral rostral areas for nonconscious faces and in dorsal areas for conscious faces; Williams and others 2001; Williams, Liddell, and others 2006). The prefrontal cortices have also been implicated in emotional self-regulation by facilitating the optimal balance of approach (reward-related) versus avoidance (danger-related) tendencies (Davidson and Irwin 1999). Regulation feasibly occurs via descending projections from the MPFC and LPFC to the amygdala and from the OFC to the accumbens (Phan and others 2002). Hippocampalmediated contextual input to the MPFC has also been highlighted in regulation and extinction of fear responses (Sotres-Bayon and others 2004). In Rolls (2000) complementary theory, the OFC is a key structure in reward processing and reinforcement of reward associations. OFC lesions lead to perseverance and impaired processing of appetitive cues (Hikosaka and Watanabe 2000). The OFC is activated by highly salient positive facial emotions (ODoherty and others 2003) as well as learned (e.g., monetary) reward cues (Taylor and others 2004). Notably, OFC engagement relies on the predictability of reward stimuli (Berns and others 2001), which is consistent with the notion of match cues. Convergent evidence suggests that the ACC is particularly sensitive to stimulus arousability and may be part of the mechanisms for initial alerting and orienting to emotionally significant stimuli.5 The ACC is recruited by these stimuli under both conscious and nonconscious conditions (Killgore and Yurgelun-Todd 2004; Williams and others 2001; Williams, Liddell, and others 2006; Williams, Das, and others 2006). Damasio (1994) proposed a similar role for the ACC in involuntary somatic reactions to emotion stimuli. The ventraldorsal gradient of the LPFC may be important to its preferential involvement in emotion processing. Ventral LPFC activation has been associated with implicit
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processing of mismatch cues of potential danger, such as novelty and abrupt sensory change (Berns and others 1997; Williams, Felmingham, and others, 2007). Like the ventral MPFC, the ventral LPFC is sensitive to arousal and is engaged with SCR orienting to these cues (Williams, Felmingham, and others 2007). On the other hand, the dorsal LPFC has been preferentially implicated in contextual processing and working-memory updating (Miller and Cohen 2001; Williams and others 2001), which may involve hippocampal interactions. During longer time scales, the dorsal LPFC, along with the hippocampus, may interact with both the MPFC and the OFC for more sustained emotion regulation and to maintain contextual information necessary for representing and monitoring motivationally relevant goals (Miller and Cohen 2001). The LPFC may also be important for longer term prioritization of danger or reward-related information in memory (Miller and Cohen 2001; Taylor and others 2004). Somatosensory-Related Cortices Somatosensory-related areas are thought to interact closely with the amygdala and the MPFC (Adolphs and others 2000; Fig. 2). For instance, in the perception of fear, somatosensory representations may integrate the sensory input needed for fear recognition (such as widened eyes) with images of somatic changes (such as body arousal). The insulaa visceral somatosensory regionmay be particularly important in conveying somatosensory information about emotion signals to the amygdala and basal ganglia (Adolphs and others 2000; Adolphs 2002; Liddell and others 2005). The ventral MPFC (including the OFC) may draw on these somatosensory images to make emotional associations between knowledge of a fear stimulus (innate or previously acquired) and corresponding body states (Damasio 1994). Consistent with these proposals, we have observed a dynamical sequence of insula, MPFC, and amygdala activation with increases in SCRs to fearful faces (Williams, Brown, and others 2004). Temporal Dynamics: Danger and Reward Comparatively little attention has been given to the temporal dimension of emotion processing. In the above theories, temporal dynamics are considered only broadly in regard to nonconscious (early) versus conscious (later) processing (Damasio 1994; LeDoux 1996). Based on depth-recording data, Halgren and Marinkovic (1995) have proposed four overlapping temporal stages in which there is preferential engagement of neural systems: orienting (rapid, automatic appraisal of emotional stimuli within the first 300 ms, involving hypothalamic, arousal, and anterior cingulate networks); event integration (more detailed evaluation of a stimulus occurring at ~300 to 500 ms and involving association cortices); response selection (associated with motor networks); and context (sustained processing at a longer time scale, involving the hippocampus, the OFC, and hormonal activity). Evidence from scalp-recorded event-related potential (ERP) studies that focused on individual emotions (such
as fear and happiness) suggests an extension and variation of this temporal sequence. Expressions of fear (compared to happiness) have been found to elicit an early frontocentral positivity within the first 100 ms (Eimer and Holmes 2002; Williams, Palmer, and others 2006; Fig. 4). This early activity reflects the precedence of potential danger cues. Fear signals showed a subsequent profile of enhanced frontal activity peaking at ~170 ms and again at ~350 ms poststimulus, consistent with appraisal of emotion and sustained evaluation and contextual processing, respectively (Fig. 4). By contrast, expressions of happiness elicit a more discrete enhancement in activity commencing later in the time course, at ~250 ms, and over temporaloccipital rather than frontal regions (Williams, Palmer, and others 2006; Fig. 4). These distinct profiles of activity provide further support for the precedence with which mismatch cues are processed. In common, fear and happiness elicit increases in the temporo-occipital N170 associated with structural encoding of face stimuli, consistent with the biological significance of these expressions relative to neutrality (Ashley and others 2004; Williams, Palmer, and others 2006; Fig. 4). Evidence of enhanced activity to fear before the N170 adds weight to the argument that emotion processing does not first require detailed perceptual analysis of the stimulus, in contrast to the conventional account (Streit and others 2000). Notably, fear stimuli presented without conscious awareness elicit even earlier increases in activity relative to neutrality (Williams, Liddell, and others 2004; Williams and others in press; Fig. 5). These findings support the view that the precedence given to fear (mismatch) cues does not require awareness. Nonconscious fear also enhances ERPs at ~230 to 300 ms. These ERPs are associated with orienting and feasibly correspond to the direct innervation of cortical regions observed in functionalneuroimaging studies. By contrast, nonconscious fearful faces do not elicit the later enhancements in activity (indicating sustained context evaluation) seen for conscious fear (Liddell and others 2004; Williams, Liddell, and others 2004; Williams and others in press; Fig. 5). Motivational Arousal Systems Seminal theories of motivational arousal have typically been formulated around a dichotomy of danger-related avoidance behaviors, on the one hand, and opposing systems for reward-related approach behaviors on the other (Gray 1987; Pribram and McGuinness 1975; Davidson and Irwin 1999; Lang 1994). Importantly, though, interconnections between these systems are also emphasized. In Grays (1987) theory, the fightflight system subserves defensive responses to danger over rapid time scales and is mediated by the amygdala, PAG, and medial hypothalamus, particularly within the right hemisphere. The behavioral inhibition system (BIS) is the core regulatory system: over short time scales, it disinhibits fightflight to allow for rapid responses to unconditioned (i.e., innate) threats, and over longer time scales, it inhibits the ongoing action program for orientation to signals of danger that

