THE NEUROBIOLOGY OF IMPULSIVE AGGRESSION

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ANGER, AGGRESSION, AND VIOLENCE

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THE NEUROBIOLOGY OF IMPULSIVE AGGRESSION Richard Kavoussi, MD, Phyllis Armstead, MD, and Emil Coccaro, MD

Aggression is a significant problem in our society, with social, psychological, and financial impacts that may be impossible to assess fully. Data from the Epidemiological Catchment Area s t u d p suggest that 3.7% of the population commit one or more acts of violence each year, and the lifetime prevalence of aggressive behavior may be about 24y0.~

The environmental and psychological roots of aggressive behavior have been studied for several centuries, yet it is only in the past 25 years that we have explored in a systematic fashion possible biologic vulnerabilities to this behavior. In this short time, much has been learned about the role of endocrine and neurotransmitter systems as inhibitors and facilitators of aggressive behavior. For example, many studies in both animals and human beings suggest that serotonin plays a sigruficant inhibitory role with respect to aggressive behavior. Reduced central serotonergic functioning may be correlated with an increased tendency toward impulsive aggressive behavior. Other studies suggest that abnormalities in norepinephrine function play a role in the vulnerability to aggressive episodes. Evidence also points to the sex steroids and vasopressin as having a role in the modulation of aggressive behavior. Unfortunately, studies of biologic vulnerability to aggression are hampered by several factors. First, although biologic factors may play an important role in the development of these behaviors, overlooking the influence of environmental and learned factors in the genesis of aggression is impossible. Second, there are problems in defining aggresFrom the Clinical Neuroscience Research Unit, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania ~~~

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sion for purposes of investigating biologic predisposing factors. All human beings experience anger and may behave aggressively given enough provocation. In addition, aggressive behavior may have varying causes, for example, delusional thinking, cognitive impairment, depression, and so on. Finally, much of what we know concerning the neurobiology of aggression comes from animal study data, and extrapolating those results to human aggression may be difficult. Given these caveats, this article attempts to examine possible neurobiologic factors that may modulate impulsive aggression in human beings. We have chosen to discuss impulsive aggression rather than premeditated aggression because the former correlates more clearly with biologic indices of neurotransmitter function. The article concludes with a discussion of the clinical implications of these findings and makes recommendations for future research. BRAIN LESIONS

The study of patients who suffer brain injuries can provide important clues to the neurobiology of impulsive aggressive behavior. As many as 70% of patients with brain injuries secondary to blunt trauma exhibit irritability and aggression.3l In addition, many patients with histories of uncontrolled rage have a history of head trauma.17 Head injury is significantly more common in male spouse batterers than in nonviolent men.37 Although there is a correlation between aggressive behavior and brain injury, the injury itself may not be responsible for increased aggression. For example, the increased incidence of brain injury in violent populations may be due to the increased likelihood that these individuals would get into situations (e.g., fights) where they would get brain injured. To demonstrate a causal relationship, showing that patients with injury to a specific region or regions of the brain consistently display increased levels of impulsive aggressive behavior would be helpful. Unfortunately, not all studies are consistent regarding where aggression-enhancing lesions might be found. For example, high violence scores correlated with CT scan and EEG abnormalities in the temporal lobes in a study of maximum security patients.51Carbamazepine, a medication used to treat temporal lobe seizures, has been found to benefit patients with episodic aggression following head trauma.25On the other hand, some studies suggest that lesions in the prefrontal cortex lead to increases in verbal and physical aggression. In a study of Vietnam veterans who had suffered penetrating head injuries, patients with frontal ventromedial lesions had much higher verbal aggression scores than did controls and patients with lesions in other brain areas.19 SEX STEROIDS In human beings, androgens appear to play a role in the regulation of aggressive behavior, but the nature of that role is unclear.38Violent

