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Annotation:The role of prefrontal deficits, lowautonomic arousal, and early health factors

in the development of antisocial andaggressive behavior in children

Adrian RaineUniversity of Southern California, USA

Background: This article selectively reviews the biological bases of antisocial and aggressive behavior inchildren with a focus on low autonomic functioning, prefrontal deficits, and early health factors.Results: Low resting heart rate is thought to be the best-replicated biological correlate of antisocial andaggressive behavior in child and adolescent populations and may reflect reduced noradrenergicfunctioning and a fearless, stimulation-seeking temperament. Evidence from neuropsychological,neurological, and brain imaging studies converges on the conclusion that prefrontal structural andfunctional deficits are related to antisocial, aggressive behavior throughout the lifespan. A prefrontaldysfunction theory of antisocial behavior is advanced. This argues that social and executive functiondemands of late adolescence overload the late developing prefrontal cortex, giving rise to prefrontaldysfunction and a lack of inhibitory control over antisocial, violent behavior that peaks at this age. Birthcomplications and minor physical anomalies are selectively associated with later violent behavior,especially when combined with adverse psychosocial risk factors for violence. Cigarette smoking duringpregnancy may increase the risk for antisocial and violent behavior in later life by disruptingnoradrenergic functioning and enhancement of cholinergic receptors that inhibit cardiac functioning.Malnutrition during pregnancy is associated with later antisocial behavior and may be mediated byprotein deficiency. Conclusions: It is argued that early health intervention and prevention studies mayprovide the most effective way of reversing biological deficits that predispose to antisocial and aggressivebehavior in children and adults. Keywords: Aggression, antisocial behavior, brain imaging, health,nutrition, psychophysiology.

There is no doubt that genetic processes play anetiological role in childhood antisocial and aggressivebehavior (Eley, Lichenstein, & Stevenson, 1999; Geet al., 1996; Slutske et al., 1997). What is much lessclear are the precise physiological mechanisms andpathways through which these genetic processesexert their influence in predisposing towards anti-social behavior. In addition, it is well known thatnon-genetic, environmental processes producephysiological changes in both CNS and ANSfunctioning in a way that can predispose to antisocialand aggressive behavior (Suomi, 2000; Raine, 1997).There are therefore strong reasons to believe thatbiological processes play a key role in the etiology ofantisocial and violent behavior in both children andadults, but what are the most important of theseprocesses, and what are their mechanisms of action?

This selective review focuses on just three biolo-gical processes, low resting heart rate, prefrontaldeficits, and early health factors, an approach takento focus on some of the most promising avenues offuture research. The first two processes are highlyspecific, but their coverage incorporates discussionof vagal tone, noradrenergic functioning, righthemisphere functioning, stimulation seeking, fear-

lessness, executive functions, head injury, andneurological processes. The last process, earlyhealth factors, is more broadly construed and in-cludes discussion of birth complications, minorphysical anomalies, exposure to smoking, and mal-nutrition.

There are different reasons for highlighting each ofthese three processes. Heart rate is highlighted be-cause it is the best-replicated biological correlate ofantisocial and aggressive behavior in children. Pre-frontal deficits are selected because brain imagingresearch is becoming an increasing source of newdiscovery on biology – antisocial relationships, andbecause they highlight the importance of futureimaging studies in antisocial child populations.Health factors are underscored because of the in-creasing focus on early biological processes that areamenable to change. Nevertheless, these are not theonly biological processes that are of importance withrespect to antisocial behavior, and readers are re-ferred to Davidson, Putnam, and Larson (2000),Fishbein (2001), Henry and Moffitt (1997), Lahey,McBurnett, Loeber, and Hart (1995), Raine (1993),Susman and Ponirakis (1997), and Volavka (1999)for reviews of other biological processes.

