Temporal and frontal lobe initiation and regulation of the top-down escalation of anger and aggression

Behavioural Brain Research 231 (2012) 386–395

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Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr

Review

Temporal and frontal lobe initiation and regulation of the top-down escalation of anger and aggression Michael Potegal ∗,1 MMC 486, 420 Delaware St SE, Minneapolis MN 55455, USA

a r t i c l e

i n f o

Article history: Received 13 September 2011 Received in revised form 26 October 2011 Accepted 31 October 2011 Available online 9 November 2011 Keywords: Amygdala GABA Hypothalamus Inhibition

a b s t r a c t The widespread, across-species strategy of stagewise escalation of aggression in agonistic encounters can be understood in terms of resource capture and control with least risk and cost. Human anger likely follows similar principles. As an adaptive phenomenon, escalation may involve particular neural circuitry. To advance beyond a standard view that the frontal lobe tonically inhibits subcortical circuits of aggression, a model is proposed which starts with the general rostrally directed flow of information in the brain. Earlier stage processing of visual and auditory input is transmitted from posterior and middle temporal cortices to anterior temporal lobe where rudimentary appraisals of threat and provocation are developed. These directly but diffusely activate cortical/subcortical anger/aggression response systems. At the same time, the anterior temporal loci transmit the modality-specific perceptual information to orbito-frontal cortex where it is integrated with information about, e.g., the opponent’s relative dominance/social status and evaluated for likelihood of potential rewards and punishments associated with different modes of responding and so forth. These frontal areas then impose an inhibitory gating or modulation and focusing of activity initiated by the anterior temporal loci through their projections to GABAergic interneurons in the same cortical/subcortical circuits. Escalation occurs as the inhibition imposed by the frontal areas is progressively lifted. Exploration of the implications, applications and hypotheses flowing from this model will improve our understanding of the biologically important and socially significant phenomena of escalation. © 2012 Published by Elsevier B.V.

Contents 1. 2. 3.

4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Escalation of aggression and anger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The neural organization of aggression, anger and their escalation in (some) mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Temporal lobe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Frontal lobe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Conclusions about VMFC and OFC function from observations of damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Neuroimaging vs. lesion data: neuroanatomical agreement, functional discrepancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Serotonin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. Temporal lobe vs. frontal lobe function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Cingulate cortex pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Does “out of control” anger indicate a shift to limbic control? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Subcortical circuitry of aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Subcortical neuroanatomy of human anger and aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Integration: the temporo-frontal model of escalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Implications and applications of the model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A few testable hypotheses derived from the model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Current address: Netherlands Institute for Advanced Study, Meijboomlaan 1, 2242 PR Wassenaar, The Netherlands. Tel.: +31 070 51 22 764; fax: +31 070 51 17 162. E-mail address: [email protected] 1 Tel.: +1 612 625 6964; fax: +1 612 624 7681. 0166-4328/$ – see front matter © 2012 Published by Elsevier B.V. doi:10.1016/j.bbr.2011.10.049

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7. 8.

Some questions and caveats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Like many motivated behaviors, aggression comes and goes, driven by season and circumstance in a multitude of species. When aggression does occur, its constituent behaviors are not all-or-none responses, but are generally modulated in duration and intensity relative to situational demands. Like some other motivated behaviors, aggression often involves a stagewise sequence of acts. In the case of intraspecific aggression, these sequences involve threat displays that are effortful and often risky, as described in more detail below. Unlike many other motivated behaviors, intraspecific and defensive aggression are most successful (and least costly) when the sequence is incomplete, i.e., when lower-level threat alone is sufficient to dominate the social situation or discourage or drive away potential competitors or predators. In these circumstances, game theoretic arguments suggest that aggressive strategies will be used that adjust and limit effort and risk-taking relative to the value of averting the threat and/or obtaining the goal (e.g., [1]). In higher animals, these are very complex sorts of calculations requiring not only general judgment of an opponent’s Resource Holding Potential (RHP, e.g., size, strength, fighting ability [2]), but also the moment-to-moment reading of its subtle signals and cues in situational context, anticipation of its possible moves (i.e., planning for contingent futures), and flexible shifting of strategies as necessary. The whole brain must be engaged to do this optimally, but the frontal lobe is especially crucial to the “executive functions” of social judgment and prediction, as shown by the inappropriate and maladaptive agonistic interactions of vervet, pig-tailed and rhesus monkeys with lesions of orbitofrontal cortex (OFC, e.g., [3,4]). Among humans, proactive vs. reactive forms of aggression have been distinguished. Proactive aggression is typically self-initiated behavior in service to dominance with no obligatory associated emotion. Reactive aggression is a response to provocation and is driven by emotion, most typically anger (e.g., [5]). There are, of course, clear categorical differences between aggression, defined as a set of motivated behaviors, and anger, defined as an emotion that may not be expressed in behavior (e.g., [6]). However, the primary impulse to action most closely associated with anger is attack (e.g., [7,8] cf. [9]). Laboratory observations of anger being accompanied by jaw-clenching [10] suggest that, at its primitive core, anger potentiates the motor reaction of biting. In questionnaire studies of trait and personality, anger and aggression are often so closely tied that factor analysis reliably yields an Anger–Hostility–Aggression complex [11]. In our current understanding, their genetics [12], physiology [13] and neurochemistry/pharmacology [14] are also thoroughly interwoven. Thus, anger and aggression will be compared and treated together in this essay on their neural circuitry. In one simple view, anger and aggression are controlled by the frontal cortex through transient release of a tonically maintained inhibition of subcortical mechanisms. This generic model was developed to account for the increase in impulsive (nonplanful) aggression that follows damage to aspects of the frontal lobe. This view is consistent with observations on the neurological level, such as the return of the snout, forced grasp and other primitive reflexes when frontal lobe function is severely disrupted (in the context of aggression, it has been claimed that 65% of murderers show one or more of these or other frontal release signs [15].

