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The studies we examined in this review have enhanced our understanding of the neurobiology of aggression and violence, but have also revealed areas of inconsistency that require clarification, as well as clues for avenues of future inquiries.
A relatively consistent and specific finding has been an association between reduced amygdala volumes and greater levels of trait aggression.
Optimal resolution of this relationship appears to require analysis of a number of additional variables, such as amygdala subregion and hemisphere, aggression subtype (reactive vs proactive), and covariant dimensions (viz, impulsivity, emotional reactivity, and psychopathy).
Inconsistencies between studies—such as some demonstrating reduced whole amygdala volumes, bilaterally, and others indicating a specific involvement of the left dorsal amygdala—likely are resolvable by accounting for these anatomical and phenomenological factors. Therefore, it is likely that different processes (viz, perceptual vs motor; effortful vs habitual) of different aggression subtypes are a function of amygdala subregion and hemisphere.
In terms of functional abnormalities, pathological aggression is associated with a more labile range of amygdala activity, as well as differential amygdala responsivity to socially threatening stimuli. Commonly, aggression is associated with heightened amygdala reactivity to socially threatening stimuli (eg, fearful or angry faces), and, remarkably, responses to neutral interpersonal stimuli (eg, neutral facial expression) are also heightened. Amygdala hyporesponsiveness to threat, however, has also been observed, and this may be related to elements of aggression that are driven by the interpersonal/affective dimensions of psychopathy. Similar to the inconsistencies of amygdala volumetric changes, disentangling the role of amygdala hyper- vs hyporesponsiveness to interpersonally salient cues will also likely require resolving the amygdala into its component functional subregions and characterizing aggression subtypes and associated dimensions. Furthermore, the 5-HTergic system also appears to be involved in determining amygdala responses to neutral and aversive interpersonal stimuli, and this effect may also be subregion- and circuit-dependent.
An important issue that remains unexamined relates to the cellular and ultrastructural basis of amygdala volumetric alterations, as well as the mechanism by which such changes yield the above-described functional differences. Animal models suggest that morphological alterations in the amygdala may reflect decreased dendritic arborization of excitatory 245 – 248 and local inhibitory neurons, 249 which could therefore disrupt both “top-down” cortical inhibition as well as local inhibitory processes. As stress hormones or glucocorticoids are involved in dendritic remodeling in limbic regions in animal models, a potential avenue for future studies may be determining whether the cortisol abnormalities observed in aggressive individuals are related to amygdala structural changes. Such a line of inquiry would also have the potential for developing therapeutic strategies, such as those that involve pharmacological manipulation of the hypothalamic–pituitary–adrenal axis.
The OFC and ACC are limbic prefrontal regions that also play a key role in the neurobiology of aggression, particularly in terms of their interconnectivity with the amygdala.
Involvement of the OFC and its coupling with the amygdala likely impairs (a) the ability to ascribe affective and motivational significance to stimuli in a manner that is integrated, moderated, and flexible; and (b) “top-down” modulation of central nucleus output, leading to an increased likelihood of a “visceral/sympathetic” component to a stimulus representation. Altered coupling between the ACC and amygdala suggests a disruption of effortful cognitive modulation of subcortical affect processing (pregenual ACC), as well as the development of negative self-referential emotional states (subgenual ACC).
A burgeoning literature has begun to illustrate the role of the striatum in aggression. Dysfunction of the ventral striatum likely contributes to aggression, owing to disturbances in the processing of expected outcome values, and therefore, phenomena such as “frustration.” Altered activity of the dorsomedial striatum may contribute to aggression by affecting the expected value or required effort associated with specific responses/actions.
Neurochemical systems are involved in aggression in at least 2 ways: (1) influencing central nervous system development during critical prenatal and postnatal periods and (2) modulating developed neural system/network parameters. The relationship between 5-HT availability during development and aggression is complex. For example, the absence of 5-HT synthesis (tph2 knock-out) as well as excessive 5-HT synthesis capacity (high-activity tph2 polymorphism) can yield an aggressive phenotype in rodent genetic models.
Furthermore, the prenatal and postnatal effects of 5-HTT pharmacological inhibition in animal models also appear to differ, as they lead to increased and decreased aggression, respectively. The developmental role of DA is also beginning to be elucidated, and excessive DA availability may contribute to a particularly severe form of aggression. A number of gene x environment interactions have been described, including polymorphisms of tph2, 5-HTT, MAOA, the D4 receptor and COMT, and early adversity.
Low basal levels of presynaptic 5-HT, particularly in corticolimbic regions, such as the ACC, are believed to contribute to trait levels of aggression, possibly by diminishing the efficacy of cognitive control of amygdala and striatal processes.
Increased 5-HT2A receptor function in the medial OFC may influence state levels of aggression, possibly by decreasing OFC-amygdala coupling.
The 5-HT1B receptor appears poised to influence aggression by its presynaptic location on 5-HTergic and GABAergic neurons projecting from the raphe and striatum, respectively, to the midbrain DAergic system. The 5-HT3 receptor also may play a role in aggression through a number of potential mechanisms, such as presynaptic modulation of DA release in the striatum. While clearly implicated in mood and anxiety disorders, the contribution of the 5-HT1A receptor in aggression is less clear; however, it may play a role in impulsivity.