Journal of Child Psychology and Psychiatry 43:4 (2002), pp 417–434

� Association for Child Psychology and Psychiatry, 2002.Published by Blackwell Publishers, 108 Cowley Road, Oxford OX4 1JF, UK and 350 Main Street, Malden, MA 02148, USA

Autonomic underarousal and low resting heart rate

Of the many psychophysiological processes thathave been studied, low autonomic arousal has beenmost repeatedly related to antisocial, criminal, andviolent behavior in both child and adult samples(Fishbein et al., 1989a; Fowles, 1993; Lahey, Hart,Pliszka, & Applegate, 1993; Raine, 1993; Patrick,1994; Volavka, 1995). While most studies have as-sessed antisocial behavior in general without differ-entiating aggressive from non-aggressive forms,studies that have assessed violence have confirmedthat relatively low resting heart rate characterizesaggressive and violent behavior (Farrington, 1997;Raine, Reynolds, Venables, & Mednick, 1997d;Raine, Reynolds, Venables, & Mednick, & Farring-ton, 1998a; Pitts, 1997; Wadsworth, 1976). Althoughthere are multiple and not always consistent psy-chophysiological correlates of aggressive, antisocial,and violent behavior (Fishbein, Lozovosky, & Jaffe,1989b; Volavka, 1995; Raine, 1993; Patrick, Zem-polich, & Levenston, 1997; Lahey et al., 1995; Sus-man, Granger, Murowchick, Ponirakis, & Worrall,1996; Dettling, Gunnar, & Donzella, 1999), lowresting heart rate is chosen for focused attention inthis review for the following reasons:

1. It is the best-replicated biological correlate ofantisocial behavior in child and adolescent samples.In a meta-analysis incorporating 29 independentsamples, the average effect size was calculated at .56(Raine, 1996). This averaged effect size from these 29samples is robust in that it is found in female (d ¼.63) as well as in male samples (d ¼ .50), and is justas strong as when heart rate is taken from a pulsereading (d ¼ .49) as when it is measured from aGrass polygraph (d ¼ .53) (Raine, 1996). As arguedby Rutter, Giller, and Hagell (1998, p. 161) there isnow extensive evidence from both cross-sectionaland longitudinal studies that antisocial, aggressiveindividuals have lower resting heart rates than con-trols (although see Van Hulle, Corley, Zahn-Waxler,Kagan, & Hewitt, 2000, for a recent failure to findthis effect in twins).

2. The relationship is not artifactual. Studies haverepeatedly ruled out potential artifacts such asheight, weight, body bulk, physical development,and muscle tone (Raine, Venables, & Mednick,1997a; Wadsworth, 1976; Farrington, 1997), poorscholastic ability and low IQ (Raine, Venables, &Williams, 1990; Farrington, 1997), excess motoractivity and inattention (Raine et al., 1997a; Far-rington, 1997), drug and alcohol use (Raine et al.,1997a), engagement in physical exercise and sports(Wadsworth, 1976; Farrington, 1997), and low socialclass, divorce, family size, teenage pregnancy, andother psychosocial adversity (Raine et al., 1990;Wadsworth, 1976; Farrington, 1997).

3. The relationship is confirmed in prospective de-signs. Five prospective studies rule out the possi-bility that living a delinquent way of life could in

some way cause low heart rate (Wadsworth, 1976;Farrington, 1987; Moffitt & Caspi, 2001; Raine et al.,1990, 1997a). One of these studies shows thatresting heart rate at early as age 3 years relates toaggressive behavior at age 11 years (Raine et al.,1997a).

4. Low heart rate is diagnostically specific. Anunusual and important feature of the relationship isits diagnostic specificity. While conduct disorder hasbeen associated with low resting heart rate (e.g.,Rogeness, Cepeda, Macedo, Fischer, & Harris,1990a), no other psychiatric condition appears tohave been linked to low heart rate. Other psychiatricconditions, including alcoholism, depression, schizo-phrenia, and anxiety disorder, have, if anything,been linked to higher (not lower) resting heart rate. Incontrast, other biological markers of childhood an-tisocial behavior such as low cortisol and low sero-tonin are also found in other childhood disorders.