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On the neuropsychological level, there are somewhat more subtle, stimulus-bound “utilization behaviors” which reflect more minor changes in this same direction [16]. On the interpersonal level, this model is also consistent with the socially inappropriate behavior which follows frontal damage (e.g., [17,18]). However, this simple model has a number of important gaps and inconsistencies. Firstly, it requires continual inhibition of subcortical structures. Maintaining excitatory and inhibitory impulse traffic is what neural circuits do, but not without metabolic cost. A number of CNS circuits do function in just this mode, a prime example being tonic Purkinje cell inhibition of deep cerebellar nuclei, but it is worth noting that these circuits participate in very frequently occurring activities. The supposition that the same costs are being incurred in less frequently activated circuits raises questions about possible alternative mechanisms. Secondly, if frontal cortex were the only pathway to subcortical mechanisms controlling aggressive responding, then lesions there would tend to produce large, sustained increases in random, unprovoked aggression, due to chronic subcortical disinhibition, and a diminished response to real threat as the sensory/perceptual cortical mechanisms for recognizing and evaluating threat are cut off from access to response generation. This is contrary to Golden et al.’s [19] literature review, which finds that when aggression occurs following frontal lobe impairment, the provocation is almost always clear, if trivial, and the response is usually directed towards that source. These observations imply there must be alternative pathways through which perceptions of threat can trigger behavioral reactions. In the spirit of Phil Teitelbaum’s focus on understanding both sides of the brain–behavior relationship [20], the next sections document the ubiquity and importance of the escalation of aggression and anger as phenomena, describe the temporal–frontal circuits and some of their physiology that may plausibly account for these and related phenomena, and discuss some implications and applications of the model. 2. Escalation of aggression and anger In considering behaviors that follow neurological insult, as Teitelbaum originally did [21], or behaviors that occur as part of naturalistic sequences or interactions, as he did later [22], he noted that a first step must be a thorough and detailed analysis of the behaviors themselves. Such analyses of agonistic displays in animals of many species shows that they consist of a series of autonomic and somatic behaviors that can be ranked along a dimension of increasing “intensity”, probability and/or severity of overt attack. This is true of intraspecific aggression in fish (e.g., piscine fin erection and display, tail beating, biting [23]), and birds (e.g., avian bill gapes, head thrusts, and wing raises [24]) as well as in mammals ranging from shrews to monkeys [25,26]. A common laboratory example of mammalian escalation occurs in the well-studied agonistic behavior of the rat in which piloerection and lateral threat posture is typically followed by a full aggressive posture and then by a bite-and-kick attack. Adams argues for a homology between aggression sequences of rats and monkeys [27]. In naturalistic, unconstrained agonistic encounters, what one animal does affects what its opponent will do next. However, escalation of aggressive responses involves internal processes as