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Fig. 4. Statistical-parameter headmaps illustrate the spatiotemporal distribution of neural activity in response to fear and happiness relative to neutral face stimuli. The time course of activity in which event-related potential (ERP) components were identified is shown in the bottom row, with corresponding labels for each component (prefix P indicates a positive going ERP component, graphed downwards, and N indicates a negative going component, graphed upwards). Each headmap shows the distribution of activity over medial frontocentral (Fz, Cz), temporal (T5, T6), and occipital (01, 02) recording sites, viewed from the back of the head. Regions colored in the red spectrum indicate an increase in activity; regions colored in the blue spectrum indicate a reduction in activity; and green indicates no significant difference. The legend shows the scale of t-values corresponding to each significant effect; positive t-values reflect increases, and negative t-values reflect reductions in activity. Fearful faces were distinguished by persistent increases in frontal positivity, reflected in the P80 (compared to happiness only) and in the vertex positive potential (VPP) and P300 (compared to both happiness and neutrality). Fear elicited an isolated reduction in the frontal N200 (compared to neutrality only). In contrast, happiness was distinguished by a discrete increase and slowing in temporo-occipital positivity for the N250. In common, fear and happiness elicited increases in the temporo-occipital N170 (consistent with enhanced face processing), with reductions in P120 and P230 positivity (which likely reflect the incipient onset and offset of the N170). The distinctive profiles for fear and happiness are consistent with the precedence of fear and the notion that mechanisms for seeking reward-related positive stimulation are suppressed until vigilance for potential danger is complete or acted on. Adapted with permission from Figure 2 in Williams, Palmer, and others (2006).
require explicit evaluation, such as learned associations with punishment. BIS activity is hippocampal dependent, although later formulations have also implicated the amygdala. The opposing behavioral activation system (BAS) is associated with approach for appetitive functions and response to reward (Gray 1987) and relies on the ventral tegmental-nucleus accumbens dopamine pathway. As highlighted by Gordon (2000), Pribram and McGuinness (1975) proposed three complementary systems: amygdala-mediated affect arousal (akin to fightflight), hippocampal-mediated effort (akin to the BIS), and activation (overlapping with the BAS but encompassing a broader set of approach behaviors). Concepts of behavioral inhibition and activation have also been reflected in Davidson and Irwins (1999) model of prefrontal emotion regulation, in which the right prefrontal cortex subserves avoidance via inhibitory functions and the left prefrontal cortex subserves approach behaviors via activation. Clearly, these concepts of motivational arousal overlap with the neural systems implicated in emotion processing. This point highlights the importance of both motivation in the present definition of emotion and the centrality of arousal in modulating motivationally relevant emotion processing. Theories of motivational arousal also emphasize a third point: the importance of modulation to the interaction of neural systems for emotion processing. For
instance, motivational-arousal systems are seen to be modulated by noradrenergic (fightflight), serotonergic (BIS), and dopaminergic (BAS) neuromodulators associated with brainstem nuclei such as the locus coeruleus and substantia nigra (Gray 1987). The autonomic nervous system (ANS) also plays a role in the modulation of emotion processing, as outlined in subsequent sections. Orienting and Arousal Mechanisms Whereas early neuropsychological theories of emotion perception were based on the presumption that arousal feedback is necessary for emotion processing (e.g., James 1884), Cannon (1927) was perhaps the earliest to argue explicitly that emotion may precede autonomic reactions. He illustrated his point that emotions do not arise causally from autonomic changes in disorders such as Bells palsy and Meobius syndrome, in which face muscles are paralyzed but emotional intensity nonetheless remains unaffected. Sokolovs (1960, 1990) seminal work on orienting has since highlighted the bidirectional contribution of body arousal (ANS) to tuning neural systems to engage with significant stimuli. The notion that orienting occurs to mismatches (following a comparison with stored information) was also introduced by Sokolov. Phasic increases in electrodermal arousal (reflected in SCRs) are one of the most general and robust autonomic
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Fig. 5. Statistical-parameter headmaps illustrate the spatiotemporal distribution of neural activity for the contrast of fearful relative to neutral face stimuli, presented under conscious and nonconscious conditions. The time course of activity in which event-related potential (ERP) components were identified is shown in the bottom row, with corresponding labels for each component (prefix P indicates a positive going ERP component, graphed downwards, and N indicates a negative going component, graphed upwards). Each headmap shows the distribution of activity over medial frontocentral (Fz, Cz), temporal (T5, T6), and occipital (01, 02) recording sites, viewed from the back of the head. Regions colored in the red spectrum indicate an increase in activity, those in the blue spectrum indicate a reduction in activity; and green indicates no significant difference. The legend shows the scale of F values corresponding to each significant effect; positive F values reflect increases, and negative F values reflect reductions. Relative to neutrality, conscious fear processing was distinguished by increases in structural encoding (N170; 120220 ms) and for later sustained evaluation and context processing (P300; 300450 ms). By contrast, nonconscious fear relative to neutral processing showed earlier increases for initial perceptual analysis over all regions (N120/P120; 80180 ms) and for automatic orienting (N250; 230330 ms). In common, conscious and nonconscious fear elicited increases in emotional appraisal (VPP; 120220 ms), which were particularly pronounced for conscious fear, and for the early P300. Adapted with permission from Figure 2 in Williams and others (in press).
indices of orienting (Boucsein 1992). Importantly, orienting occurs for salient stimuli of both negative and positive valence (Lang and others 1997) but may be lesser for positive stimuli (e.g., Pourtois and others 2005). This distinction is particularly apparent for preattentive (or nonconscious) processing (Ohman 1979). Preattentive orienting is also enhanced for a broad range of potential danger cues such as rapid motion and high intensity (Robinson 1998). These findings are consistent with the notion that orienting is elicited by elemental mismatch cues rather than valence per se. Because mismatches linked to potential danger through evolution are more intense than matches, they may consequently elicit greater orienting. Particularly arousing mismatches (such as loud startle stimuli) may elicit a reflexive or involuntary form of orienting known as the defensive response, which facilitates mobilization to potential danger and may not readily habituate (Graham 1979). Defensive responses accord with the fightflight and affect-arousal systems outlined above. Voluntary orienting is associated with more controlled and conscious processing. Notably, recovery of skin-conductance responses is prolonged with controlled evaluative functions (Vossel and Zimmer 1992), feasibly an index of the body-arousal feedback that supports these functions. Voluntary orienting accords with the BIS reviewed above.
Autonomic Nervous System: Sympathetic and Parasympathetic Arousal Associated changes in the balance of sympathetic versus parasympathetic arousal interact with orienting to modulate danger and reward stimuli and associated neural systems. The excitatory sympathetic and inhibitory parasympathetic systems are the two primary divisions of the ANS.6 Sympathetic arousal underlies the general state of activation needed for responses to danger. The two key sympathetic neurotransmitters are acetylcholine (preganglionic) and noradrenaline (postganglionic), which have a widespread synapsing of preganglionic to postganglionic neurons and together produce the somatic changes for an alert state, or fightflight. Acetylcholine stimulates action potentials, and noradrenaline stimulates the autonomic changes seen in defensive orienting (heart rate acceleration; raised blood pressure; pupil dilation; shunting of blood away from the skin and viscera to the brain, heart, and skeletal muscles; and facilitation of liver glycogen conversion to glucose for energy to muscles; Fig. 3). The only inhibitory effects (peristalsis in the gastrointestinal tract and contraction of the bladder and rectum) are also aimed at facilitating emergency responses (Boucsein 1992; Porges 1997). The parasympathetic division, on the other hand, is responsible for relaxation of the alert state that the