Greater DAergic synthesis and storage capacity may attenuate aggression, possibly by modulating error/reward signals in striatal regions and/or by enhancing cortical cognitive processes. The neuropeptide VIP may enhance aggression through its actions in the central nucleus of the amygdala, in a manner possibly antagonistic to that of 5-HT’s effect. The steroid hormones cortisol and testosterone interact to determine aggression and related constructs, such as psychopathy, possibly through their effects on amygdala–frontal connectivity.
The standard view has been that low cortisol permits high testosterone to promote aggression; however, their inter-relationship appears to be more complex and dependent on a number of other variables.
There are a number of essential questions that deserve the focus of future studies. The first relates to the various forms of heterogeneity and potential confounds in the study of aggression: What are the convergent and divergent neural correlates of aggression subtypes, namely, reactive and proactive aggression? Further, how do the neural correlates of reactive and proactive aggression relate to those of their associated personality dimensions, viz, negative emotionality and impulsivity, and psychopathy, respectively? How does aggression differ between nonclinical participants, and personality disordered patients with and without IED? How do the various etiopathogenetic variants of aggression differ both phenomenologically and neurobiologically? And how do different etiopathogenetic factors interact—eg, MAOA and 5-HTT risk polymorphisms, and do these interactions possibly contribute to qualitative differences in aggression severity? In addition to these phenomenological and etiopathogenic factors, it will also be essential that neuroanatomical regions are well defined with respect to their functional subdivisions.
Future neurobiological studies will also offer the opportunity to address important clinical goals. In this review, we described various candidate therapeutic targets that deserve further characterization, such as the 5-HT1B and 5-HT3 receptors, the D4 receptor, and the AVP V1a and V1b receptors. Therefore, PET imaging studies of these receptors may help to clarify their role in the pathophysiology of aggression, and pharmacological challenges with ligands to these targets, in combination with brain imaging and laboratory aggression paradigms, may provide initial evidence as to their anti-aggressive efficacy.
The genetic and developmental studies described here have laid the groundwork for identifying biomarkers that could be used to identify at-risk individuals and to develop potential interventions to disrupt the pathogenesis of aggression. Clarifying, for example, the differential contribution of 5-HT vs DA in MAOA-dependent pathogenic mechanisms would allow for more rationally designed developmental interventions.
Finally, as the neural circuitry of aggression is now better understood, dimensional biomarkers could be characterized that would represent sensitivity to specific treatments.
A relatively consistent and specific finding has been an association between reduced amygdala volumes and greater levels of trait aggression.
Optimal resolution of this relationship appears to require analysis of a number of additional variables, such as amygdala subregion and hemisphere, aggression subtype (reactive vs proactive), and covariant dimensions (viz, impulsivity, emotional reactivity, and psychopathy).
Inconsistencies between studies—such as some demonstrating reduced whole amygdala volumes, bilaterally, and others indicating a specific involvement of the left dorsal amygdala—likely are resolvable by accounting for these anatomical and phenomenological factors. Therefore, it is likely that different processes (viz, perceptual vs motor; effortful vs habitual) of different aggression subtypes are a function of amygdala subregion and hemisphere.
In terms of functional abnormalities, pathological aggression is associated with a more labile range of amygdala activity, as well as differential amygdala responsivity to socially threatening stimuli. Commonly, aggression is associated with heightened amygdala reactivity to socially threatening stimuli (eg, fearful or angry faces), and, remarkably, responses to neutral interpersonal stimuli (eg, neutral facial expression) are also heightened. Amygdala hyporesponsiveness to threat, however, has also been observed, and this may be related to elements of aggression that are driven by the interpersonal/affective dimensions of psychopathy. Similar to the inconsistencies of amygdala volumetric changes, disentangling the role of amygdala hyper- vs hyporesponsiveness to interpersonally salient cues will also likely require resolving the amygdala into its component functional subregions and characterizing aggression subtypes and associated dimensions. Furthermore, the 5-HTergic system also appears to be involved in determining amygdala responses to neutral and aversive interpersonal stimuli, and this effect may also be subregion- and circuit-dependent.
An important issue that remains unexamined relates to the cellular and ultrastructural basis of amygdala volumetric alterations, as well as the mechanism by which such changes yield the above-described functional differences. Animal models suggest that morphological alterations in the amygdala may reflect decreased dendritic arborization of excitatory 245 – 248 and local inhibitory neurons, 249 which could therefore disrupt both “top-down” cortical inhibition as well as local inhibitory processes. As stress hormones or glucocorticoids are involved in dendritic remodeling in limbic regions in animal models, a potential avenue for future studies may be determining whether the cortisol abnormalities observed in aggressive individuals are related to amygdala structural changes. Such a line of inquiry would also have the potential for developing therapeutic strategies, such as those that involve pharmacological manipulation of the hypothalamic–pituitary–adrenal axis.