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well. As pioneered by Hinde’s [28] studies of chaffinch mobbing calls emitted in response to immobile predator models, increases in the intensity and/or rate of attacks have been documented in fish and birds during the first few minutes of exposure to an unchanging provocation. Within the “dual process” model of habituation, these short-term increases in aggression are denoted as “sensitization” (e.g., [29]). Because standard, non-reactive stimuli are used in these studies (e.g., a conspecific fish in a small tube) these increases must be the results of processes internal to the subjects. More compellingly, perhaps, aggressive behavior can persist even after the initial challenge is terminated. In Heiligenberg’s classic study [30], adult male cichlids were provoked by briefly presenting a male conspecific outside their tank. After the provoking fish was withdrawn, subjects’ attacks against the blind fingerling fish that inhabited their tanks increased abruptly, then dropped back to baseline over the next 10 min. Considerably longer persistence of aggressive motivation, in the absence of both provocation and target, is found in “attack priming” studies of hamsters and rats in which exposure to a first intruder in the home cage reliably reduces the latency and/or increases the probability of attack on a second intruder introduced minutes to hours later (e.g., [31]). In our species, disagreements and low-level conflict are frequent and probably unavoidable in ordinary social interaction; it is their escalation to assault and homicide that is so traumatic to individuals and costly to society. Escalation from verbal to physical aggression has been documented in children (e.g., [32]) and in adult’s marital disputes [33]. As noted above, anger is a major component of reactive aggression. On functionalist accounts, anger is an instrument of interpersonal threat, intimidation, coercion, and domination (e.g., [34]). On evolutionary accounts anger, like aggressive threat, has been shaped as a low-cost signal to forestall exploitation, intimidation, and attack by rivals and to enhance and protect reputation [35]. Empirically, a survey of more than 15,000 adolescents by the Josephson Institute of Ethics found that 75% of boys and more than 60% of girls reported hitting someone in the past year because they were angry [36]. Among adults, a sequence of escalating behaviors recurs in the retrospective self-reports of aggressive interactions in samples of the “general population”, ex-criminal offenders, and ex-mental patients (Table 6.3 in [37]). The reported sequence included “reproaches” (e.g., complaints), “insults” (including yelling), and then threats. On some occasions, the sequence progressed to physical assault. Working backwards from adjudicated homicides, Luckenbill [38] used official records (e.g., eye-witness accounts) to identify the escalation leading to murder in 71 cases. In a Canadian national sample “anger and arguments” were the trigger for 11% of stranger murders and 60% of acquaintance murders; if anger-related motives such as jealousy and revenge are included, the figures are 15% and 77%, respectively [39]. The escalation of adult anger has been recreated in the laboratory [40,41]. Participants in a money-making task were thwarted by the experimenter’s confederate who consistently withheld needed supplies. Subjects responded in a stereotyped sequence, from mild requests to impatient demands, and then complaints, angry statements, threats and harassment. Importantly, in these studies the behavior of the confederate remained constant. Thus, as in the studies of other animals, the motivational changes underlying escalation must have taken place within the participants. In fact, a major feature of escalation is that it is often internally generated and automatic; we do not consciously plan to escalate and often must consciously struggle not to. Human analogies to the post-provocation persistence of aggressive behavior and motivation in fish and rodents might include angry “rumination” and revenge fantasies (e.g., [42], for review see [43]).

3. The neural organization of aggression, anger and their escalation in (some) mammals Here, we briefly review the roles of temporal and frontal neocortices and subcortical structures in anger and aggression and then propose a model of how they coordinate to produce escalation. 3.1. Temporal lobe One early study found lower medial temporal lobe activity (relative to occipital lobe activity in the same subject) in 7 highly disturbed and violent criminals (6 males) compared to female neurological control patients presenting with “vague generalized symptoms” such as fatigue [44]. Among the sex differences and other methodological issues in this study, the criminals were imaged while in handcuffs; presumably, the controls were not. More appropriate non-violent control subjects and methodologies were featured in 17 other neuroimaging studies of psychiatric or neurological patients or incarcerated offenders with histories of extensive and serious aggression reviewed by Bufkin and Luttrell [45]. In at least 10 of these studies, significant temporal lobe abnormalities were found, usually in the direction of reduced tissue volume and/or activity and increased anatomical or functional abnormalities, relative to controls. When the difference(s) were identified as lateralized, it was always to the left hemisphere. Bufkin and Luttrell’s [45] review primarily focused on violent adults. Similar left temporal hypometabolism was found in children with intractable epilepsy and aggressive behavior relative to non-aggressive children with comparable epilepsy; the severity of aggression correlated inversely with left temporal glucose metabolism ([46]; for review of related findings in temporal lobe epilepsy, see [47]). Kruesi et al. [48] reported neuroanatomical evidence for temporal lobe involvement in the form of significantly reduced right temporal lobe and right temporal gray matter volumes in 10 youths with early onset conduct disorder compared to healthy controls matched for age, sex and handedness. Clearly, the issue of laterality remains unresolved. However, unlike the case for the frontal lobe described below, no imaging studies appear to show activation of temporal neocortex during experimentally induced anger or aggression. One possibility is that such specific temporal lobe activity is more difficult to detect against a continual background of general sensory/perceptual processing. Additionally or alternatively, it may be that the relevant neural activity is not associated with measurable changes in blood flow or glucose metabolism. Thus, in contrast to positron emission tomographic (PET) findings showing reduced prefrontal, but not temporal, glucose metabolism in murderers during an attention task, resting EEG in some of these same individuals revealed significant increases in slow-wave activity in the temporal, but not the frontal, lobe [49]. Slow wave activity is associated with suboptimal cortical function [50]. In any event, absence of imaging evidence for acute involvement of temporal neocortex is not evidence of its absence. According to Golden et al.’s [19] review, the effects of damage to temporal and frontal lobes differ. Temporal lobe dysfunction results in unwarranted, poorly directed anger outbursts; when the frontal lobes are impaired, some provocation, even if trivial, can almost always be identified, and the response is usually directed towards that source. 3.2. Frontal lobe Accumulating evidence from clinical lesion and neuroimaging studies has identified orbital (ventral) and medial aspects of the frontal lobe as the most closely involved in the control of anger and aggression. Neuroanatomically, tract tracing work shows that the