5. Findings have been replicated in at least 6 dif-ferent countries. Low heart rate is a robust markerindependent of cultural context, with the relation-ship having been established in England (e.g., Far-rington, 1987), Germany (Schmeck & Poustka,1993), New Zealand (Moffitt & Caspi, 2001), the US(e.g., Rogeness et al., 1990a), Mauritius (Raine et al.,1997a), and Canada (Mezzacappa et al., 1997).

6. Low heart rate is an independent predictor ofviolence. Low heart rate is predictive of later violenceindependent of all other psychosocial and family riskfactors. In a series of six regression analyses aimedat establishing the best independent predictors ofconvictions for violence in the Cambridge Study inDelinquent Development (Farrington, 1997), out of48 family, socioeconomic, attainment, and person-ality predictors, only two risk factors were inde-pendently related to violence (i.e., independent of allother risk factors) in all six analyses – low restingheart rate and poor concentration. Indeed, low heartrate was more strongly related to both self-reportand teacher measures of violence than having acriminal parent. These findings led Farrington(1997) to conclude, ‘These results suggest thatlow heart rate may be one of the most importantexplanatory factors for violence’ (p. 99).

7. The relationship is consistent with genderdifferences in antisocial behavior. There are robustgender differences in resting heart rate, with malesbeing lower than females (Voors, Webber, & Beren-son, 1982), a gender difference in the same directionas gender differences in antisocial behavior. Fur-thermore, this gender difference in heart rate is inplace at age 3 years (mean difference ¼ 6.1 beats/minute, d ¼ .36, p < .0001), just before age 4 yearswhen gender differences in antisocial, aggressivebehavior begin to emerge (Shaw & Winslow, 1997).Because gender difference is one of the most salientfeatures of adult violence, any compelling develop-mental account of such behavior has ultimately toaccount for this effect. The strong and replicated

418 Adrian Raine

gender difference in resting heart rate provides suchan explanatory avenue.

8. Low heart rate is heritable, and the offspring ofcriminal parents have low resting heart rates. Twinstudies of heart rate have repeatedly found sub-stantial heritability for resting heart rate, with her-itabilities in the .65 to .82 range (Ditto, 1993;Boomsma & Plomin, 1986; Boomsma, Van-den-Bree, Orlebeke, & Molenaar, 1989; Theorell, de-Faire, & Fagrell, 1978). Intriguingly, studies havealso found that the offspring of criminal parents havelow resting heart rates (Farrington, 1987; Venables,1987). Given the facts that (a) there is significantheritability for childhood aggression and adult anti-social behavior and (b) there is intergenerationaltransmission of antisocial behavior, low heart ratecould turn out to be one of the genetic mechanismsthat helps account for the transmission of antisocialbehavior from one generation to the next.

9. Low heart rate characterizes life-course per-sistent antisocial individuals in particular. Moffittand Caspi (2001) have recently found that lowresting heart rate assessed at ages 7, 9, and 11years is particularly characteristic of life-coursepersistent offenders, a group who has been hypo-thesized as having early neurobiological deficits(Moffitt, 1993).

10. Low heart rate characterizes female as well asmale antisocial individuals. Several studies, inclu-ding two that are prospective, have now establishedthat within females, low heart rate is linked toantisocial behavior (Rogeness, Javors, Mass, &Macedo, 1990b; Maliphant, Hume, & Furnham,1990; Raine et al., 1997a; Moffitt & Caspi, 2001).This further demonstrates the generalizability of therelationship.

11. Heart rate interacts with psychosocial riskfactors. Boys with low resting heart rates are morelikely to become violent adult offenders if they alsohave a poor relationship with their parent, and ifthey come from a large family (Farrington, 1997).Furthermore, boys with low heart rate are especiallylikely to be rated as aggressive by their teachers iftheir mother was a teenage parent, they come from alow SES family, or they were separated from a parentby age 10 (Farrington, 1997).

12. High heart rate protects against crime devel-opment. Raine, Venables, and Williams (1995) reporton a 14-year prospective study from England inwhich autonomic and CNS measures of arousal,orienting, and conditioning were taken in 101 un-selected 15-year-old male schoolchildren. Of these,17 antisocial adolescents who desisted from adultcrime (Desistors) were matched on adolescent anti-social behavior and demographic variables with 17antisocial adolescents who had became criminal byage 29 (Criminals), and with 17 non-antisocial, non-criminals (Controls). Desistors had significantlyhigher resting heart rates, higher skin conductance(SC) orienting, and higher SC conditioned orienting

responses relative to Criminals. Thus, particularlyhigh heart rate may act as a protective factor in thosepredisposed to adult crime.

