Psychobiology of persistent antisocial behavior: Stress, early vulnerabilities and the attenuation hypothesis

Neuroscience and Biobehavioral Reviews 30 (2006) 376–389 www.elsevier.com/locate/neubiorev

Review

Psychobiology of persistent antisocial behavior: Stress, early vulnerabilities and the attenuation hypothesis Elizabeth J. Susman * Biobehavioral Transitions Laboratory, Department of Biobehavioral Health, The Pennsylvania State University, E.108 Health & Human Developement Building, University Park, PA 16802, USA

Abstract Stress experienced during the sensitive prenatal, postnatal and early childhood periods of brain development can have damaging consequences for developing biological systems. Stressors imposed by early physical vulnerabilities and an adverse care giving environment is proposed to set in motion early precursors of later persistent antisocial behavior. The purpose of this report is to present an integrated theoretical perspective of potential mechanisms involved in the development of persistent antisocial behavior with an emphasis on early stressors and the neuroendocrinology of stress. The attenuation of endocrine physiology of the stress system is considered a key mechanism involved in persistent antisocial behavior. The amygdala is considered a structure/process linking subjective experiences, emotional learning, brain development and stress physiology. Attenuated cortisol level subsequent to early vulnerabilities is considered a risk marker for persistent antisocial behavior. q 2005 Elsevier Ltd. All rights reserved. Keywords: Persistent antisocial behavior; Stress physiology; Cortisol; Early learning; Brain development

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Background of the problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The stress system and antisocial behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The endocrine stress system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. HPA axis and antisocial behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. SNS and antisocial behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Neurotransmitter regulation of the stress response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. GABA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms of attenuation of the stress system and antisocial behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Genetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Neurotransmitters: serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Monoamine oxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Amygdala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Unpredictable and adverse environments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Nonoptimal conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Child-caretaker interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms of attenuation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Early learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Psychological mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. The adaptiveness of attenuation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding author. E-mail address: [email protected].

0149-7634/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2005.08.002

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Dynamic systems and structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Implications for antisocial behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Implications for prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Recent studies have yielded important findings showing a pattern of endocrine, psychophysiological, and neurotransmitter hypoarousal in individuals at risk for antisocial behavior and in established offenders (Raine, 2002; Susman and Pajer, 2004). The purpose of this report is to present an integrated theoretical perspective on the development of antisocial behavior with an emphasis on hypoarousal of the stress system, early stressors, the neuroendocrine aspects of stress, and later persistent antisocial behavior. Specifically, the perspective integrates aspects of biological, psychological and contextual individual development based on recent empirical studies of aggressive and criminal behavior. These empirical findings are interpreted in relation to current integrated heuristic models of human development (Magnusson and Cairns, 1996; Lerner, 1998; Lerner and Walls, 1999; Magnusson and Stattin, 1998; Magnusson, 1999; Susman and Rogol, 2004). Stress experienced during the sensitive prenatal and early postnatal period can have damaging consequences for developing biological systems and later behavior (Dawson et al., 2000). Because of its inherent plasticity, neurobiological development is especially vulnerable to the effects of stress (Dawson et al., 2000; Nachmias et al., 1996). In spite of the importance of early physical biological vulnerabilities, specific biological processes hypothesized to be involved in aggressive and violent behavior have only recently begun to be considered by behavioral and neuroscientists. The proposal is that stress system physiology is attenuated under novel and threatening situations later in the life span in individuals with early biological vulnerabilities and adverse family environments. The perspective includes the central notion that these early risks are amenable to interventions to prevent the development and continuity of antisocial behavior. In this report, the word antisocial refers to the wide range of socially unacceptable or deviant behaviors that persist from at least childhood to young adulthood. Different forms of antisocial behavior are considered given the transformations in the development of aggressive behavior across the life span. It refers to physical aggression toward self or others; delinquent, criminal and violent behavior toward self, others, and institutions, and other illegal, socially sanctioned behaviors. The rationale for considering this constellation of behaviors is based on the existing literature and the proposition that the neurobiology of aggressive behavior and more serious forms of aggression, delinquency and crime are accompanied by arousal that is manifested in basal and reactive levels of hormones and neurotransmitters.

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Consideration of the early etiology of persistent antisocial behavior is critically important as early onset disruptive disorders can result in serious criminal behavior, poor physical health, and high rates of substance use and antisocial personality disorder later in the life span (Loeber et al., 2000; Moffitt, 1993; 1998; Pajer, 1998). These health and social problems cast a high cost on contemporary societies. Proposed here is that early modes of functioning conducive to antisocial behavior are influenced by early biological vulnerabilities (e.g. fetal exposure to teratogenic substances like drugs and alcohol, infections) and a less than optimal care giving environment. After discussing the background of the problem, dysregulation in the physiology of the stress system, as reflected in the attenuation of the stress system, is considered a risk/marker for persistent antisocial behavior. The amygdala then is introduced as a structure/process linking early vulnerabilities, subjective experiences, emotional learning and brain development in the ontogeny of antisocial behavior. The central tenets of the perspective then are presented; if fetal, neonatal, and childhood emotional and physical vulnerabilities are present and if caretakers are noncontingently responsive, if pain or distress is an unpredictable or frequent occurrence, the developing brain, specifically, the hypothalamic/autonomic nervous system (ANS) stress system will adapt in a manner that presents a risk for persistent antisocial behavior. 1. Background of the problem Stressors imposed by early physical vulnerabilities, such as genes, exposure to teratogenic substances, and an adverse care giving environment are proposed to set in motion early biological precursors of later disruptive and aggressive behavior. The problem is that the biological mechanisms involved in antisocial behavior remain unknown as the findings are disconnected and tend to examine one biological system at a time with little integration across systems. Thus, an opportunity to intervene to prevent later antisocial behavior, based on these early markers, may be lost in early life as most interventions with high risk families to reduce antisocial behavior are initiated during later childhood or adolescence. Biological parameters associated with antisocial behavior include components of the endocrine arm of the stress system; corticotropin releasing hormone (CRH) and cortisol, the autonomic nervous system (ANS), and neurotransmitters; serotonin (5-HT) and GABA. This review draws these biological parameters of antisocial behavior into a developmental perspective that has as its core the roles of early physical vulnerabilities and the stress system in persistent antisocial behavior. The perspective rests on the premise that