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sympathetic system puts the body into. The main nerves of the parasympathetic division are the cranial nerves, of which the tenth (vagus) may be particularly important for autonomic regulation. Unlike in the sympathetic division, acetylcholine at postganglionic neurons synapses with just a few postganglionic neurons, such that effects are specific. Moreover, parasympathetic effects are inhibitory rather than excitatory, including heart rate deceleration and pupil constriction as well as increases in blood flow to skin and viscera and peristalsis of the gastrointestinal tract (Fig. 3). Using concurrent heart-rate and functional neuroimaging recording, acceleration in the heart rate (feasibly reflecting relatively greater sympathetic arousal) has been linked with activation in the brainstem, amygdala, early visual association areas, and ACC activation for expressions of anger and sadness, whereas heart rate deceleration correlates with activation in the OFC for happiness and disgust (Critchley and others 2005). This dissociation may reflect changes in the balance of sympathetic and parasympathetic arousal according to the degree of mismatch and match for negative and positive (or approach-related) emotion, respectively. Drawing on these findings, we propose that the balance of activity in sympathetic and parasympathetic systems contributes to the modulation of emotion processing as it unfolds in relative degrees along a temporal continuum (Fig. 3). Integrating Emotion, Orienting, and Arousal: A Continuum Model of Significance Processing We draw together evidence for motivation-related emotion processing, awareness, neural systems, and arousal to propose a continuum model of emotion processing. In this model, we represent current dichotomies as specific points on a temporal continuum. In terms of neural systems, it is pertinent to take into account the millions of years of primate and hominid evolution that have affected networks for processing emotion at many levels of organization (Gordon 2000). We emphasize a deep integration and connectivity between evolutionary older brain systems and more recently evolved ones along the continuum of processing. The progressive organization of prefrontal regions in particular has resulted in a general expansion in the range, flexibility, and control of emotional functions. This view is complementary to a sharply delineated dichotomy of subcortical networks for rapid, nonconscious emotion processing and cortical ones for slower, conscious processing. In relation to the temporal dimension, it is proposed that mismatch and match appraisal may occur without sensory awareness within the first ~100 ms of processing to facilitate a rapid response to potential danger in particular. We draw on a consensus that the capacity for conscious processing of emotion emerges at ~200 to 300 ms poststimulus, supported by central and body re-entrant feedback, whereas contextual processing of the stimulus occurs at ~300 to 500 ms (Fig. 2). In this continuum
model, we have focused on the detail of the neural systems involved at these short time scales (up to 500 ms), given their importance to survival-related processing (Fig. 2). We also highlight arousal modulation (including associated neurotransmitters) in the dynamics of neural activity along this temporal continuum. SCRs are increased with ERPs at ~250 ms poststimulus during conscious (but not nonconscious) emotion perception, consistent with the role of arousal enhancement in the emergence of consciousness in this time frame (Williams, Liddell, and others 2004). Moreover, ERPs persist beyond 250 ms for conscious but not nonconscious processing (Williams, Liddell, and others 2004). Patients with peripheral failure (who have an absence of central feedback from arousal) are specifically impaired on emotional-attribution tasks (which require conscious appraisal of feelings) but not on motivational decision making, which may proceed with initial feed-forward arousal from lower brainstem circuits (Heims and others 2004). We propose that the human nervous system is tuned 7 to give precedence to mismatch cues of potential danger such that there are parallel trajectories for danger- and reward-related processing during the first ~300 ms. At rapid time scales (within 100 ms), a crude initial differentiation of the degree of mismatch and match is possible, subserved by brainstem sensory nuclei such as the superior colliculus without the need for conscious appraisal (Fig. 2). Detection of a mismatch will trigger a defensive orienting response and a feed-forward cascade of activation, innervating the amygdala along with brainstem PAG and ARAS (involving the locus coeruleus) within the first 100 ms of processing (Fig. 2). This focus on mismatch cues as fundamentally arousing accords with convergent evidence that the amygdala has a key role in appraising the arousing properties of stimuli to facilitate orienting to their significance (Davis and Whalen 2001). Indeed, amygdala lesions cause greater impairments in decoding the arousability of facial expressions than in recognition of their valence (Adolphs and others 1997). Defensive responses will be facilitated within the subsequent 100- to 250-ms time frame (Fig. 2). Detection of mismatches signifying potential danger will increase sympathetic arousal underlying orienting and will be reflected in the heart rate acceleration of a defensive response (Fig. 3). The direct and widespread projections of the ARAS provide a mechanism for diffuse increases in arousal and innervation of cortical areas such as the ACC and the interconnected ventral portion of the MPFC (Fig. 2). Defensive orienting will in turn facilitate enhanced sensory appraisal of the stimulus (involving early visual association areas). Central representations of the arousing and salient aspects of the stimulus will involve somatosensory regions such as the insula and the MPFC (Adolphs 2002; Fig. 2). Within the first 300 ms, processing of reward-related match cues may trigger a partially separable trajectory when danger is not detected. Because of the initial check for potential danger, reward signals will typically be