13. Low heart rate characterizes aggression inanimals. Eisermann (1992) reported that rabbitswho are more aggressive and dominant have lowerresting heart rates than subordinate, nonaggressiverabbits. Furthermore, when dominance is experi-mentally manipulated, heart rate reduces as domi-nance increases. Similar relationships have beenfound in macaques, baboons, and tree-shrews(Cherkovich & Tatoyan, 1973; Holst, 1986).

Mechanisms by which low heart rate maypredispose to aggressive and antisocial behavior

Low resting heart rate represents one of the bestreplicated, most easily measured, most promising,yet perhaps least understood, biological correlates ofantisocial and aggressive behavior in child andadolescent samples. What are the mechanismswhereby low resting heart rate predisposes to anti-social behavior? Low arousal, stimulation seeking,fearlessness, increased vagal tone/vagal passivecoping, reduced noradrenergic functioning, and re-duced right hemisphere functioning represent sev-eral of the possible processes which, either bythemselves or in combination, may predispose achild to aggression. Physiological explanations of theheart rate–antisocial relationship consist of arousaltheory, vagal tone, norepinephrine, and right hemi-sphere dysfunction.

Low arousal. The most obvious and simple physio-logical explanation is that heart rate is a measure ofautonomic arousal, and that low physiologicalarousal in general is a predisposition to antisocialand criminal behavior (Eysenck, 1987; Raine et al.,1990). In support of this relatively simple theory,which also invokes stimulation-seeking (see below),there is growing evidence that other measures ofautonomic and central nervous system functioning,including resting EEG (Raine et al., 1990), skinconductance activity (Fowles, 1993; Raine et al.,1990), and cortisol (McBurnett et al., 1991; Susman& Petersen, 1992; van Goozen et al., 1998) are re-lated to antisocial and conduct disordered behaviorin children.

On the other hand there appears to be no unitaryarousal system, as intercorrelations between thesedifferent measures of arousal are low or even non-existent in the general population (e.g., Raine et al.,1990). However, it is conceivable that an extreme(antisocial) group within this general populationdoes have low arousal on multiple arousal measures.Some evidence does exist for underarousal on atleast two separate physiological measures of arousalin antisocial child and adolescent samples (e.g., vanGoozen et al., 1998; Raine et al., 1990).

Prefrontal deficits and antisocial behavior 419

Stimulation seeking theory. Stimulation-seekingtheory argues that low arousal represents an un-pleasant physiological state; antisocial individualsseek stimulation in order to increase their arousallevels to an optimal or normal level (Eysenck, 1997;Quay, 1965; Raine et al., 1997a). Antisocial behavioris thus viewed as a form of stimulation-seeking, inthat committing a burglary, assault, or robberycould be stimulating for some individuals.

In support of this theory, El-Sheik, Ballard, andCummings (1994) found that preschool boys whochose to watch videotapes depicting intense angerhad lower heart rates than controls, and also thatlow resting heart rate was associated with external-izing problems. This indicates some support for theview that low heart rate characterizes both stimula-tion-seeking and antisocial behavior. Similarly,resting heart rate at age 3 years has been foundto characterize stimulation-seeking behavior at3 years, as well as aggressive behavior at 11 years(Raine et al., 1997a, 1998a).

Fearlessness theory. Fearlessness theory arguesthat low levels of arousal during mildly stressfulpsychophysiological test sessions are markers of lowlevels of fear (Raine, 1993, 1997). For example,particularly fearless individuals such as bomb dis-posal experts who have been decorated for theirbravery have particularly low heart rate levels andreactivity (Cox, Hallam, O’Connor, & Rachman,1983; O’Connor, Hallam, & Rachman, 1985), as doBritish paratroopers decorated in the Falklands war(McMillan & Rachman, 1987).