M. Potegal / Behavioural Brain Research 231 (2012) 386–395

OFC, which forms the ventral surface of the frontal lobe, receives and processes input from the temporal lobe [51]. However, even at the temporal pole, the most anterior aspect of the temporal lobe, perceptual inputs remain segregated into dorsal (auditory), medial (olfactory) and ventral (visual) streams [52]. Thus, the OFC is a site where anger-provoking perceptions may be first integrated, e.g., the perceived verbal slur is combined with the perceived visual sneer to produce the global perception of an insult. Clinically, in Grafman’s study [53], Vietnam veterans whose combat-inflicted wounds included “mediofrontal” cortex were more frequently aggressive and violent by both self and family report, while those whose lesions included OFC were reported to be the most aggressive and violent, even though they tended not to be as aware of these emotions and behaviors. Two studies of neurosurgical patients with partial frontal lobectomies for tumors, aneurysms or arterial hemorrhage have been published more recently by Rolls and collaborators. Hornak et al. [54] found major changes in felt emotion associated with OFC lesions in a small group of patients; there were more increases than reductions in anger. Similar effects were observed with unilateral damage to medial frontal pole/anterior cingulate gyrus (mFP/ACG). [Consistent with this localization, trait anger was positively correlated with activation in subgenual ACG in the normal group of Goldstein et al.’s [55] PET study.] Both mFP/ACG and OFC lesions also reduced patients’ perception of other people’s vocal anger [54]. Berlin et al. [56] compared a larger group of OFC patients to those with other frontal lesions. OFC patients reported experiencing more anger and less happiness than either neurologically intact or lesion control groups, but there were no differences in sadness, fear or disgust. In this study, the OFC group’s anger and aggression also correlated with their generally disinhibited and inappropriate ‘frontal’ behavior. Developmentally, in one case of frontal lobe agenesis [57] and two of OFC and lateral prefrontal cortex damage at or before 15 months of age [58], failure to acquire appropriate social/emotional functioning, and/or elevated hostility in adulthood, contrasts with the more normal development of other neurocognitive functions, such as language, in these individuals. These observations suggest a deep rooting of social/emotional function in the frontal lobe as well as a lack of developmental plasticity in the cortical regulation of anger. The ventromedial frontal cortex (VMFC) includes the medial aspect of the frontal pole. The output of VMFC to visceromotor nuclei of the hypothalamus and periaqueductal gray [51] strongly suggest its involvement in the activation of the peripheral autonomic effects which accompany anger and aggression (e.g., [59]). The VMFC also evaluates response-related rewards [60], perhaps calculating the benefits of aggression in the presence of anger. Activation of dorsal VMFC was correlated with intensity of the punishing stimulus chosen for revenge in competition tasks [61,62]. However, integration of anger-focused and aggressive behavior oriented research remains incomplete because these studies reported no measures of experienced emotion. 3.2.1. Conclusions about VMFC and OFC function from observations of damage (1) VMFC and OFC are involved in the normal inhibitory control of felt emotions, (2) VMFC may participate in the processing of perceptions of self and/or other’s anger, but OFC seems to be more strongly involved in these functions, (3) OFC may be more specifically associated with anger (among the negative emotions) and aggressive behavior. In the context of current views of prefrontal cortical function, VMFC and OFC may mediate the effects of anger on the calculation of the potential payoffs and punishments for aggressive responding. Additionally, the OFC may mediate empathy with the potential target of aggression [61], and, according to Blair’s [63]

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innovative suggestion, rules of social conduct that modulate displays of anger and aggression according to relative social status. That is, the OFC may guide angry individuals to approach and confront an offender who is subordinate to them, but to retreat from and avoid an offender who ranks above them (e.g., [64]). 3.2.2. Neuroimaging vs. lesion data: neuroanatomical agreement, functional discrepancy The foregoing lesion work provides the most easily interpreted picture of OFC–VMFC inhibitory control of angry aggression. In general, neuroimaging of induced emotion supports this localization but complicates the functional interpretation. Two studies by Dougherty and colleagues confirm that anger recalled by control or healthy subjects is associated with increased regional cerebral blood flow (rCBF) in what seems to be an anterior locus within the left VMFC/OFC angle [65,66]. The latter study also included identification of increased sympathetic and decreased parasympathetic autonomic activity which characterizes anger and differentiated it from the cerebral rCBF patterns associated with happiness and sadness. Using different aggression inducing paradigms, provocation was associated with activation in the OFC of borderline patients [67] and with increasing revenge stimulus intensity in the far lateral OFC of a small group of violent psychopaths [68]. Thus, neuroimaging confirms that OFC seems to be specifically associated with anger rather than with all negative and highly arousing emotions. It further suggests that lateral OFC may specifically regulate aggressive behavior. However, interpretation is complicated by the expectation from lesion data that increased anger and/or aggression would be associated with a reduction of frontal activation. Pietrini et al. [69] reported just such a result, but neuroimaging generally reveals increases in rCBF and glucose utilization associated with anger. A physiological explanation for this discrepancy starts from the hypothesis that provocation results in temporal lobe activation of GABAergic interneurons in OFC, which inhibit OFC output neurons, thus disinhibiting aggressive responses. At the same time, cortical output to the striatum engages mesolimbic dopamine feedback loops that modulate the cortical GABAergic interneurons (e.g., [70]). The overall increase in cortical activation seen on neuroimaging reflects the dopaminergically amplified activity of these inhibitory neurons which, metabolically speaking, more then makes up for the reduced activity of the output neurons. This involvement of mesolimbic pathways can account for the (expected) reduction in anger-related rCBF in OFC observed in two studies of recalled anger in cocaine-dependant subjects [55,71]. That is, their hypoactive dopamine pathways do not modulate the cortical inhibition, and the observed decline of rCBF in their OFCs indicates an unmasking of the reduced activity in their OFC output neurons. This conjecture highlights the discrepancy between lesion and neuroimaging data as a challenge to be met as well as an opportunity to understand the complex circuitry of aggression. 3.2.3. Serotonin An extensive, older literature demonstrates that serotonin is the neurotransmitter most strongly and consistently associated with the tonic inhibition of various types of aggression in many species [72,73]. More recent research by Mizcek, de Boer, and others has implicated 5-HT1A and 5-HT1B autoreceptors in promoting shortterm escalations of aggression within agonistic encounters (e.g., [74]). Thus, some types of 5HT receptors may mediate serotonin’s chronic suppressive effects while other 5HT receptor types mediate its acute escalating effects; serotonergic terminals and all types of receptors are found in meso-limbic frontal cortex, which may be the locus of both inhibition and escalation.