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processed with a later latency than danger (within 150 ms rather than 100 ms), as reflected in ERP recordings (Williams, Palmer, and others 2006). Neuroimaging studies have also revealed reduced amygdala activation for matchrelated stimuli (positive expressions) that have low arousal (Whalen and others 1998). Once safety is assured, detection of reward cues may elicit activation in the MFB circuits (Fig. 2) and a relative deactivation in the amygdala. Concomitant activation in the reciprocally connected hypothalamic areas (LHA, VMH) will facilitate a return from the alert for potential danger and the initiation of approach-related action tendencies such as exploration. OFC activation may also occur within 150 ms (Kawasaki and others 2001) and may support the central representation of reward-related match cues and approach tendencies. Matches will also elicit some degree of initial sympathetic orienting. Once safety is assured, however, relatively greater parasympathetic arousal will be associated with innervation of OFC reward circuits to bring the body back from alert and to facilitate approach tendencies (Fig. 2, Fig. 3). Within the subsequent 150 to 300 ms, this profile of brain and body activation will facilitate greater sensory processing (involving early visual association areas) with ongoing input from the MFB and OFC regions (Fig. 2). As is the case for danger processing, somatosensory regions such as the insula will also support central representations of the arousal changes associated with reward cues (Fig. 2). During the later time scale of 300 to 500 ms, match and mismatch cues may engage similar networks for common processes of contextualization and memory consolidation. We emphasize that the amygdala and the MFB and MPFC/OFC circuits may also continue to be re-engaged by these later processes, shaping processing at multiple time points. During the 300- to 500-ms time frame, hippocampal dorsal lateral prefrontal cortex (DLPFC) networks may respond to contextual cues and prior associations to update working memory with emotionally significant information. The parietal cortex has also been implicated in working-memory updating (Clark and others 2000). These processes appear to be unrelated to the arousing nature of mismatch (or match) stimuli (Bechara and others 1995; Williams and others 2001; Williams, Das, and others 2005; Fig. 2). These cortical networks are also implicated in the transfer of significant events to longer term memory during time scales of seconds to minutes (Fig. 2). During these longer time scales, danger processing may require some degree of parasympathetic control (Fig. 3), consistent with the notion of BIS or effort arousal regulation (Gray 1987; Pribram and McGuinness 1975). On the other hand, reward processing may require sympathetic activity to support ongoing approach behaviors or sustained attention. It is proposed that the cumulative effect of emotionally significant stimuli on memory systems will contribute to the ongoing plasticity of the brain across time scales of hours and days. This cumulative effect will also influence
the way in which neural systems respond to subsequent stimuli via widespread association networks and tonicarousal modulation (Fig. 2). Changes in tonic arousal will reflect corresponding changes in the set point at which the nervous system responds to potential mismatches or matches. Consistent with this view, recent models of orienting suggest that tonic arousal reflects variations in vigilance (akin to set point) and its role in amplifying the phasic response to significant stimuli (Barry 2006). The concepts of set point, tonic arousal, and vigilance can all be represented as the gain within a unified biophysical model of brain function (Robinson and others 2003). Stimulus-related activity can likewise be regarded as caused by localized, transient gain changes (Rennie and others 2002). Biophysical modeling may therefore be a means to test the mechanisms of repeated exposure to threat in terms of cortical gains, without the need for longitudinal research. The Importance of Connectivity In the continuum model, there is an emphasis on the importance of danger and reward cues to organizing information processing. In this regard, evolution-determined emotion cues may be central to determining which networks are bound moment by moment. High temporal-resolution neural binding is thought to be a necessary (although possibly insufficient) mechanism in the emergence of consciousness, defined as sensory awareness (Engels and Singer 2001). Yet, the importance of danger and reward cues may mean they are an exception and can elicit binding without awareness. Initial support for this proposal has come from a candidate index of neural binding: in-phase synchronous activity in the high-frequency (40 Hz) -band (Engels and Singer 2001; Lee and others 2003). Expressions of fear and happiness have been found to elicit -synchrony for both conscious and nonconscious presentations (Williams LM, Palmer D, Liddell B, Boord P, Mathersul D, Silverstein S, Gordon E. Evolutionary emotion: An exception to the rule that neural binding requires sensory awareness? [under review]). Synchrony varies with awareness in several ways, however. First, nonconscious synchrony was most pronounced over the temporal cortex and conscious synchrony over parieto-occipital regions, which may reflect the involvement of direct and indirect pathways for sensory input, respectively (Williams and others under review). Second, synchrony was modulated by individual stimuli in the conscious condition (greatest for fear, followed by neutrality, then happiness) but only for fear in the nonconscious condition. This latter finding is consistent with a unified notion of match and mismatch, in which highly arousing danger-related mismatches rather than valence per se may mediate neural binding without awareness, whereas awareness may be necessary for binding of specific valence information. Complementary findings have come from functionalconnectivity analysis with neuroimaging data. Distinct modes of functional connectivity were found to support