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the pattern of hypoarousal or attenuated biological, emotional and behavior systems conducive to early and persistent antisocial behavior is established in the neonatal and young childhood periods of development. The concept of persistent antisocial behavior evolved from Moffitt (1993) and others (Aguilar et al., 2000) who identified what is designated, adolescence limited and life course persistent antisocial behavior, and discussed possible causal factors in both life trajectories. The aggressive and antisocial behavior and criminal career of some individuals is short and well defined whereas for others it is persistent from childhood into adulthood. The contributions of biological processes to persistent antisocial behavior first began to appear in the 1980 s. 2. The stress system and antisocial behavior Hypoarousal of the sympathetic nervous system (SNS) components of the stress system is related to antisocial behavior in vastly differing populations. In the 1980 s, Raine and Venables (1984) showed that antisocial subjects were characterized by lower tonic heart-rate levels. An interpretation of these findings was that lower heart rate levels in antisocial adolescents may reflect a vagal passive adaptation to mildly aversive events. Raine also showed that underarousal of both the central nervous system (CNS) and the autonomic nervous system (ANS) in adolescence is related to criminal behavior in male adults (Raine et al., 1990). Adult criminals had significantly lower electrodermal, cardiovascular, and cortical (EEG) arousal at age 15 years than did noncriminals. Not only is low resting heart rate related to concurrent or adolescent aggression, but low resting heart rate at only age 3 predicted aggression at age 11 (Raine et al., 1997) [See Raine (2002) for related findings]. Attenuation of the ANS arm of stress system and persistent antisocial behavior also was demonstrated in urinary catecholamines. Already at an early age, those who engage in persistent antisocial activities during adulthood were lower on urinary catecholamine levels than those who were temporarily engaged during adolescence, and those who never engage in serious antisocial activities (Magnusson, 1986, 1994). (Additional findings relating attenuation to persistent antisocial behavior appear below.) This report proposes that an integrated view of endocrine, SNS, and neurotransmitter activity is needed to explain the onset and maintenance of persistent antisocial behavior. 2.1. The endocrine stress system The stress system evolved to assist organisms to adapt to their constantly changing environment. It functions to regulate homeostasis in the face of a dynamic and changing external milieu (context). The basic components of the stress system include the locus ceruleus (LC)/Noradrenergic (NE) sympathetic system and the hypothalamic-pituitary-adrenal (HPA) axis consisting of CRH secreting neurons in the hypothalamus, the pituitary, and the adrenal glands. The LC component of the

stress system, the flight and fight system, responds immediately to threatening stimuli from the environment. The HPA neuroendocrine component responds somewhat later and coordinates secretion of stress-related CRH from the hypothalamus, ACTH from the pituitary, and cortisol from the adrenal glands in response to physical and emotional stressors (Chrousos and Gold, 1992). In novel, threatening, and challenging environments, activity of the stress system normatively is characterized by activation of the flight or fight CRH LC/NE stress system to threatening situations followed by the release of CRH, ACTH and glucocorticoids that facilitate escaping danger. The principal glucocorticoid, cortisol, facilitates the mobilization of energy, release of catecholamines, increase in cardiovascular activity, alteration in cognitive and sensory thresholds, increase in alertness, facilitation of selective memory enhancement, promotion of stress-induced analgesia, and suppression of nonessential functions like growth, eating and reproduction (Chrousos and Gold, 1992; Vazquez, 1998). When cortisol secretion reaches a certain level, a negative feedback system signals the hypothalamus and anterior pituitary to reduce production of CRH, ACTH, and cortisol, thus, returning the system to a prestress state (Sapolsky et al., 2000). Failure to inhibit the stress response system increases vulnerability to diseases through increasing allostatic load, which refers to the wear and tear that result from chronic overactivity of allostatic systems (McEwen, 1998). The set point for inhibiting or dampening the response of the stress system varies across individuals and may be low precluding its activation in threatening situations or too high resulting in the lack of rapid termination of the stress response. In brief, the endocrine HPA axis and LC systems form the basic conditions for the individual to be prepared to act effectively and solve problems in dangerous and demanding situations, to avoid some situations, or to flee still other situations. 2.1.1. HPA axis and antisocial behavior Low basal cortisol levels in antisocial individuals have been demonstrated in children, adolescents and adults. Cortisol levels are lower in aggressive and antisocial adult males (Bergman and Brismar, 1994), incarcerated males who were habitual violent offenders (Virkkunen, 1985), prepubertal sons of parents with a substance use disorder (Moss et al., 1995), and disruptive behavior disorder boys (McBurnett et al., 1991). In the disruptive boys, low cortisol persisted in a longitudinal follow-up (McBurnett et al., 2000). Reduced cortisol levels also are reported in youth in association with aggression toward peers (Tennes et al., 1986), hostility toward teachers (Tennes and Kreye, 1985) and severity of oppositional-defiant behavior (van Goozen et al., 1998) and conduct disorder (Vanyukov et al., 1993). Cortisol reactivity or the direction of change in levels following a stressor also is related to antisocial behavior. Some studies show attenuated cortisol response in reaction to experimental stressors (Moss et al., 1995; van Goozen et al., 1998; Woodman et al., 1978). In other studies, hyperresponsivity of the HPA axis is related to antisocial behavior (Brody, 2002; Fishbein et al., 1992; Tucker-Halpern et al.,

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2002; Susman et al., 1997). In yet, other studies there were no relationships between disruptive behavior disorder and cortisol (Engeland, 2000; Klimes-Dougan et al., 2001). The explanation for the lack of differences cannot be deciphered at this time because of differences in stressors used in experimental situations, the age and type of subjects, and the events that occurred just prior to the experimental stressor. Although previous studies of antisocial behavior included primarily males, a paradigm shift toward interest in antisocial behavior in girls has led to a concerted examination of cortisol parameters in antisocial girls. Pajer and colleagues (Pajer et al., 2001a) report that girls with conduct disorder diagnoses had significantly lower cortisol levels than nonconduct disorder girls in the comparison group across three, early morning serum cortisol samples. The differences were not due to methodological factors such as demographic characteristics, use of oral contraceptives, antidepressants or season. A second study examined girls with varying rates of neurobehavioral disinhibition and showed that girls with low cortisol were characterized by poor executive cognitive function, lack of empathy, impulsivity, and aggression (Pajer et al., 2001b). Pajer et al. (2001a) suggest that adolescent girls with conduct disorder appear to experience stress system dysregulation similar to or even greater than that reported in males. In summary, although the relationship between antisocial behavior and lower cortisol is not entirely consistent, there is strong evidence of this neurobiological link. Given the number of studies showing hypoarousal in individuals exhibiting some form of antisocial behavior, and that this pattern of arousal is not the norm in threatening situations in most species, attenuation of cortisol levels and cortisol reactivity is worthy of further examination as a potential valid marker of the biology of antisocial behavior.