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3.2.4. Temporal lobe vs. frontal lobe function There are several reports of temporal and frontal lobe neuropathology co-occurring in aggression-prone individuals [46,75]. Reduced glucose metabolism in both areas in violent psychiatric patients is a similar co-occurrence [76]. Neuropathology occurring in both areas may increase the risk of angry aggression over that associated with neuropathology in either area alone. Whether these co-occurrences are due to similar physiological vulnerabilities or a tight functional linkage between the areas is unknown. It also remains to be determined if dysfunction of temporal neocortex enhances aggression by allowing the amygdala’s cruder processing of threat more access to aggressive response systems. In any case, Golden et al.’s [19] literature review concludes that focused, if exaggerated, aggressive responses are associated with frontal lobe damage while poorly directed outbursts of anger are associated with temporal lobe dysfunction. For similar statements about outbursts of intense but unfocussed anger (without directed aggression) associated with temporal lobe epilepsy, see [77]. As noted above, Vietnam veterans with OFC injury were unaware of their increased anger and aggression, which was reported by their relatives [53]. In contrast, veterans whose lesions included anterior temporal lobe were likely to self-report more felt anger or hostility than was indicated by friends and relatives, but they were not different from non-head injured veteran controls in overt aggression as reported by these observers. This contrast suggests that increased anger may be experienced, even though it is not expressed, as a consequence of temporal lobe dysfunction. 3.3. Cingulate cortex pathways It has long been known that “spontaneous” emotional expressions of the face are preserved after strokes of the middle cerebral artery (MCA) that eliminate “voluntary” expressions, i.e., patients cannot smile when asked to (willed or “voluntary” action), but will smile when socially pleased or told a joke (spontaneous or “involuntary” action). Conversely, facial appearance is characteristically emotionally “flattened” or “blunted” following infarction of the anterior cerebral artery. The neuroanatomical basis for these clinical differences are that three motor areas of cortex that project to the facial nucleus (ventral lateral premotor cortex, primary motor cortex, and caudal cingulate motor cortex) lie on the lateral surface of the hemisphere, in the territory of the MCA, while two other facial motor areas (supplementary motor and rostral cingulate motor cortex) are located on the medial wall of the hemisphere, in the territory of the anterior cerebral artery [78]. Both lateral and medial systems have bilateral projections to parts of the facial nucleus that innervate the upper facial musculature but differ in their innervation of the lower face. More importantly in the current context, their differential involvement in emotional expression shows that some emotionally driven actions have preferential pathways. The initial activation of anger by anterior temporal lobe and its gating by OFC may involve preferential transmission through medial cingulate pathways. This conjecture is supported by the neuroimaged localization of anger associated sites in mid-cingulate (see Fig. 5 in [79]) and clinical reports of intense anger as post-ictal sequelae of cingulate seizures [80]. With regard to aggression, the posterior cingulate was a second area whose activation was associated with increasing revenge stimulus intensity in Veit et al.’s [68] competition study of psychopaths. 3.4. Does “out of control” anger indicate a shift to limbic control? Some people experience anger as being “out of control”; this is more true for women than men (e.g., [81]). Feelings of being out of control are a core aspect of the “anger attacks” had by up to 40% of depressed individuals (more men than women [82,83]).