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offenders appear to have higher testosterone levels than criminals who commit nonviolent crimes (burglary, theft, drug dealing), and those with high testosterone levels also are more aggressive in prison settings.I6 In violent alcoholic offenders, high free testosterone concentration in cerebrospinal fluid (CSF) is associated with increased aggressiveness and sensation seeking. Also, alcoholic, impulsive offenders with antisocial personality disorder appear to have high mean CSF testosterone concent r a t i o n ~ In . ~ ~aggressive children, there may be a relationship between salivary testosterone levels and observed aggre~sion.~~ Although testosterone levels may be elevated in aggressive offenders, the use of testosterone-lowering agents has been of limited benefit in reducing aggressive behaviors. There are cases, however, of antiandrogens being effective in the reduction of acting-out behavior.' In addition, anti-androgens, such as medroxyprogesterone acetate and cyproterone acetate, appear to lower both deviant and nondeviant sexual drive and activity in men with paraphilas, and this behavioral improvement is associated with testosterone SEROTONIN The connection between serotonin (5-HT) and aggression has been established with the repeated observation that abnormalities in central 5-HT function correlate with impulsive aggression. For example, many studies show that the major metabolite of serotonin, 5-hydroxyindolacetic acid (5-HIAA), is reduced in the CSF of subjects with a history of aggression (violence toward others and violent suicide attempts) compared with those with no such history. It was in 1976 that Asberg and associates2first published their findings that concluded that those who attempted suicide had low CSF 5-HIAA compared with those who did not. Subsequently, Brown and colleagues8 found reduced levels of CSF 5-HIAA in 24 nondepressed, personality-disordered men with a history of aggressive behaviors. Linnoila and associatesz6also found an inverse relationship between aggressive behaviors and CSF 5-HIAA in their study of violent offenders incarcerated in a Finland prison. More important, this study suggested that low CSF 5-HIAA correlated with impulsive aggression and not with premeditated aggression. Similarly, impulsive arsonists have lower CSF 5-HIAA concentrations than do arsonists who also engage in other, nonimpulsive, antisocial acts.48These findings suggest that abnormalities in the brain's serotonergic functioning predispose individuals to impulsive aggressive behaviors rather than nonimpulsive, premeditated aggressive behaviors. Pharmacochallenge studies examine the neuroendocrine response to acute administration of an agent that acts on a specific central neurotransmitter system. One advantage of this method is that the outcome measures reflect dynamic functioning of central neurotransmitter systems in specific brain areas (e.g., within the limbic-hypothalamic-pitu-

itary axis). This type of study also shows evidence of a relationship between decreased central 5-HT function and impulsive aggression. For example, fenfluramine is a medication that releases 5-HT from presynaptic neurons and blocks the uptake of serotonin, making serotonin more available at the synaptic level. This increase in central 5-HT usually results in a transient but marked increase in serum prolactin. Monkeys that have a low prolactin response to fenfluramine display more aggressive gestures in response to a threatening slide of a human being than those with a high response.24These findings have been replicated in human beings. Patients with high degrees of lifelong irritability and impulsive aggression have a lower prolactin response to fenfluramine compared with normal controls. There is a strong inverse relationship between the prolactin response to fenfluramine challenge and measures of irritable, impulsive aggression in male personality disorder patients whatever the particular personality disorder.I5 Other studies have found an inverse relationship between indices of central serotonin system function and impulsive aggression in patients using other challenge agents. These findings have been replicated using the direct serotonin receptor agonist m-chlorophenylpiperazine (m-CPP)21 and the serotonin 1A receptor agonists buspirone" and ipsapirone.12 Other measures of central 5-HT system function are abnormal in patients with a history of impulsive aggressive behavior. For example, tritiated imipramine binding (a measure of presynaptic 5-HT functioning) is reduced in the brains of violent suicide victims.43Measures of 5HT platelet uptake correlate inversely with measures of impulsivity in male patients with episodic aggre~sion.~ Violent offenders display higher platelet imipramine binding than do nonviolent offenders, schizophrenic patients, or normal volunteer^.^^ Reduced numbers of platelet 5-HT transporter sites are associated with life history of aggressive behavior in patients with personality di~0rder.I~ There is also preliminary evidence for a genetic disturbance in serotonergic function that might predispose individuals to impulsive aggressive behavior. Part of the gene for tryptophan hydroxylase (the rate-limiting enzyme for serotonin synthesis) has been discovered to exist as at least two alleles: U or L. Investigation in human subjects has suggested that the presence of either the UL or LL genotype is associated with impulsive aggressive and suicidal behavior and low levels of CSF 5-HIAA in violent o f f e n d e r ~ . ~ ~ Further evidence of the important role that serotonin plays in regulating aggression comes from studies that show that serotonergic enhancing drugs can be effective in reducing impulsive aggressive behavior. In a 13-week, double-blind study of 21 patients with borderline personality disorder, there was a clinically and statistically significant decrease in anger among patients receiving fluoxetine, independent of changes in d e p r e ~ s i o n .In ~ ~an open trial, sertraline was effective in reducing impulsive aggression and irritability in nondepressed patients with a variety of personality disorders.22In a double-blind, crossover study, treatment with the selective serotonin reuptake inhibitor citalo'