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Few studies have examined epinephrine or norepinephrine as an index of ANS functioning in relation to antisocial behavior. Given that epinephrine reflects the degree of ANS LC/NE activation, low levels are expected in antisocial individuals. In an early study, subjects high in psychopathy did not react with an increase in either adrenalin or noradrenaline in the highest of three experimentally induced stressful sessions (Lidberg et al., 1978). They also had conspicuously lower noradrenaline excretion, as compared to subjects low in psychopathy, who showed a reversed pattern. As discussed above urinary catecholamines were lower in adolescent boys who became persistent criminals than in nonpersistent or comparison adolescents (Magnusson, 1986). In addition, adult children of alcoholics, during an aggressioninduction session, had lower norepinepherine levels than controls (Gerra et al., 1999). However, heroin dependent males after experimentally induced aggressiveness increased in plasma norepinephrine (NE) and epinephrine (EPI) levels more than in healthy controls (Gerra et al., 2004). The somewhat consistent finding of low arousal reflected in catecholamines is parallel to the findings for cortisol and support the attenuation hypothesis as a marker of antisocial behavior. 2.3. Neurotransmitter regulation of the stress response Neurotransmitters are involved in the regulation of the endocrine and SNS levels of the stress system. Specifically, 5-HT has an activational effect whereas gamma aminobutyric acid (GABA) has an inhibitory effect on both CRH and LC/NE. Both the serotonin and GABA systems are related to antisocial behavior. Attenuation of the serotonergic system tends to be characteristic of antisocial individuals where research on GABA in humans is too scarce to draw conclusions about its relationship with human antisocial behavior.

2.2. SNS and antisocial behavior The LC/NE components of the stress system similarly are related to antisocial behavior (Raine, 2002). Children at risk for aggressive behavior displayed significant and consistent suppression of respiratory sinus arrhythmia (RSA) during a challenging situation compared to children in the low risk group (Calkins and Dedmon, 2000). Similar findings show that aggressive children had lower heart rates than nonaggressive children even at age 3 (Raine et al., 1997). In addition, low resting heart rate at age 3 predicted aggressive behavior at age 11 (Raine et al., 1997). An atypical finding was that aggressive children exhibited higher heart rates at baseline and lower heart rate reactivity (Schneider et al., 2002). Studies with adult criminals show that they had significantly lower levels of heart rate when they were age 15 than noncriminals (Raine et al., 1990). Differences were not attributable to biological, psychological, or psychiatric mediators and confounds. Higher heart rate is considered a protective factor against antisocial behavior (Raine et al., 1995). In summary, indices of the SNS suggest that low arousal as reflected in heart rate or variability is a concurrent marker and longitudinal predictor of antisocial behavior.

2.3.1. Serotonin Serotonin is a chemical, 5-hydroxytryptamine (5-HT), found in the brain, platelets, gastrointestinal mucosa, and mast cells. Five-HT stimulates the stress system, thus, levels tend to be high under stressful situations (Addell et al., 1997). It is lower in individuals with aggressive and antisocial behavior than in nonaggressive individuals (Coccaro et al., 1995; Manuck et al., 2002; Matykiewicz et al., 1997; Modai et al., 1989; Moffitt et al., 1998; Virkkunen et al., 1987). In addition, levels of 5-hydroxyindoleacetic acid (5-HIAA), the primary metabolite of 5-HT in cerebral spinal fluid (CSF), were significantly lower in the offspring of mothers categorized as antisocial than in nonantisocial mothers (Constantino et al., 1997). Men and women with aggressive character disorders (including antisocial personality disorder) have low 5-HT (Coccaro et al., 1997; New et al., 1997). In 5-HT challenge tests, buspirone, a 5-HT 1a agonist, produced a blunted prolactin response in violent (including females) compared to nonviolent parolees (Cherek et al., 1999) indicating lower 5-HT levels in the violent parolees. In a vastly different type of sample, tryptophan (the dietary precursor for serotonin) depletion during the luteal phase of the menstrual cycle

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increased premenstrual aggression in women (Bond et al., 2001). These empirical findings were supported by a recent meta-analysis of the serotonin metabolite 5-HIAA and antisocial behavior (Moore et al., 2002). Results showed a significant overall mean effect size in the direction of lowered 5-HIAA in antisocial versus nonantisocial adults. The pattern of low 5-HT and 5-HIAA is consistent with the low cortisol and heart rate in antisocial individuals. This consistency reflects the integration of the serotonergic and CRH LC/NE systems as these systems communicate closely and each system can stimulate the other (Hanley and Van de Kar, 2003). One exception to this coordinated pattern of relationships is that serotonin is low but cortisol is high in patients with typical clinical depression. The relationship between products of the serotoneric systems and aggressive behavior has not been examined likely because of the measurement problems involved in serotonin but could provide a potentially important risk of antisocial behavior. 2.3.2. GABA Gamma aminobutyric acid (GABA) is an amino acid that is found in the central nervous system and acts as an inhibitory neurotransmitter. GABA is a neurotransmitter/neuromodulator of the stress response that has received scant attention in the human aggression literature. In humans, a small scale study showed that GABA is correlated with childhood aggressiveness (Kemph et al., 1993). GABA, type A (GABAA) receptor shows promise as a neurotransmitter affected by neurosteroids and results in inhibitory neurotransmission though out the brain (Lambert et al., 2003). With regard to aggressive behavior, although direct stimulation of GABA receptors generally suppresses aggression, a number of studies report that positive allosteric modulators of GABAA receptors can cause increases in aggressive behavior (Miczek and Fish, 2003). Thus, the action of GABA may be stimulatory for aggressive behavior in humans as well as in smaller animals. Research on the role of experience on influencing GABA is scant. However, based on rodent-model studies, Miczek and colleagues (Miczek et al., 2002) suggest that social and pharmacological experiences decisively determine the effects of GABAergic positive modulators on aggression. The absence of research, or even speculation, on the important role of GABA in human antisocial behavior is striking given its important role in rodent aggressive behavior. 3. Mechanisms of attenuation of the stress system and antisocial behavior The theoretical perspective put forth is that inherited vulnerabilities and early life adversities predispose some children toward patterns of attenuation of arousal and these patterns are stable aspects of the psychobiology of persistent antisocial behavior. The stress system is proposed to mediate inherited vulnerabilities and nonoptimal conditions of child rearing through early learning and memory via the amydalar system and its extensive network of connections to the hypothalamus, hippocampus and prefrontal cortex. The process