In these patients, the normal reciprocal activation of left VMFC and amygdala was found to be reversed, so that their activity was positively correlated [65]. The suggestion that this reorganization predisposes to intense anger is consistent with a case report that, when the activity of the OFC and amygdala became more coherent during a seizure, that patient experienced anger and an impulse to bite [84]. The sense of being out-of-control may be the selfperceived consequence of a shift from the routine and accustomed control of response choice and initiation by dorsal aspects of frontal cortex to the relative novelty of responses initiated by atypically synchronized limbic structures like OFC, amygdala, and medial cingulate. 3.5. Subcortical circuitry of aggression Cortical structures execute species-typical aggressive acts through a set of subcortical nuclei. The amygdala is part of anterior temporal lobe circuitry and additional recent support for the longstanding hypothesis that the lateral amygdala functions as an early, crude, bottom-up system for detection of threat [85,86], would be generally consistent with the role proposed for the anterior temporal lobe. Much as the proactive–reactive distinction exists for humans, interspecific predation, intraspecific offense and affective defense are types of aggression in other animals that differ in their evoking stimuli and sensory detection modalities, motivation, target and topography of attack, hormone sensitivity, and other associated physiology. Lateral amygdala activation is associated with anxiety and fear [87]. Thus, its early and crude detection of threat would most likely trigger affective defense. Projections from specific nuclei in the amygdala descend through well-defined tracts to areas of hypothalamus that, in turn, project to specific sites in midbrain and upper brainstem where the motor and autonomic aspects of aggressive responses are generated and coordinated. Which subregions are involved depends upon the particular type of aggression. A classic example of behavioral differentiation of aggression systems in cats is the silent, neck-biting, predatory attack elicited by lateral hypothalamic stimulation vs. the hissing, snarling, piloerected, back-arched affective defense elicited from medial hypothalamus (e.g., [88]). As Teitelbaum and Stricker [20] noted, integrated behaviors incorporate, and may be built upon, reflex structures. A classic example in aggression is the hypothalamically gated biting described by Flynn et al. (e.g., [89]) in which a light touch on the lips from which a cat will ordinarily withdraw will elicit biting if the attack area of the hypothalamus is being stimulated concurrently (for review and analogous effects on visual tracking of prey and touch-triggered paw strikes, see [90]). Brain stimulation has been a major tool in these studies. The acts elicited by brain stimulation range from natural looking speciestypical behaviors that are well integrated into the immediate environment to stereotyped, artificial seeming behavior fragments. While species-typical attacks of varying intensity have been elicited from the hypothalamic attack area (HAA) of the rat by brain stimulation, as extensively mapped by Kruk et al., the lateral threat display of this species has not [91]. We comment below on why this might be so and note an experiment to test the idea. 3.6. Subcortical neuroanatomy of human anger and aggression The structures that have been identified as major elements of aggression circuitry in rodents and cats serve similar functions in humans. Although acute activation of the amygdala elicits fear much more frequently than anger [92], clinical cases and series as well as reports of surgical and pharmacological interventions in several countries over many decades indicate that angry aggression in humans is associated with chronic amygdala pathology,

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particularly of the medial amygdala [93]. Conversely, since bilateral amygdalotomy to reduce severe aggression was first reported in 1963 [94], more than 500 cases have been published (see [95] for review). Significant post-operative reductions of aggression has been claimed for 33–100% of cases with reportedly no effects on cognitive function or language in the majority, even in three 2–9 year post-surgery follow-ups. However, details of the postoperative assessments were meager. Caudal to the amygdala, angry aggression is associated with acute increases [68] and chronic reductions [96] in hypothalamic activation in neuroimaging studies. Such aggression also follows hypothalamic dysfunction due to tumors (see [88] for review) and, as found more recently, hamartomas. More than 75% of children whose hypothalamic hamartomas cause gelastic seizures and general cognitive deterioration present with clinical increases in negativity, aggression and rage [97,98]. Conversely, older studies report that hypothalotomy reduces angry aggression; purportedly with few side effects and persisting improvement (e.g., [99]). More recent case reports claim clinically significant reduction of pathological aggression by stimulation in the posterior hypothalamic “triangle of Sano” (e.g., [100], but see [101]). Neuroimaging caudal to the hypothalamus has identified anger-related changes in midbrain and anterior pons [102]. Note that if aggression is the action impulse of anger, and these more caudal pathways of aggression are conserved across species, then the neuronal circuitry and patterns of activation that distinguish anger from other emotions and action patterns must lie in the cortex and rostral limbic structures which activate the lower pathways. 4. Integration: the temporo-frontal model of escalation Clinical and experimental data clearly show that temporal and frontal lobe modulate aggression through their connections with amygdala, hypothalamus and brainstem, but how is this circuitry involved in the temporal sequence of escalation? In short, rudimentary appraisals of threat and provocation developed at anterior temporal loci directly but diffusely activate cortical/subcortical anger/aggression response systems. At the same time, these temporal loci transmit the perceptual information to OFC and VMFC where it undergoes higher level integration and evaluation. These frontal areas then impose an inhibitory gating or modulation and focusing of activity initiated by the anterior temporal loci through their projections to the same cortical/subcortical circuits. Escalation occurs as the inhibition imposed by the frontal areas is progressively lifted. Some of the evidence for this model follows. We start with general neurological principles of information flow in which earlier stage processing of visual and auditory triggers must involve posterior and middle temporal cortices. As this processing proceeds, it evokes memory of related events (e.g., past interactions with the same individual) and other relevant information from more anterior temporal areas [103]. A key feature of the model is that the preliminary perceptions of agonistic challenge that are shaped there then directly activate cortical and subcortical circuits that prime and mediate angry/aggressive actions via, e.g., cingulate motor areas 23 and 24 and medial/basal amygdala. Such direct pathways from the temporal lobe to somato- and visceromotor brain structures do, in fact, exist, e.g., [104,105]. At the same time, the initial appraisals of provocation in mid and anterior temporal lobe are rapidly transmitted anteriorly through the uncinate and cingulate fasciculi to VMFC and OFC where crucial ancillary factors like the opponent’s relative social status, familiarity with and/or empathy for him, and the likelihood of potential rewards and punishments associated with different modes of responding are calculated. Obviously, frontal decision-making about escalation will be updated as the encounter proceeds. Because