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Fig. 6. Psychophysiological-interaction analysis of fMRI data showing the functional connectivity between the amygdala and the regions of interest during conscious fear (A) and nonconscious fear (B) relative to neutrality. Red arrows represent positive functional connectivity between the amygdala and regions of interest, and blue arrows represent negative connectivity. Conscious fear (A) was distinguished by negative functional connectivity in a cortical (striatethalamic LGN) amygdala pathway with links to both the left and right amygdala. Negative connectivity was also observed between the bilateral amygdala and other cortical regions (extrastriate and dorsal medial prefrontal) as well as the subcortical brainstem region. Conscious fear elicited positive functional connectivity between the bilateral amygdala and dorsal anterior cingulate (ACC). The right amygdala in particular also covaried positively with the ventral ACC, extrastriate, and periaqueductal grey regions of the brainstem (not shown). Nonconscious fear (B), in contrast, elicited positive functional connectivity in a subcortical (brainstemposterior thalamic) amygdala pathway localized to the right amygdala. Positive relationships were also observed between the bilateral amygdala and rostral regions of the medial prefrontal and ACC. For nonconscious fear, the right amygdala showed negative relationships with additional cortical regions: the extrastriate and ventral medial prefrontal cortices (not shown). A = amygdala; LGN = lateral geniculate nucleus of the thalamus; B = brainstem; ACC = dorsal anterior cingulate cortex; dACC = dorsal ACC; MPFC = medial prefrontal cortex; dMPFC = dorsal MPFC. Adapted with permission from Figure 4 in Williams, Das, and others (2006).
the conscious versus nonconscious perception of fear, consistent with distinctive profiles of synchrony. Nonconscious fear was supported by predominantly positive connections within amygdala pathways (including the direct superior colliculo-pulvinar circuits), whereas awareness of fear relied on predominantly negative connections and a greater involvement of cortical connections (Williams, Das, and others 2006; Fig. 6). These findings also support the view that awareness for danger-related cues is not simply determined by a neat subcorticalcortical separation. The concept of neuromodulation raised in preceding sections is also a key mechanism in mediating connectivity, which may link real-time measures of -synchrony and slower hemodynamic signals from neuroimaging. Mechanisms of -synchrony involve the mutual interaction of excitatory pyramidal neurons and inhibitory regulation from GABAergic neurons (Lee and others 2003). Neuromodulators such as noradrenaline, serotonin, dopamine, and their cousin, acetylcholine, modulate this interaction by their relatively excitatory or inhibitory influence on synaptic activity, including at the slower time scale of hemodynamic activity (Williams, Das, and others 2006). Variations in the balance of neuromodulators may contribute to variations in -synchrony and functional connectivity across the time course of emotion processing.
We conclude with a brief consideration of how a temporal continuum model of emotion processing may be applied to understanding individual differences in the stabilities and instabilities inherent in psychiatric disorders. Individual Differences in Emotional Stabilities Sex Differences A growing pool of evidence points to sex differences in brain-arousal mechanisms of danger and reward processing (Cahill 2005), which may reflect selective evolutionary pressures. For example, women show relatively enhanced detection of threat-related expressions and greater activity in the brainstem, amygdala, and ACC networks to these stimuli (Kemp and others 2004; Williams, Barton, and others 2005). Women also show more persistent amygdala and related sympathetic-arousal response than men (Williams, Barton, and others 2005). Together, these findings point to heightened defensive response in women during the early 0- to 300-ms time frame, which may contribute to enhanced vigilance and a more sensitive threshold for detecting mismatches. This profile accords with the typically slighter physique of females in an environment of evolutionary adaptation that has valued physical