whereby these mechanisms operate consists of the following. In the process of interaction with the external world, the child must maintain its integrity and the equilibrium of its internal metabolic milieu as well as emotional and behavioral regulation within a dynamic, complex and unpredictable environment. The mechanisms involved in attenuation of the stress system include: genetic and biological vulnerabilities, brain development (the amygdala), unpredictable, stressful and adverse environments, early learning. Infants and young children adapt by attenuating emotions and biological arousal in order to maintain equilibrium to foster their own development. 3.1. Genetic Aggressive traits are considered partially heritable and a few studies report associations between specific genes and aggressive behavior, to date. This trend is likely to be reversed given the wave of new studies on the genetics of complex behavioral traits. The studies cited below are illustrative of recent studies on the genetics of antisocial behavior. 3.1.1. Neurotransmitters: serotonin Davidge and colleagues (Davidge et al., 2004) sought to investigate the relationship between childhood aggression and polymorphisms of two serotonin system genes: the 5HT1D beta receptor gene, the serotonin transporter (5HTT) gene and variable number of tandem repeats (VNTR) polymorphisms. The findings reached only a trend level of significance for 5HTT VNTR 10R in children with persistent aggression. Similarly, 5HTTLPR (promotor) was not found to be significantly associated with aggression, but there was an association between this polymorphism and attention deficit hyperactivity disorder, which is associated with aggressive behavior. Although circumstantial the findings do support the role of 5HT in aggressive behavior. 3.1.2. Monoamine oxidase Monoamine oxidase A (MAO) has an association with mood states and lower activity is associated with aggressiveness. This gene has a functional polymorphism with a variable number tandem repeat (VNTR) in the upstream regulatory region (Huang et al., 2004). Hence, hypotheses are that there is an association between the MAO A (MAOA-uVNTR) polymorphism and mood disorders, suicidal behavior, aggression/impulsivity, and effects of reported childhood abuse (Huang et al., 2004). The lower expression allele was associated with a history of abuse before 15 years of age in male subjects and with higher impulsivity in males but not females. The results suggest that the lower expression of the MAOA-uVNTR polymorphism is related to a history of early abuse and may sensitize males, but not females, to the effects of early abuse experiences on impulsive traits in adulthood. The polymorphism may be a marker for impulsivity that in turn may contribute to the risk for abuse. This trait could then be further aggravated by abuse. (See also a relevant review of

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the genetics of the serotonergic system in suicidal behavior, Arango et al., 2003). Others as well have shown an interaction between MAO, child abuse and depression. Caspi and colleagues (Caspi et al., 2002) reported an interaction between MAO A and a history of child maltreatment and a higher incidence of adult depression. Caspi et al. (2003) also showed an interaction between 5-HTTLPR and childhood maltreatment and adult depression. The evidence regarding the effects of early life stress as moderators of genetic influences is recent, the studies need to be replicated, and several collateral questions remain to be addressed. However, the following may hold true. Serotonin and MAO genes are implicated in aggressive behavior. Serotonin and MAO interact with childhood experiences to increase the risk of antisocial behavior in adulthood. In addition, abusive experiences are stressful. Therefore, genetic influences on antisocial behavior may be mediated partially by early life experiences. 4. Brain development 4.1. Amygdala The amygdala is considered a key mediator of emotions (Davidson and Irwin, 1999; Joseph, 1999) and conditioning and extinction of fear. Therefore, it is proposed that the effects of the early environment are mediated, at least in part, by altering the degree of neural activity within the amygdala. This heterogeneous structure is involved in the modulation of neuroendocrine functions, visceral effector mechanisms, and complex patterns of integrated behavior including defense reactions, ingestion, aggression, reproduction, memory, and learning (DeOlmos, 1990). Modulation is accomplished through a vast network of connections with other brain regions, such as the lateral basal forebrain area, nucleus ambiguous, reticular formation, brain stem and dorsal motor nucleus of the vagus (Davis, 1986; DeOlmos, 1990). As suggested above, the amygdala nuclear complex plays a central role in emotional learning (positive and negative emotions), emotional memory, acquisition and expression of fear (Davis, 1998), storage, and expression of fear memory, and the establishment of adaptational strategies to fearful, novel and threatening environments (Cahill and McGaugh, 1998; LeDoux and Muller, 1997; LeDoux, 2000). The amygdala is activated in response to stimuli denoting threat or fear (Buechel et al., 1998). The role of the amygdala in emotional learning in young children has not been well researched. Kagan (2001) hypothesizes that a person’s temperament, such as the behavioral response to unfamiliar and unexpected events (behavioral inhibition), may be directly related to the threshold of excitability of the amygdala. Functional magnetic resonance imaging (fMRI) has validated the role of the amygdala in emotional processing in adult humans. Voluntary modulation of negative emotion is associated with changes in neural activity within the amygdala (Schafer et al., 2002). Negative and neutral pictures were presented with instructions to either ‘maintain’ the emotional