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many of the tracts involved include both afferent and efferent axons, information from caudal structures about internal state as well as the external situation impinges upon and influences rostral structures [106]. Note that this temporo-frontal model does not require the frontal cortex to exercise tonic inhibition, just to modulate activity acutely initiated by the temporal lobe. Some recent supporting evidence for this model is a report that when subjects self-induce anger by recall of a provoking incident in their past, those with a history of violence do not show the activation of frontal lobe that non-violent control subjects do [107]. This suggests that the violent individuals failed to engage frontal inhibitory systems when provoked. They did show relatively greater activations in the left amygdala, pontine, and cerebellar regions compared to controls, as if they were activating potential response systems. Because cortical output is typically glutaminergic and excitatory, inhibition by OFC must be imposed locally at target structures. A common arrangement for such inhibition is through projections to local GABAergic neurons. Neuroanatomically, neurons in medial prefrontal cortex of the rat do project to GABAergic neurons in limbic and paralimbic structures, e.g., rhinal cortices [108], ventral tegmental area [109] and dorsal raphe [110]. Functionally, medial frontal projections terminate on clusters of GABAergic neurons which regulate neuroendocrine stress response in the hypothalamus [111]. Of potentially great interest in the current context is a group of GABAergic cells adjacent to the hypothalamic attack area [112] and projections from medial frontal cortex to the area [113] identified by Haller and colleagues; studies testing the predicted functional inhibition of HAA through the medial frontal projections to the adjacent GABAergic neurons await. In rhesus monkeys, OFC axons heavily target the intercalated masses of the amygdala, which send inhibitory projections to the central nucleus [114]. Clearly, the heart of the model is the hypothesis that decisions to escalate are made in the frontal lobe and executed via its disinhibition of subcortical circuits. While plausible and consistent with all the evidence presented, there is no evidence available which directly supports or disconfirms it. The aim of this paper is to inspire sufficient interest in the temporo-frontal model that appropriate experimental tests will be designed and carried out. The remaining sections of this paper are intended to encourage that process. 5. Implications and applications of the model Here we note two conjectures about normal and improved function and two about the effects of system pathology. 1. Impulsivity is about making prepotent, default mode responses to the immediate stimulus without thought to either alternative reactions or consequences. For many antisocial youth, these are rapid, angry aggressive responses to perceived provocations, as formalized in Social Information Processing models (e.g., [115]). Correspondingly, widely used therapeutic approaches for these youth involve training programs to, e.g., “Stop & Think” [116] or “Stop Now and Plan” [117]. The frontal lobe functions as the cerebral instantiation of stop and think, so this training may be reasonably thought to involve modification of these circuits. In fact, a recent study of evoked potentials elicited during a go/no-go task found that children with externalizing problems had larger N2 (second negative potential) magnitudes and smaller frontal P3 (third positive potential) magnitudes than controls [118]. N2 has been related to the inhibition of prepotent responses. Only externalizing children whose behavior improved with the stop and think-type treatment, according to parent and teacher report, showed a marked reduction in N2 wave magnitude. Source analyses during N2 indicated that the