The OFC and ACC are limbic prefrontal regions that also play a key role in the neurobiology of aggression, particularly in terms of their interconnectivity with the amygdala.
Involvement of the OFC and its coupling with the amygdala likely impairs (a) the ability to ascribe affective and motivational significance to stimuli in a manner that is integrated, moderated, and flexible; and (b) “top-down” modulation of central nucleus output, leading to an increased likelihood of a “visceral/sympathetic” component to a stimulus representation. Altered coupling between the ACC and amygdala suggests a disruption of effortful cognitive modulation of subcortical affect processing (pregenual ACC), as well as the development of negative self-referential emotional states (subgenual ACC).
A burgeoning literature has begun to illustrate the role of the striatum in aggression. Dysfunction of the ventral striatum likely contributes to aggression, owing to disturbances in the processing of expected outcome values, and therefore, phenomena such as “frustration.” Altered activity of the dorsomedial striatum may contribute to aggression by affecting the expected value or required effort associated with specific responses/actions.
Neurochemical systems are involved in aggression in at least 2 ways: (1) influencing central nervous system development during critical prenatal and postnatal periods and (2) modulating developed neural system/network parameters. The relationship between 5-HT availability during development and aggression is complex. For example, the absence of 5-HT synthesis (tph2 knock-out) as well as excessive 5-HT synthesis capacity (high-activity tph2 polymorphism) can yield an aggressive phenotype in rodent genetic models.
Furthermore, the prenatal and postnatal effects of 5-HTT pharmacological inhibition in animal models also appear to differ, as they lead to increased and decreased aggression, respectively. The developmental role of DA is also beginning to be elucidated, and excessive DA availability may contribute to a particularly severe form of aggression. A number of gene x environment interactions have been described, including polymorphisms of tph2, 5-HTT, MAOA, the D4 receptor and COMT, and early adversity.
Low basal levels of presynaptic 5-HT, particularly in corticolimbic regions, such as the ACC, are believed to contribute to trait levels of aggression, possibly by diminishing the efficacy of cognitive control of amygdala and striatal processes.
Increased 5-HT2A receptor function in the medial OFC may influence state levels of aggression, possibly by decreasing OFC-amygdala coupling.
The 5-HT1B receptor appears poised to influence aggression by its presynaptic location on 5-HTergic and GABAergic neurons projecting from the raphe and striatum, respectively, to the midbrain DAergic system. The 5-HT3 receptor also may play a role in aggression through a number of potential mechanisms, such as presynaptic modulation of DA release in the striatum. While clearly implicated in mood and anxiety disorders, the contribution of the 5-HT1A receptor in aggression is less clear; however, it may play a role in impulsivity.
Greater DAergic synthesis and storage capacity may attenuate aggression, possibly by modulating error/reward signals in striatal regions and/or by enhancing cortical cognitive processes. The neuropeptide VIP may enhance aggression through its actions in the central nucleus of the amygdala, in a manner possibly antagonistic to that of 5-HT’s effect. The steroid hormones cortisol and testosterone interact to determine aggression and related constructs, such as psychopathy, possibly through their effects on amygdala–frontal connectivity.
The standard view has been that low cortisol permits high testosterone to promote aggression; however, their inter-relationship appears to be more complex and dependent on a number of other variables.
There are a number of essential questions that deserve the focus of future studies. The first relates to the various forms of heterogeneity and potential confounds in the study of aggression: What are the convergent and divergent neural correlates of aggression subtypes, namely, reactive and proactive aggression? Further, how do the neural correlates of reactive and proactive aggression relate to those of their associated personality dimensions, viz, negative emotionality and impulsivity, and psychopathy, respectively? How does aggression differ between nonclinical participants, and personality disordered patients with and without IED? How do the various etiopathogenetic variants of aggression differ both phenomenologically and neurobiologically? And how do different etiopathogenetic factors interact—eg, MAOA and 5-HTT risk polymorphisms, and do these interactions possibly contribute to qualitative differences in aggression severity? In addition to these phenomenological and etiopathogenic factors, it will also be essential that neuroanatomical regions are well defined with respect to their functional subdivisions.
Future neurobiological studies will also offer the opportunity to address important clinical goals. In this review, we described various candidate therapeutic targets that deserve further characterization, such as the 5-HT1B and 5-HT3 receptors, the D4 receptor, and the AVP V1a and V1b receptors. Therefore, PET imaging studies of these receptors may help to clarify their role in the pathophysiology of aggression, and pharmacological challenges with ligands to these targets, in combination with brain imaging and laboratory aggression paradigms, may provide initial evidence as to their anti-aggressive efficacy.
The genetic and developmental studies described here have laid the groundwork for identifying biomarkers that could be used to identify at-risk individuals and to develop potential interventions to disrupt the pathogenesis of aggression. Clarifying, for example, the differential contribution of 5-HT vs DA in MAOA-dependent pathogenic mechanisms would allow for more rationally designed developmental interventions.
Finally, as the neural circuitry of aggression is now better understood, dimensional biomarkers could be characterized that would represent sensitivity to specific treatments.