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response or ‘passively view’ the picture without regulating the emotion. Of note, is that greater signal change was observed in the amygdala during the presentation of negative as opposed to neutral pictures. This increase in amygdala signal due to the active maintenance of negative emotion was significantly correlated with self-reported levels of negative affect. The results indicate that consciously evoked cognitive mechanisms that alter emotional response are mediated at least in part by the degree of neural activity within the amygdala. fMRI results also show stability in patterns of arousal over time. Adults who had been categorized in the second year of life as inhibited, compared with those previously categorized as uninhibited, showed greater functional MRI signal response within the amygdala to novel versus familiar faces (Schwartz et al., 2003). If early emotional experiences affect amygdala functioning, then the effect of these experiences is expected to be sustained. One theory is that emotional stimuli (like fear) are registered by the amygdala, then, by way of pathways through the lateral hypothalamus and medulla, the SNS (i.e. adrenal medulla) and HPA stress axises are activated (McGaugh et al., 1993). The stress system is involved in emotional learning and memory via projections between the amygdala, hypothalamus and prefrontal cortex thereby creating a permissive effect for communication between experienced stress, fear, novelty and threat, SNS, and the CRH stress response (LeDoux, 1998; Sapolsky, 1996; Vazquez, 1998). Finally, the amygdala is crucial for learning the association between stimuli and punishment and rewards (Holland and Gallagher, 1999). Memory plays a central role in this process. Of note is that stress-related hormones [epinephrine and cortisol (Cahill and McGaugh, 1998)] are involved in memory consolidation, memory storage, and are considered endogenous modulators of memory. If the amygdala is damaged even to a moderate degree, conditioned fear may be extinguished or may fail to develop. The initial harm to the amygdala is that regulation of neural circuitry may be permanently altered so as to change neurophysiological reactivity of the CRH system, hippocampus, hypothalamus, other structures and related functions. Damage to the amygdala results in the attenuation of SNS and HPA axis normal reactions to fear (LeDoux, 1998). Thus, if a child with inherited vulnerabilities is exposed to insensitive and unresponsive care giving, alterations in the important sensory amygdala and CRH pathways may develop in a manner that fails to optimize emotional, and CRH and SNS responses to stressors. In the child with attenuated emotions and HPA and ANS activation, memories for fearful situations and interactions may be either suppressed or current fearful situations may fail to activate appropriate emotions. This perspective is put forth considering the importance of the amygdala, notably the anxiogenic influence of CRH projections from the amygdala to the locus ceruleus, for the expression of behavioral responses to stress. Given the high sensitivity of the stress response in infants (Gunnar et al., 1989a,b), we further propose that a nonresponsive care taking environment, insecure attachment and unpredictable and inconsistent affective exchanges are key

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influences on activation of the amygdala and regulation of emotional learning and memory. Specifically, the amygdala through its connections with other brain regions is proposed to mediate emotions and ANS and HPA axis response to novel and threatening situations. With regard to research on the amygdala, studies specifically designed to contrast a group of persistent antisocial individuals with a group who are not is still lacking. Young aggressive children are ideal candidates for assessment with rapid fMRI to determine, first, if there are group differences in amygdala functioning in aggressive and nonaggressive children, and, second, if there no group differences do these amydala differences emerge over time in aggressive children. Targeting the development of preschool and young grade school children may provide key information concerning the role of the amygdala as a site of establishment of attenuated fear. As of yet we do not know if this structure is involved in the development of antisocial behavior in children. One question that could be asked is whether early poor attachment and inconsistent parenting, risks for aggressive behavior, have implications for amydala processing of emotions. An additional important and untested hypothesis is whether attenuation of the HPA axis is accompanied by amygdala differences in both children and adults. 4.1.1. Unpredictable and adverse environments Optimal conditions for early development of the stress response. Greenough et al. (1987) showed that neurobiological systems are experience-dependent requiring varied types of experience to develop. Incoming sensory stimulation is meaningless until it is cognitively transformed into selfrelevant information that is then used to organize behavior (Cahill and McGaugh, 1998; Crittenden, 1999). A cognitive strategy that gives meaning to the environment is temporal sequencing or regularity in the ordering of events. Regularity and predictability in sensory and emotional stimulation are essential for optimal brain development, such as for synaptic formation, and related perceptual, cognitive and emotion processing, particularly at an early sensitive stage of brain organization (Dawson et al., 2000). Phylogenetically, older brain areas develop before more advanced areas like the frontal cortex. Thus, the regulatory mechanism necessary for optimal regulation of environmental stimulus is not yet fully developed in young children. A key aspect of regularity is a child’s first relationship, usually with the mother, which shapes the capacity to regulate later emotional relationships (Schore, 1994). To adapt to the maternal and care giving environment, the brain identifies and interprets regularities. Through regularity and sequential ordering of the neonate’s demands and the caregiver’s responses, the infant’s emotions, behavior and physiology become synchronized with environmental demands. If the caregiver is temporally and contingently responsive to the infant’s need for comfort and sustenance, the infant and young child will develop a secure base with regard to the infantcaregiver system. A secure attachment during infancy buffers responses to a threat as indexed by a low cortisol response

(Nachmias et al., 1996). A resulting positive pattern of adaptation will enable the infant to regulate physiology, emotions, and behavior consistent with the demands of social contexts, including the ability to resist aggressive impulses and behavior. 4.1.2. Nonoptimal conditions Plasticity in the developing brain represents a window of opportunity for healthy growth in optimal child rearing circumstance but a period of vulnerability in nonoptimal rearing environments (Als et al., 2004; Nelson and Carver, 1998). Early brain development is especially vulnerable to the effects of environmental stressors (Dawson et al., 2000; Nachmias et al., 1996). If trauma or inconsistent parenting is experienced then the result can have negative implications for later development including memory, dreams, and emotional impairments (Nelson and Carver, 1998). If the experience of care giving is noncontingently responsive, if pain or distress is an unpredictable or frequent occurrence, the brain, specifically, the hypothalamic/ANS stress system, is proposed to adapt in a manner that is inconsistent with optimal cortical development. Much of the evidence for the effects of the early environment on emotions and cognition is derived from atypical maternal-child interactions. For instance, depressed mothers show inconsistencies in response to the child’s needs for comfort and sustenance when confronted with threatening situations. It is extensively documented that depressed mothers produce children who are at risk for problems in emotional self regulation, peer relationships, behavior problems and affective dysfunctions (Oyserman et al., 2002; Shaw et al., 1996). This process likely begins in the fetal period. Infants born to mothers expressing negative affect in the first trimester of pregnancy had lower heart rate variability in the first year of life (Ponirakis et al., 1998). In brief, infant-caregiver interactions characterized by irregularity and unpredictability are proposed to attenuate the infant’s SNS, CRH and LC/NE stress system response to emotionally arousing situations via the mediating effects of early learning and the amygdala. As discussed, low levels of cortisol and adrenaline in persistent criminals (Magnusson, 1996), low heart rate in children at risk for antisocial behavior (Raine, 2002), and low serotonin in criminals are proposed as markers of the attenuation of systems that are affected as a consequence of early childcaregiver experiences. Being born into a crimogenic family and developing later antisocial behavior is not entirely a random event as pre- and neonatal vulnerabilities evolve in interaction with unpredictable and dysfunctional properties of the fetal and external environment, especially in a low socioeconomic environment. A child born into a crimogenic family may exhibit vulnerabilities because of prenatal genetic factors, intrauterine trauma and disease (brain damage, placental infections, poor nutrition, exposure to alcohol, smoking and elicit drugs and inadequate prenatal care). Maternal smoking, for instance, is related to antisocial behavior in a dose response pattern (Brennan et al., 2002). Children in crimeogenic families also may experience physical abuse and brain trauma, which