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survival and in which infant survival has typically relied on maternal care. During longer time scales, sex differences in laterality suggest a heightened processing of emotion-stimulus details in women (see Cahill 2005 for review), which might flow from enhanced vigilance. These variations may contribute to sex differences in vulnerability and resilience to the emotion-related instabilities outlined in the following section: for instance, mood disorders such as anxiety, which reflect excessive vigilance for threat, are more frequent in women (Kessler and others 1994). Age-Related Differences There is also accumulating evidence for changes in emotion processing during the human life span. Young individuals show comparatively greater startle facilitation along with enhanced activation of the amygdala to fearful faces and the basal ganglia to happiness (Mather and others 2004; Gunning-Dixon and others 2003; Williams, Brown, and others 2006). Hyper-responsivity may reflect heightened sensitivity to match and mismatch cues, necessary for learning about sources of danger and reward, together with immaturity of prefrontal mechanisms involved in emotion regulation. Complementary evidence suggests that the effect of amygdala lesions on arousal responses to fear is less with older age (Dolan 2002). We have observed a corresponding increase in MPFC regulation of danger cues versus reward cues (Williams, Brown, and others 2006). This increase predicted better emotional stability and less emotional intensity (arousability) with older age, consistent with the accumulation of learning about emotion-related outcomes (Williams, Brown, and others 2006; Whittington and Huppert 1998). Genetic Variation Genetic variation contributes to individual differences in the spectrum of emotional stability and instability. Among the single nucleotide polymorphisms (SNPs) identified as having a role in brain function, several have been shown to affect the modulation of emotion processing in terms of both brainstem amines and mechanisms of plasticity. Individuals with the short allele of the serotonin transporter (5HTT) polymorphism tend to have less efficient 5HT transcription and greater risk for anxietyrelated temperamental traits (Pezawas and others 2005). The short allele is also associated with poorer connectivity in amygdala-MPFC networks, suggesting disrupted regulation of responses to mismatch danger cues, a characteristic of anxiety (Pezawas and others 2005). These findings accord with linkages between the 5HTT short allele and mood disorder (Caspi and others 2003). The catechol-o-methyltransferase (COMT) Va1108/ 158Met polymorphism is involved in catabolism of prefrontal dopamine and locus coeruleusgenerated noradrenaline and adrenaline (Smolka and others 2005). Notably, COMT Met carriers (with excessive noradrenalin caused by reduced catabolism) show heightened activation in regions to which the locus coeruleus projects for negative emotion
cues. Thus, COMT variants may also contribute to individual differences in sensitivity to mismatch-related defensive responding and risk or resilience for mood disorder, consistent with evidence from clinical groups (e.g., Woo and others 2004). Brain-derived neurotrophic factor (BDNF) is involved in the mechanisms of synaptic communication and may influence development and plasticity of the amygdala hippocampal pathways (Rattiner and others 2005). For the BDNFVa166Met polymorphism, Met carriers have the poorest synaptic function, which is exacerbated with exposure to stress. Met carriers with higher stress have impaired hippocampal tissue along with arousal dysregulation and slowed neural processing of positive expressions of emotion (e.g., Gatt and others 2007; Gatt J, Kuan S, Dobson-Stone C, Paul RH, Joffe R, Kemp AH, Schofield PR, Gordon E, Williams LM. Alpha band neural activity mediates the role of the BDNF Va1166Met polymorphism in risk for depressive features [under review]). This profile may reflect disruptions to contextual evaluation and transfer to memory for these individuals. Future research into genetic variation and emotion processing might draw on large-scale analyses that delineate profiles of genetic expression within the relevant neural systems. As an example, high-density microarray analysis has revealed two distinct sets of genes222 genes in the amygdala and 145 in the hippocampusthat differ in expression and regulation patterns (Mei and others 2005). Psychiatric Disorder and Emotional Instabilities Instabilities in emotional brain systems may manifest in psychiatric disorders, characterized by disturbances in emotion and motivation. Although in-depth coverage of all disorders is beyond the scope of this review, we consider several examples: schizophrenia, anxiety, depression, anorexia nervosa, and attention-deficit hyperactivity disorder (ADHD; Fig. 7). Schizophrenia Schizophrenia is characterized by a fundamental disorganization of perception, thought, and motivation. These breakdowns are consistent with an inability to appropriately distinguish match versus mismatch cues and organize information processing accordingly, from the earliest automatic to the later controlled time frames (Fig. 7). Convergent evidence for this view includes the following:
1. Within 120 ms: Highly arousing mismatch stimuli continue to elicit ERPs and electromyogram activity despite prior exposure in sensorimotor gating tasks (Swerdlow and Geyer 1998). 2. From 100 to 500 ms: ERPs do not show the differentiation seen in controls to match versus mismatch signals in oddball tasks (Brown and others 2000). 3. Across the time course: There is a loss of normal neural binding and functional connectivity in response to mismatch cues