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pram reduced aggressiveness in chronically violent schizophrenic inpatients." The serotonin receptor 1A agonist buspirone was effective in reducing aggressive behavior in mentally retarded DOPAMINE AND NOREPINEPHRINE

The brain's dopaminergic and noradrTergic systems also appear to play a role in the genesis of impulsive aggressive behavior. Animal studies suggest that increasing brain dopamine activity creates a state in which animals are more prepared to respond impulsively and aggressively to stimuli in the en~ironment.~ Antidepressant medications that inhibit noradrenergic uptake or stimulate noradrenergic output increase aggressive behavior in isolated mice,1° and this effect can be blocked by denervating noradrenergic neurons.30In addition, CSF norepinephrine concentrations are correlated positively with high rankings of aggression in free-ranging rhesus monkeys.20 Hyperactivity of noradrenergic functioning has been found to correlate with aggressive behavior in human beings as well. For example, there is increased beta-adrenergic receptor binding in the prefrontal and temporal areas of the cortex in the brains of violent suicide victims compared with accident victims.28CSF 3-methyl-4-hydroxyphenolglycol levels are elevated in violent suicide attempters compared with nonviolent suicide at tempter^.^^ Growth hormone responses to the alpha-2 adrenergic agonist clonidine are greater in personality-disordered patients versus remitted demessives or controls. These remonses correlate positively with self-repoh measures of lifetime irritabihty (but not assaultiveness) in both personality-disordered patients and normal control~.~~ Involvement of the noradrenergic system in impulsive aggression is further supported by the finding that noradrenergic receptor blockade is clinically useful in the treatment of aggressive behavior. For example, several studies have found that beta-adrenergic blockers, such as propranolol and nadolol, are effective in reducing aggressive behavior in chronic psychiatric inpatients, independent of psychotic symptoms.35,42 Propranolol also has been effective in reducing aggressive behavior in patients with brain injuries52and adult patients with attention deficit disorder and temper OTHER NEUROBIOLOGIC FACTORS

Other brain systems have been implicated to play a role in the vulnerability to aggressive behavior. For example, central effects of arginine vasopressin (AVP) may influence aggressive behavior. Microinjection of AVP-receptor blockers into the anterior hypothalamus of a hamster has been found to decrease aggression, whereas injection of AVP into the ventrolateral hypothalamus leads to offensive aggression.18

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Nitric oxide (NO) is a neurotransmitter found in high densities in emotion-regulating regions of the brain. Mice with targeted disruption of neuronal NO synthase (nNOS) are observed to have a large increase in aggressive behavior and excessive inappropriate sexual behavior.32A genetic deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, recently has been associated with impulsive aggressive behavior in men of a Dutch family? INTERACTIONS BETWEEN SYSTEMS

Hypothesizing that only one neurobiologic system influences aggressive behavior would be naive. Unfortunately, there have been few studies on the interaction between the different brain systems that may contribute to the regulation of aggressive behavior. Studies conducted suggest intriguing possibilities. For example, when rats that had become dominant following administration of testosterone received serotonin agonists, a dose-dependent decrease in aggression was displayed.6These data suggest that serotonergic systems may interact with sex steroids to regulate aggressive behavior. Similarly, 5-HT may antagonize AVP activity in the CNS. For example, micro-injection of 5-HT into the anterior hypothalamus inhibits AVP-induced aggression whereas intraperitoneal injection of fluoxetine blocks AVP-induced offensive aggression. Thus, it is possible that serotonin interacts with AVP to modulate offensive aggression.18 In another study, low CSF 5-HIAA concentration was associated primarily with general impulsivity whereas high CSF testosterone concentration was associated with aggressiveness or interpersonal viol e n ~ eThis . ~ ~finding suggests that different biologic factors may regulate different parts of the aggressive behavior spectrum. SUMMARY