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predispose to antisocial behavior (Cicchetti and Lynch, 1995). In brief, the pre- and neonatal and early life vulnerabilities and family and economic contexts can interact to predispose a child to atypical stress reactivity and later antisocial behavior. 4.2. Child-caretaker interactions As discussed above, the kind and degree of maladaptive behaviors at a specific period of development are influenced by the child’s early behavioral and biological vulnerability in interaction with an unpredictable environment (Magnusson, 1983; Raine et al., 1996). Antisocial behavior does not arise de novo at adolescence independent from the family environment. Parental care during infancy serves to program behavioral responses to stress in children by altering the development of the neural systems that mediate fearfulness (Caldji et al., 1998). Of note is that certain types of family and community environments interact with biological and behavioral vulnerabilities to sustain learned patterns of adaptation. For instance, boys with low resting heart rate (a risk factor) are more likely to become violent adult offenders if they also have a poor relationship with their parent (Brennan et al., 1997), if they come from a large family (Farrington, 1997), or if there are of low socioeconomic status (Aguilar et al., 2000; Shaw et al., 1996). Support for the importance of early experience effects on the HPA axis is derived partially from assessment of cortisol and behavior in early infancy (Skonkoff and Phillips, 2000). The stress response is present at birth and is highly reactive to stressful procedures (Gunnar, 1998; Gunnar et al., 1989 a,b; Gunnar and Donzella, 2002). The stress system also is characterized by plasticity as reactivity to stressors is moderated by the care taking environment. In the first week of life repeated experiences with a physical exam lowered cortisol reactivity whereas heel stick blood draws elicited more of a response upon repetition (Gunnar et al., 1992). Poor quality of parenting also elevated cortisol. Provision of a sensitive, responsive and attentive babysitter completely prevented elevations in cortisol to a maternal separation: in contrast, infants left with a baby sitter who ignored them showed a significant increase in cortisol (Gunnar et al., 1992). Intuitively, one might hypothesize that cortisol should increase in children in adverse circumstances. However, humans as well as rodents dampen their cortisol responses to chronic stressors over the first year of life (Gunnar and Donzella, 2002). These attenuated hormone, neurotransmitters, and ANS hypoarousal indices are proposed to reflect an atypical yet organized response to early learning. The question then becomes what are the mechanisms whereby the stress system becomes attenuated. 5. Mechanisms of attenuation 5.1. Early learning Learning theory suggests that fear is learned after a sufficient number of pairings of a neutral and conditioned stimulus (CS). Long-term changes are established in the brain, such that a CS begins to elicit behavioral, autonomic and

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endocrine responses that are usually associated with danger (LeDoux, 1986, 1996, 1998). Conditioned fear is an amygdaladependent form of learning (Rogan et al., 1997). Fear extinction is considered to be influenced by similar principles of learning (Davis and Myers, 2002). The neural basis of extinction involves the neurotransmitters GABA and glutamate. GABA may act to inhibit brain areas involved in fear learning (i.e. the amygdala), and glutamate may play a role in neural plasticity (Davis and Myers, 2002). In addition, findings suggest that amygdala N-methyl- D-aspartate (NMDA) receptors play a key role in triggering the neural changes that support fear learning and loss of fear that accompanies extinction training (Walker and Davis, 2002). These studies implicate both an environmental and neural component to fear extinction. The cellular and molecular substrates explaining the links between CS, memory and behavior change are beginning to be identified. Long-term potentiation (LTP) is involved in memory fear conditioning (Rogan et al., 1997). In rats, fear conditioning alters auditory CS-evoked responses in the lateral nucleus of the amygdala in the same way as LTP induction. The changes parallel the acquisition of CS-elicited fear behavior, are enduring, and do not occur if the CS and UCS remain unpaired. LTP-like associative processes thus occur during fear conditioning and these LTP changes may underlie the long-term memory of the conditioning experience. Overall, conditioned learning has both a cellular and molecular basis (Schafe et al., 2001). It follows that if the infant’s emotions and behavior have no caregiver consequences, in time, the infant’s distress cues and cortisol secretion will become extinguished in nonrewarding situations. 5.2. Psychological mechanisms Based on studies with adults, psychological explanations for attenuated arousal with regard to criminal behavior include the fearlessness theory and stimulus seeking. The former suggests that low heart rate is a marker of a fearless personality (Raine, 1993; 2002; Raine et al., 1998). The latter, stimulus seeking, suggests that low arousal is an uncomfortable state, thus, individuals seek out dangerous situations to reduce the uncomfortable state (Eysenck, 1977; Raine, 2002). Both perspectives are appropriate for adults but the applicability to children may be limited because of experiential, cognitive and emotional immaturity. 5.3. The adaptiveness of attenuation Adaptation refers to the process whereby the organism maintains its integrity and the equilibrium of its internal metabolic milieu as well as behavioral and psychological regulation under varying and complex conditions. Adaptation is a fundamental principle of human development involving the ability to adapt to new conditions while simultaneously undergoing structural and functional changes. The efficacy of adaptation strategies varies across the life span. Infants are born with adaptive, or regulatory, capacities to maintain