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reductions were likely to be in medial and ventral prefrontal cortex as well as anterior medial temporal lobe. The authors suggest that these treatment-induced reductions in evoked potential magnitude might indicate a more “efficient” use of this circuitry. 2. As a greater extreme of inhibition, commentators as long ago as Aristotle [119] noted that a provocation that would elicit retaliatory aggression when coming from a low status offender may not even elicit anger when coming from a very high status individual. This could happen through inhibitory feedback from the OFC to anterior temporal lobe that not only suppresses aggressive responding, but forestalls the experience of anger as well. By extension, the OFC is likely to coordinate with other frontal areas in selecting non-aggressive solutions to provocations, such as ignoring, problem-solving, prosocial responding and so forth. 3. Because the processes are rapid and interactive, the relative timing of temporal activation and coordinated frontal gating is crucial. Disruption of temporal–frontal white matter pathways would disturb this timing, leading to less effective damping of aggressive impulses by frontal cortex. Indeed, recent diffusion tensor imaging studies suggest that disruption of these pathways is associated with behavioral dysregulation [120,121]. 4. Fornazzari et al. [122] reported three patients whose visual hallucinations of violence were triggered by seizures arising in deep frontal areas. The OFC was suggested as the source. If so, it may mean that the effects of OFC normally inhibitory output can be reversed under pathological conditions. 6. A few testable hypotheses derived from the model (1) During escalatory sequences, there should be evidence of decreasing frontal inhibition of target subcortical structures. Because these changes are so rapid, they are probably measurable only by electrophysiology. In other species, excitatory postsynaptic potentials elicited in amygdala and hypothalamus by medial frontal stimulation should increase during behavioral escalation. In humans, corresponding changes in frontal N2 and P3 evoked potentials should be detectable during angerinducing and aggression-provoking experimental paradigms. (2) Tractotomy of the uncinate and cingulate fasciculi should shift agonistic encounters in the direction of higher initial levels of aggression, but less escalation within the encounter. (3) Lateral threat in the rat is not elicited by low (or high) level stimulation of the HAA. If lateral threat represents partially inhibited aggression, it might be elicited by simultaneous or alternating stimulation of HAA and medial frontal cortex. 7. Some questions and caveats (1) Harmon-Jones et al. have repeatedly found that left, as opposed to right, frontal activity is associated with anger in neurologically intact individuals (e.g., [123]); some evidence extends this to left temporal activity in 4 year olds [47]. To the extent that this lateralization holds true, the temporo-frontal model of escalation may apply more to the human left hemisphere than the right, or the model may be otherwise modified as a function of hemisphere (cf. [124]). (2) As noted above, escalation is often automatic and rapid. As such, there are likely to be mechanisms of escalation at lower anatomical levels in aggression control pathways. These might include effects of 5-HT1A and 5-HT1B autoreceptors at subcortical levels. Another example of this appears to be the aggression-promoting positive feedback between cortisol secretion and HAA activation identified by Kruk et al. [125]. If such mechanisms represent “bottom-up” modes of escalation,

(3)

(4)

(5)

(6)

withdrawal of OFC inhibition may be viewed as a “top down” mode, perhaps more likely to be used in the context of complex strategy. A substantial body of older studies by Albert and others implicates the lateral septal nuclei in the inhibition of aggression [126]. Whether their input to the hypothalamus is unrelated to, parallel to, or mediates temporo-frontal disinhibition of escalation awaits analysis. Some of the same neural circuitry discussed above is involved in the perception of other people’s angry and aggressive behavior (e.g., [127]). Given the supposition that a principal function of the OFC is to generate impulses to action, including facial expressions, it is worth noting that OFC damage also interferes with perceptions of anger. The involvement of this actionrelated area suggests that subthreshold activation of motor programs for one’s own angry facial expressions may be part of forming a perception of other’s anger [128]. The model focuses on reactive aggression and anger. However, proactive aggression surely escalates as well, e.g., when the target of the aggression resists [129]. The circuits involved in this escalation remain to be elucidated. Finally, the tonic inhibition model of frontal function that introduced this paper served as something of a straw man. It is perfectly possible that frontal cortex does exert some level of tonic inhibition, but is also thrown into greater activity as it appropriately gates or modulates the aggressive activation triggered/generated by anterior temporal cortex in response to provocation or threat. By the same token, frontal cortex may modulate activity triggered by anterior temporal sites through a mix of excitatory and inhibitory effects.

8. Summary Stagewise escalation of aggression in agonistic encounters is widespread across species. It can be understood in game-theoretic terms of resource capture and control with least risk and cost. Human anger, sometimes associated with reactive aggression, is likely to follow the same principles. As a common, adaptive phenomenon, escalation is likely to operate via particular neural circuitry. The proposed temporo-frontal model of escalation is based on the normal neurological course of posterior to anterior information flow in the brain, in which early stage, modalityspecific appraisals of threat and provocation are developed at anterior temporal loci (amygdala and neocortex). From these loci, cortical and subcortical systems mediating anger and aggression are directly but diffusely activated. At the same time, the perceptual information at the anterior temporal loci is transmitted through the uncinate and cingulate fasciculi to OFC and VMFC where it is crossmodally integrated, combined with contextual information about the situation (e.g., opponent RHP, resource value), and evaluated in terms of relative dominance status, empathy, likelihood of potential rewards and punishments, and so forth. These frontal areas then impose an inhibitory gating or modulation and focusing of activity initiated by the anterior temporal loci through their projections to the same cortical and subcortical circuits. Escalation occurs as the inhibition imposed by the frontal areas is progressively lifted. Exploring the implications, applications and hypotheses derived from this model will improve our understanding of the biologically important and socially significant phenomena of escalation. Acknowledgements This work was supported by NICHHD grant R01-HD055343 and by a grant from The Netherlands Institute for Advanced Study in the Humanities and Social Sciences (NIAS) to MP.

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