As noted previously, it is likely that the tendency to lash out verbally or physically at others is influenced by an interaction among multiple complex biologic factors. We need to investigate how these systems interact with each other to develop a more thorough understanding of the brain’s influence over aggressive behavior. We are at a very early stage in our understanding of the neurobiology of aggression. There are no simple tools for studying the complex neurophysiology of the human brain. The studies cited in this article include techniques limited in their utility. As our technologies improve, discovering a more thorough picture of the brain’s influence over aggressive behavior may be possible. For example, functional neuroimaging may help to localize abnormal neurotransmitter functioning in the brains of individuals with impulsive aggressive behavior. Our technologies are beginning to reveal the differential effects of subsystems of neurotransmitter regulation. Subtypes of serotonin

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receptors may differentially mediate impulsive aggressive behaviors. Animal studies suggest that 5-HT 1A receptor stimulation results in a decrease in aggressive b e h a ~ i o r .As ~ noted previously, aggressive personality-disordered patients show a blunted prolactin response to the 5-HT1A agonist buspirone." Antagonism of 5-HT 2 receptors appears to decrease aggression, and this effect may explain the ability of newer antipsychotic agents (which, unlike older antipsychotic medications, block 5-HT 2 receptors) to produce a dramatic reduction in aggression and agitation independent of effects on psychotic symptoms.16 Neglecting psychosocial factors in the causes of aggressive behavior would also be naive. Although environmental factors account for much of the predisposition to aggression, there have been few systematic studies to explore the relationship between life experiences and aggression. In addition, there have been no well-designed studies of the interaction between biology and an individual's environment in the genesis of aggressive behavior. There is some evidence of an association between childhood abuse and neglect and adult antisocial personality but this relationship might be merely an artifact of the genetic relationship between parental and offspring antisocial personality As we discussed in the introduction, one of the biggest hurdles in the study of the neurobiology of aggression is the lack of a consensus on definitions. "Intermittent Explosive Disorder" is the only category in DSM-IV that directly addresses individuals with problems with aggression, but the criteria are vague and only focus on a handful of the many patients who exhibit problems with aggressive behavior. It is our hope that investigators in this field can work together toward developing more precise and encompassing diagnostic criteria to study effectively both the neurobiology and treatment of these disorders. References 1. Arnold SE: Estrogen for refractory aggression after traumatic brain injury. Am J Psychiatry 15031564-1565, 1993 2. Asberg M, Traksman L, Thoren P: 5 HIAA in the cerebrospinal fluid: A biochemical suicide predictor? Arch Gen Psychiatry 33:119>1197, 1976 3. Beckett SR, Lawrence AJ, Marsden CA, Marshall PW: Attenuation of chemically induced defense response by 5-HT1 receptor agonists administered into the periaqueductal gray. Psychopharmacology 108:llO-114, 1992 4. Blackbum JR, Pfaus JG, Phillips AG: Dopamine functions in appetitive and defensive behaviors. Prog; Neurobiol 39:247-279, 1992 5. Bland R, O m h: Family violence and psychiatric disorder. Can J Psychiatry 31:129137, 1986 6. Bonson KR, Johnson RG, Fiorella D, et al: Serotonergic control of androgen-induced dominance. Pharmacol Biochem Behav 49:313-322, 1994 7. Brown CS, Kent TA, Bryant SG, et al: Blood platelet uptake of serotonin in episodic aggression. Psychiatr Res 275-12, 1989 8. Brown GL, Goodwin FK, Ballenger JC, et al: Aggression in humans correlates with cerebrospinal fluid metabolite. Psychiatry Res 1:131-139, 1979 9. Brunner HG, Nelen M, Breakefield XO, et al: Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262:578-580, 1993

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Richard Kavoussi, MD Allegheny University Hospitals Eastern Pennsylvania Psychiatric Institute 3200 Henry Avenue Philadelphia, PA 19129