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Fig. 7. A summary of the hypothesized core disturbances in emotion processing and their time frame(s) in exemplar disorders of mental health. Schizophrenia psychosis is hypothesized to involve neural disorganization across the time course of match-mismatch processing, such that there is a fundamental inability to determine relevant from irrelevant information regardless of the degree of awareness and depth of processing. This proposal is consistent with evidence for impairments in the activation and functional connectivity of brainstem, limbic, and basal ganglia networks and their prefrontal projections. The proposed mechanism for the anxiety disorder PTSD is a shift towards exaggerated bottomup automatic processing of danger-related cues within 150 ms, involving hypersensitivity to the arousability of mismatch cues, and producing an enhancement of defense-related action tendencies. This mechanism of PTSD accounts for excessive activation of amygdala and it prefrontal projections during nonconscious processing of fear cues, and excessive startle facilitation. These alterations occur with a concomitant loss of top down contextual evaluation of danger dues, such that hypersensitivity may generalize to other motivationally relevant stimuli. Anorexia nervosa (AN) is hypothesized to involve excessive hypersensitivity to interoceptive arousal cues, involving dysregulation of the LHA and VMH. In the initial automatic appraisal of arousability (within 150 ms), consumptive reward-related match cues are appraised as having the same arousability as mismatch cues, such that these match cues trigger defensive rather than approach-type action tendences, and associated amygdala-prefrontal activation. Depression is hypothesized to reflect a mechanism of burnt-out anxiety, leading to hypoarousal and grey matter loss. Hypoarousal is reflected in impaired appraisal of the arousability of motivationally relevant match-mismatch cues within 150-300 ms, involving dysregulation of amygdala and MPFC/ventral ACC networks, and ineffective contextual evaluation of match-mismatch cues over the 300-500 ms time frame, involving hippocampal-LPFC networks. ADHD is associated with core disturbances across the 150 to 500 ms time scale, due to a failure to appraise the arousability of mismatch cues, such that these cues are not distinguished from irrelevant noise and put in an appropriate context. In ADHD, these disturbances involve a breakdown in the central representation of locus coeruleusmediated arousal in cortical networks. Legend for spatial brain networks: 1) brainstem superior colliculus; 2) brainstem locus coeruleus; 3) brainstem periaqueductal gray (PAG); 4) amygdala; 5) ventral portions of the prefrontal cortex (PFC), including medial sector, and anterior cingulated (ACC); 6) visual association areas (e.g., fusiform gyrus); 7) dorsal medial prefrontal cortex (MPFC); 8) somatosensory-related areas (e.g., insula); 9) dorsal lateral prefrontal cortex (LPFC); 10) hippocampus; 11) parietal cortex; 12) lateral hypothalamic area (VMH) and ventromedial hypothalamus (VMH); 13) Ventral tegmental area (VTA); 14) Medial forebrain bundle (MFB); 15) Orbitofrontal cortex (OFC).
including oddball targets and fearful faces (Symond and others 2005; Das and others in press). Reductions in gray matter (particularly GABAergic neurons) may contribute to the loss of synchrony (Whitford and others 2007). 4. There is associated disjunction in arousal and emotional brain systems to mismatches (Gruzelier and Venables 1972; Kring and Neale 1996; Williams, Das, and others 2004). For instance, schizophrenia patients have been found to show excessive phasic arousal to fearful faces but a reduction in amygdala and medial prefrontal activation (Williams, Das, and
others 2004; Fig. 8). Thus, there may be a dissociation in stimulus arousability and the neural machinery for processing it.
Anxiety Anxiety disorders such as posttraumatic stress disorder (PTSD) are characterized by hypervigilancerelated to heightened associations with fear cuesand an inability to extinguish or regulate these associations. In PTSD,
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Fig. 8. Activation maps (radiological presentation) for analysis of fMRI data according to the presence (with arousal) versus absence (without arousal) of skin-conductance responses to fearful faces, relative to a neutral baseline, in 27 schizophrenia patients and 22 healthy controls. For controls, with-arousal responses to fear were localized to the amygdala (Amyg), extending into the periaqueductal gray area (PAG); A, the temporal cortex including middle temporal gryus (Gtm), extending to superior temporal gyrus; and B, frontally, the medialfrontal gyrus of the medial prefrontal cortex (MPFC) and motor area (motor). Without-arousal responses for controls were distinguished by activation in the hippocampus (Hi; C) and dorsallateral prefrontal cortex (DLPFC; D). In contrast, schizophrenia patients showed reduced activity in witharousalspecific regions: the amygdala, extending to the PAG and middle temporal gyrus (E), and the MPFC and motor regions (F). For without-arousal responses, schizophrenia patients showed less-specific reductions in the thalamus (Th), the superior temporal gyrus (Gts; G), the postcentral gyrus (SII; H), and the visual region of the inferior parietal lobule (IPL; H). Adapted with permission from Figure 2 in Williams, Das, and others (2004). Coordinates for regions of activation are provided in Table 2 of Williams, Das, and others (2004).
evidence suggests that these features are caused by the automatic hyperresponse of brain-arousal systems to mismatch cues early in the time course (Fig. 7), with a complementary reduction in later, more controlled contextual evaluation and regulation. Processing of reward-related match cues may also be suppressed because of persistence of the alert state. Supporting evidence includes the following:
1. There is excessive amygdala and MPFC/ACC activation during automatic processing of fearful faces presented without awareness (Rauch and others 2000; Bryant RA, Kemp A, Felmingham K, Barton M, Olivieri O, Liddell B, Gordon E, Peduto A, Williams LM. Enhanced amygdala and medial prefrontal activation during nonconscious processing of fear in posttraumatic stress disorder: An fMRI Study. Human Brain Mapping (in press).
2. MPFC and LPFC activation are reduced during controlled, conscious processing of mismatch cues including fearful faces and oddball targets (Bryant and others 2005; Williams, Kemp, and others 2006). 3. There is heightened sympathetic arousal (e.g., heart rate acceleration to startle) with a reduction in parasympathetic arousal (e.g., heart rate variability; Cohen and others 1997).
Depression Consistent with the frequent comorbidity of anxiety and depression, the latter may be conceptualized as a depleted or burnt-out form of anxiety. Although the initial stages of depression may involve hyperarousal similar to that in anxiety, the accumulated effects of stress may disrupt hippocampal context-processing networks and lead to