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a consistent internal milieu (Cannon, 1932). Many of these regulatory processes are reflex actions, others are triggered at birth and yet others develop after birth (Rovee-Collier and Lipsett, 1982) originating in interaction with the care giving environment. An optimal pattern of physiological and psychological adaptive responses to a perceived threat is characterized by integration, activation of the amygdala and CRH and LC/NE stress system consisting of increases in heart rate, CRH, ACTH and cortisol, epinephrine, and the emotions of fear and anxiety. These basic responses are essential for long-term survival. Cahill and McGaugh (1998) remind us that the adrenal hormones epinephrine and corticosterone in animals (cortisol in humans) have an important adaptive function in response to emotional experiences. These hormones aid immediate responses to flee or fight the threat (Johnson et al., 1992) and also aid adaptation by enhancing declarative memory. The attenuation of patterns of arousal discussed above is considered an adaptive strategy to cope with a chaotic environment. Down regulation of the stress system enables the organism to regulate the stress system so as not to continually evoke a chronic emotional, endocrine, and cardiovascular response to threatening situations. This down regulation avoids chronic arousal and excessive energy expenditure, which would eventually increase allostatic load leading to morbidity and early mortality. 6. Dynamic systems and structures Any model that aims at contributing to understanding and explaining complex aggressive, delinquent and criminal behavior is by definition an integrated perspective that considers emotional, contextual and neurobiological processes (Magnusson and Cairns, 1996; Lerner, 1998; Lerner and Walls, 1999; Magnusson and Stattin, 1998; Magnusson, 1988; Magnusson et al., 1999; Susman and Rogol, 2004). At a general level, the holistic nature of neurodevelopmental processes implies that they proceed, at all levels from the molecular level upwards in the total person-environment system. An integrative view extends the concept of context to include internal biological stress-related processes. At all levels of the total organism, the functioning of each element of a system is dependent on its context (Edelman, 1987), both horizontally between elements at the same level of analysis and vertically between systems at different levels (Hinde, 1987). The information that affects this process may stem from either internal (e.g. neurotransmitters) or external (e.g. family) environments. It follows that a complex problem like aggressive behavior will develop simultaneously drawing components from internal and external environments. That is, the development of persistent antisocial behavior is an integrated process of biological, emotional and behavior systems working in synchrony from the fetal period onward. Two interconnected elements of the process are of particular relevance to this discussion: (1) A crucial element underlying the activation of the CRH and LC/NE sympathetic system is the individual’s emotions adhered to experienced novelty and challenge. A general characteristic of individuals executing

persistent antisocial behavior is their lack of positive or negative emotional reactions in normatively emotional situations (Cleckley, 1976; Fisher and Blair, 1998; Loney et al., 2003; Zahn-Waxler and Usher, in press). Although the systems that prepare the individual to respond to novel and threatening situations, initially, are established through emotional learning, over time and with experience both become attenuated or down regulated. (2) The adaptational process is dependent on the interpretation of the situation as fear inducing. It is this meaning that elicits the CRH and LC/ NE sympathetic activity. Persistent, antisocial individuals may not experience threatening situations as fear inducing and may not respond with normative stress responses. In brief, the manner in which an individual behaves in a real situation represents an integrated, complex, dynamic, and adaptive brain-behavior integrated pattern of functioning that develops over time. 6.1. Implications for antisocial behavior Self organization is a characteristic of open integrated systems and refers to a process by which new structures and patterns emerge from existing ones. Self organization is basic to understanding and explaining the structural organization of the ontogenetic processes involved in antisocial behavior from conception onward (See also Cicchetti, 1994). The effect is that the functioning of the organism, at each stage of development, from conception to death, is self-organized and guided by inherent psychological and biological principles. As a consequence of the self-organizing principle, an essential feature of development is transformation, that is, the reorganization of psychological and biological structures and functions. Novel patterns of functioning, such as different manifestations of antisocial behavior, arise during ontogeny and differences in the rates of antisocial behavior may produce differences in the configurations of antisocial behavior within the same individual. Transformations can lead to persistent antisocial behavior with different phenotypes over time. Importantly, transformations can lead to desistence from antisocial behavior. In addition, prolonged CRH endocrine system arousal related to chronic stressor exposure can transform hyperarousal in acute stressful situations to the hypoarousal state described above (Zarkovic et al., 2003). Two aspects of transformation during early development are noteworthy: the plasticity of the brain to all for transformation and the speed with which the transformation leads to new states. During the fetal and early infancy periods, the total system is vastly more open for change than during childhood, adolescence, and adulthood, and development proceeds at a more rapid pace (Huttenlocher and Dabholkar, 1997). The characteristics of openness for change makes the environmental conditions under which the infant/child develops extremely important for optimal normative emotional and reactivity to threatening situations. When the integrated neurobiological system has become established, it remains open for change given brain plasticity, but develops under the correlated constraints of the individual’s biological, psychological,

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behavioral and contextual characteristics (Cairns et al., 1993). Thus, scientists should be alert to the importance of the early establishment phase in persistent antisocial behavior. This suggestion does not imply that all studies necessarily begin in the fetal or early neonatal period. Rather the notion is that all studies will assume that future manifest behavior will build on the early established integrated psychobiological systems. Future research questions will ask: What is the role early established psychobiological systems will play in the further development of an individual? How do early emperiences alter structural and functional changes in brain development at will increase or decrease risk of later antisocial behavior. A final set of questions will focus on the plasticity of the emotionamygdala-stress system links. To be productive, the studies will necessarily be guided by systematic holistic (or configural) theoretical approach. 6.2. Implications for prevention To develop effective interventions, based on an integrated holistic perspective, conceptual models of prevention will address multiple biological, behavioral and psychological risks for antisocial behavior within the individual as well as risks emanating for the prenatal and postnatal social contextual environment. Individual biological factors might include complications during gestation, labor and delivery, and childhood illnesses. Interventions to change biological risk profiles that, in turn, will change behavior have not been the focus of prevention research. In addition, interventions tend to focus on behavioral factors rather than biological processes. Finally, the wider social contextual influences, like poverty, and their influence on antisocial behavior have received moderate attention. An integrated perspective will orient prevention scientists to patterns of biological, psychological and social contextual influences that contribute to the outcome of persistent antisocial behavior. Recent perspectives on prevention to improve children’s development acknowledge the complex processes that need to be considered. Furthermore, Sameroff (2003) proposed two important principles of prevention science that are relevant to an integrated approach. First, poor outcomes in children’s development, in this case persistent antisocial behavior, are not the consequence of a specific cause. Complex behaviors are the result of an interwoven constellation of influences as discussed above. Second, different outcomes have different constellations of influences. In the case of antisocial behavior, violent aggressive behavior is likely to have very different precursors than oppositional behavior. Therefore, universal treatments applicable to all children at risk for antisocial behavior may not be as effective as targeted interventions. Implications of this perspective then are three fold. (1) Assessment of risks for persistent antisocial behavior will use a multirisk strategy that spans the prenatal, early infancy and early childhood periods. (2) Variables at the individual biological (e.g. HPA response to stressors, specific genes), behavioral (e.g. aggressive behavior and temperament), and prenatal and social context (e.g. SES, family history, family