Antisocial and violent behavior (e.g., fights andassaults) requires a degree of fearlessness to exe-cute, and lack of fear of socializing punishments inearly childhood would contribute to poor fear con-ditioning and lack of conscience development (Raine,1993). Fearlessness theory receives support from thefact that low heart rate also provides the underpin-ning for a fearless or uninhibited temperament ininfancy and childhood (Scarpa, Raine, Venables, &Mednick, 1997; Kagan, 1994).

Vagal tone. Another physiological mechanisms toaccount for the heart rate–antisocial relationship isincreased vagal tone. Raine and Venables (1984) firstsuggested that the low heart rate recorded in anti-social individuals may be a function of increasedvagal tone and reflect a passive coping response tomildly stressful situations (i.e., so-called ‘restingstates’ prior to some other experimental manipula-tion).

Data since then have not supported this hypo-thesis, favoring instead increased parasympatheticactivity in antisocial individuals. For example, Mez-zacappa et al. (1997) found that antisocial 15-year-old boys were characterized by low resting heartrates, but also found evidence for reduced, not in-creased, vagal functioning. Furthermore, Pine et al.

(1996) found reduced, not increased, vagal tone wasassociated with aggressive behavior in children. Ifreduced vagal tone does prove a systematic correlateof antisocial behavior, it will indicate that the restingheart rate–antisocial relationship is driven by par-ticularly strong sympathetic underarousal which ispowerful enough to overcompensate for the lack ofparasympathetic influences (low vagal tone) whichwould otherwise be expected to increase heart rate inantisocial children.

Reduced noradrenergic functioning. Strong un-derarousal of the sympathetic nervous system wouldsupport a neurochemical explanation of the heartrate–antisocial relationship based on reduced nor-adrenergic functioning. The monoamine norepi-nephrine, found in autonomic nervous systemneurons and produced in the locus coeruleus, iscentrally involved in attention and vigilance andforms one of the four arousal systems in the brain-stem.

While studies of peripheral measures of norepi-nephrine in antisocial children have found weakpositive or null effects (Berman, Kavoussi, & Coc-caro, 1997), a meta-analytic review found a signifi-cant negative effect size of .41 between reducedcentral (cerebrospinal fluid) measures of norepi-nephrine and increased antisocial behavior (Raine,1993). Furthermore, Rogeness et al. (1990a, b) foundboth reduced heart rate and reduced noradrenalinein conduct disordered children.

Reduced right hemisphere functioning. Poor righthemisphere functioning could underlie the low heartrate–antisocial relationship. The right hemisphere isdominant for the control of autonomic functions,including heart rate (Lane & Jennings, 1995) andboth lesion and intracarotid amobarbital studiesconfirm that reduced heart rate is associated withdecreased right hemisphere functioning (Zamriniet al., 1990; Yokoyama, Jennings, Ackles, Hood, &Boller, 1987). In turn, although left hemispheredysfunction has frequently been implicated in viol-ence and crime (Raine, 1993), poor right hemispherefunctioning has also been found in antisocial andviolent populations as measured by functionalmagnetic resonance imaging (fMRI – Raine et al.,2001a), computerized tomography (CT – Huckeret al., 1988), neuropsychological tests (Day & Wong,1996), spatial IQ measures (Raine, Yaralian, Rey-nolds, Venables, & Mednick, in press), EEG deficits(Evans & Park, 1997), and event-related potentials(ERPs – Drake, Pakalnis, Brown, & Hietter, 1988).

Poor right hemisphere functioning (particularlythe anterior regions) has been associated with defi-cits in the withdrawal system, a system that pro-motes retreat from aversive and dangeroussituations (Davidson, Eckman, Saron, Senulis, &Friesen, 1990; Davidson, 1998). Furthermore, pa-tients with right hemisphere lesions, compared to

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those with left hemisphere lesions, have been shownto have reduced heart rate and skin conductanceresponses to films depicting negative emotions (e.g.,anger) (Zoccolotti, Caltagirone, Benedetti, & Gain-otti, 1986). Reduced right hemisphere functioningand a consequent weaker withdrawal system couldmake children less averse to dangerous, risky situ-ations that increase the probability of antisocialbehavior.