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hypoarousal (Fig. 7). In states of hypoarousal, cortical systems for regulation of danger-reward cues may not be effectively engaged (Fig. 7). Consistent with this profile, evidence for depression includes the following:
1. There is excessive amygdala activity to mismatch cues, including both fear and sadness (Fu and others 2004; Sheline and others 2001), similar to that in anxiety. 2. Hippocampal volume is reduced, related in particular to stress exposure (Hasler and others 2004). 3. There are distinct forms of depression (and response to treatment), suggesting a dynamic shift from anxiety-related hyperousal to depressive hypoarousal that is defined by disconnections in 1) MPFC-OFC systems for regulating dangerreward processing, 2) hippocampal-LPFC systems for context processing, and 3) ventral ACC circuits involved in appraising arousability of emotionally salient stimuli (Seminowicz and others 2004). 4. There are alterations in prefrontal laterality, consistent with excessive responses to danger-related avoidance but reduced reward-related approach tendencies (Davidson and Irwin 1999).
ADHD ADHD is characterized by an inability to discriminate mismatches from noise, reflected in a failure to orient to and contextualize mismatch cues at ~150 to 500 ms (Fig. 7). As a result, working memory may not be effectively updated, and noise stimuli may intrude on processing. We hypothesize that this impairment occurs primarily during overt (conscious) processing of mismatch cues, and involves a breakdown in the cortical networks for representing locus coeruleusmediated arousal. Relevant findings include the following:
1. Errors are caused by intrusion or lack of inhibition of noise stimuli as well as by poor processing of mismatches including threat-related faces (Hermens DF, Cooper N, Clarke S, Kohn M, Clark CR, Keage H, Gordon E, Williams LM. Defining a standardized profile for ADHD: cognitive and brain function markers [under review]). 2. Slowed and reduced ERPs are associated with processing of context and working memory (Keage and others in press; Hermens and others under review). 3. There is cortical and autonomic hypoarousal (Hermens, Clarke, and others 2005; Hermens, Kohn, and others 2005).
Anorexia Nervosa In addition to the defining symptom of abnormal loss of weight in anorexia nervosa (AN), the control of eating and the perception of food as disgusting and threatening suggest a marked reversal of the normally rewarding nature of appetitive stimuli. We propose that this reversal is caused by hypersensitivity to the arousing properties of interoceptive emotion cues, such that reward-related consumptive cues are appraised as similarly arousing to mismatch cues and trigger the networks for danger processing as a result. Moreover, this mechanism will also result in a confusion of feedback from central representations of arousal, which may account for the disjunction in expressed and felt emotion in individuals with AN. Here, we propose the following:
1. Hypersensitivity to interoceptive arousal cues occurs over early time scales (within 150 ms) and results in appraisal of innately rewarding cues (especially consumptive cues related to food) as highly arousing (similar to mismatch cues). Thus, defense-related rather than approach-related action tendencies are elicited. This mechanism may be akin to the generalization of fear conditioning and lack of extinction in anxiety. 2. The confusion of normally rewarding cues with danger (e.g., fear, disgust) may reflect dysregulation of hypothalamic reward circuits within 150 ms: for instance, reduced LHA and excessive VMH activity may cease consumptive responses and produce associated aversive reactions. Engagement defensive tendencies to match cues will be reflected in excessive activation of amygdala and prefrontal projections. 3. In an attempt to compensate for interoceptive hypersensitivity, AN individuals may shut down interoceptive signals. Thus, cessation of eating may act as a maladaptive compensatory strategy that serves to numb the normal homeostatic processes, producing a broad shutdown of interoceptive cues. A state of numbing may provide secondary reinforcement: that is, it may be perceived as a state of safety and control (over internal feelings) that acts as a reward-related outcome for AN individuals who experience distress from maturational changes and family or environmental conflict.
These ADHD impairments may also limit the initiation of reward-related processing. Conclusion From the review of evidence in the preceding sections a Continuum Model of emotional significance has been proposed to capture the dynamical organization of the emotional brain, and its contribution to modulating both the stability and instability of information processing. Future research using an integration of data from measures of psychological function, brain function (both high spatial and high temporal resolution techniques), brain structure, and genetics will be important for further elucidating the dynamical organization of the emotional brain, and the disorganization of function that contributes to psychiatric disorder.
Notes
1. In the selfish gene critique of Darwin and his successors, it is argued that masking of genuine emotions may be more advantageous for one individual to exploit or compete with another. However, this review is emphasizing basic emotions that are generated spontaneously or involuntarily. 2. Panskepp (1998) was the first to articulate a specific set of primitive prototypes that were linked to motivations and specific neural systems. These included attachment, bonding, and nurturance; sadness, separation, and distress; rage, fear, and play or joy; and seeking and expectancy. 3. Comoli and others (2003) note that although it is well established that the superior colliculus detects unexpected stimuli (consistent with mismatches), it is not yet known how an unexpected (as opposed to predictable) reward stimulus is detected as rewarding. 4. The brainstems parabrachial nucleus (PBN) has also been implicated in positive emotion. 5. This proposal may be reconciled with other proposals that the ACC has a key role in 1) error monitoring, given that errors are a form of mismatch that feasibly increase arousal, and 2) integrating cognition
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and emotion, given that sensitivity to arousal would facilitate allocation of attention to emotionally significant stimuli. 6. There is also a third part of the autonomic nervous system, which is not usually referred to: the enteric nervous system. This is a complex of nerves that regulates the activity of the stomach, producing the experience of butterflies when a person is nervous. 7. Reward stimuli are most predictable when they are given a similar precedence to danger in information-processing systems. Such predictable reward cues may engage a correspondingly direct and short-latency brainstem pathway from superior colliculus to dopamine-containing neurons of the substantia nigra, supporting the relay of low-level visual reward cues to reach the ventral midbrain (Comoli and others 2003).
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Organización Dinámica Del Cerebro Emocional

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The Neuroscientist

Dynamic Organization of the Emotional Brain: Responsivity, Stability, and Instability

Dynamic Organization of the Emotional Brain

Volume 13, Number 4, 2007

Dynamic Organization of the Emotional Brain

Dynamic Organization of the Emotional Brain

Volume 13, Number 4, 2007

Dynamic Organization of the Emotional Brain

Volume 13, Number 4, 2007

Dynamic Organization of the Emotional Brain

Volume 13, Number 4, 2007

Dynamic Organization of the Emotional Brain

Volume 13, Number 4, 2007

Dynamic Organization of the Emotional Brain

Volume 13, Number 4, 2007

Dynamic Organization of the Emotional Brain

Volume 13, Number 4, 2007

Dynamic Organization of the Emotional Brain

Volume 13, Number 4, 2007

Dynamic Organization of the Emotional Brain

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