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structure and domestic aggression) will be considered. (3) Interventions will take place at more than one level of analysis. Realistically, any one intervention cannot include all aspects of the individual and the social ecology. Thus, the following guidelines might help to foster effective integrative prevention efforts: (1) the assessment will be multimodal assessing individual biological and behavioral factors, and social context factors. This recommendation does not imply that biological risks, like attenuated HPA axis functioning, need to be specifically targeted for intervention as prevention and intervention efforts rarely target a specific risk factor. Important to note is that early interventions change biological functioning as well as behavior. Raine and colleagues (Raine et al., 2001) showed that early educational and health enrichment is associated with long-term increases in psychophysiological orienting and arousal, a protective factor against crime. Intensive treatments delivered early in life to comorbid disruptive behavior and attenuated biological processes may prevent continuation of antisocial behavior. (2) A hierarchy of the most salient risks based on existing literature and the current situation will guide the intervention, and (3) the intervention will be evaluated long-term as proximal treatment may only become apparent in the years to follow. The question as to who will be the recipients of interventions has not been adequately addressed. Moffitt et al. (2002) suggest that interventions are desirable with all aggressive children and with all delinquent adolescents to prevent a variety of maladjustments in adult life. With regard to preventing antisocial behavior, targeting the recognition of emotions and enhancing parent-child interaction in the early years is proposed to have the outcome of increasing arousal with the result of more empathetic responding to others and attention and recognition of environmental cues that are required for competent interpersonal interactions.

7. Conclusions Integrated theories consider development as successive changes that entail structural biological change as well as dynamic functional changes in psychological capabilities (Hinde, 1987; Lerner, 1986; 1998; Magnusson, 1988; Mayr, 1988; Susman, 1998). Absent in previous models, with Moffitt as the exception, were notions about the synchronization of neurophysiological processes with emotional, cognitive, and care giving contextual processes in the establishment and maintenance of persistent antisocial behavior. On the other hand, exclusively neurobiological views on persistent antisocial behavior ignore the reality that the functioning of individuals’ neurobiological-psychological-behavioral systems is closely connected with the character of the physical and sociocultural environment in which the individual is embedded. The processes involved in the early establishment of biological systems that serve adaptation and developmental changes are dependent on the amount, characteristics, predictability, variability, and structure of information from the external environment.

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Findings from basic and applied research on an integrated perspective of persistent antisocial behavior and attenuation of biological markers will have implications for the content of prevention and intervention programs, the timing and type of interventions, and the modalities for delivering the program message. To understand antisocial behavior, determinants of attenuated and exaggerated responsivity and the underlying molecular and neural processes will require examination in an integrated way (Wiedenmayer, 2004). Recent advances in brain imaging technology will be instructive in identifying integrated brain-behavior functioning of individuals. Moffitt (1993) suggests that more will be learned about the etiology of severe, persistent antisocial behavior if the childhood-onset persistent cases are singled out for study, if studies begin during infancy, or even prenatally, and the same individuals are followed to adulthood. The same can be said about studying the stress system and antisocial behavior. By combining all antisocial individuals, the high arousal individuals will be subsumed into a larger category of individuals who are of moderate or high levels of arousal thus, attenuating effect sizes for the low arousal individuals. The result will be to conclude that biological substances have no role in persistent antisocial behavior. By adopting a within person approach that integrates neurosicence tools with the perspective of modern psychology, the science of antisocial behavior will be advanced in major ways. Acknowledgements Thank you is extended to David Magnusson for his wise input to this manuscript. This report was made possible by a grant from the Swedish Council for Humanities and Social Sciences to David Magnusson for inviting Elizabeth J. Susman as a distinguished guest researcher to the Laboratory for Developmental Science at Stockholm University, Stockholm, Sweden. References Addell, A., Casanovas, J.M., Artigas, F., 1997. Comparitative study in the rat of the actions of different types of stress on the release of 5-HT in raphe nuclei and forebrain areas. Neuropharmacology 36, 735–741. Aguilar, B., Sroufe, L., Egeland, B., Carlson, E., 2000. Distinguishing the early-onset/persistent and adolescence-onset antisocial behavior types: From birth to 16 years. Dev. Psychopathol. 12, 109–132. Als, H., Duffy, F.H., McAnulty, G.B., Rivkin, M.J., Vajapeyam, S., Mulkern, R.V., Warfield, S.K., Huppi, P.S., Butler, S.C., Conneman, N., Fischer, C., Eichenwald, E.C., 2004. Early experience alters brain function and structure. Pediatrics 113, 846–857. Arango, V., Huang, Y.Y., Underwood, M.D., Mann, J.J., 2003. Genetics of the serotenergic system in suicidal behavior. J. Psychiatr. Res. 37, 375–386. Bergman, B., Brismar, B., 1994. Hormone levels and personality traits in abusive and suicidal male alcoholics. Alcohol. Clin. Exp. Res. 18, 311–316. Bond, A.J., Wingrove, J., Critchlow, D.G., 2001. Tryptophan depletion increases aggression in women during the premenstrual phase. Psychopharmacology 156, 477–480. Brennan, P.A., Raine, A., Schulsinger, F., Kirkegaard-Sorensen, L., Knop, J., Hutchings, B., Rosenberg, R., Mednick, S.A., 1997. Psychophysiological protective factors for male subjects at high risk for criminal behavior. Am. J. Psychiatry 154, 853–855.

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