Conclusions on heart rate

Of the positions outlined above, stimulation-seek-ing, fearlessness, and reduced noradrenergic func-tioning may ultimately be shown to be the mostlikely partial explanations of the heart rate–antiso-cial behavior relationship. Nevertheless, it is prob-able that no one of the above processes bythemselves can explain the link between low heartrate and antisocial behavior. Furthermore, otherprocesses may play a significant role. For example,low heart rate may also index a lack of empathy inchildren, which in turn could predispose to exter-nalizing behavior problems (Zahn-Waxler, Cole,Welsh, & Fox, 1995). Instead, it is likely that severalof the explanations, in part or in combination, arerelevant in explaining the relationship. The reasonwhy low heart rate is a robust marker for antisocialbehavior may be because it is a broad, global con-struct that taps into multiple physiological andpsychological processes of relevance to antisocialbehavior.

The next generation of research in this area needsto identify the specific cardiovascular processes(e.g., sympathetic versus parasympathetic) that areactive in shaping the relationship between low heartrate and antisocial/aggressive behavior. There isalso a need to assess whether manipulations ofresting heart rate cause changes in antisocial be-havior. For example, stimulants act by increasingboth norepinephrine and dopamine (dopamine be-comes norepinephrine through the attachment ofthe enzyme dopamine b-hydroxylase). Stimulantshave also been found to increase heart rate (Wachtel& de Wit, 1999) as well as to reduce the symptomsof conduct disorder independent of any effect ofhyperactivity (Klein et al., 1997). Further research isneeded, too, into the developmental context of theheart rate–antisocial relationship. Studies of adultpsychopaths have failed to find resting heart ratedifferences (Raine, 1993) but these studies have al-most exclusively compared psychopaths to crimi-nals who are not psychopaths, leaving open thepossibility that both these groups may have lowerheart rates than non-criminal controls. The fact thatlow heart rate in childhood and adolescence predictsantisocial and criminal behavior in adulthood sug-gests that low heart rate is of etiological significancefor adult criminal behavior as well as child antiso-cial behavior (Raine et al., 1990; Farrington, 1997;

Moffitt & Caspi, 2001; Wadsworth, 1976; Raineet al., 1997a).

Frontal deficits and antisocial/violent behavior

Perhaps the main difference between human andanimal brains is the massive development of theprefrontal cortex in the former. It is likely that thisprefrontal development has allowed humans to de-velop a social system that emphasizes close co-operation, reciprocal altruism, and close living ingroups. Such behavior requires a particularly effi-cient system of aggression regulation. The followingsection explores the notion that the prefrontal cortexplays a key role in the regulation of anger andviolence, and that deficits in prefrontal structure orfunction can result in dysregulated, aggressivebehavior in adults and children.

Frontal functional deficits in adults

Over the past decade brain imaging studies havebegun to converge on the conclusion that antisocialand violent offenders have functional impairments tothe prefrontal region of the brain. Reviews of brainimaging studies of violent and psychopathic popu-lations conducted up to 1994 have been reviewed byRaine (1993), Raine and Buchsbaum (1996), andHenry and Moffitt (1997). These reviews, whileshowing variability in findings across studies, con-cur in indicating that violent offenders have func-tional deficits to the anterior regions of the brain,particularly the frontal region.

Since these reviews, at least seven more recentstudies support this key finding of anterior braindysfunction. Goyer et al. (1994), using positronemission tomography (PET) in an auditory activationcondition, showed that an increased number of ag-gressive impulsive acts were associated with reducedglucose in the frontal cortex of 17 personality-disordered patients. Volkow et al. (1995), using PETin a non-activation, eyes open, resting state,observed reduced glucose metabolism in both pre-frontal and medial temporal regions in 8 psychiatricpatients (3 with schizophrenia) with a history ofviolence. Kuruoglu, Arikan, Karatas, Arac, and Isik(1996), using single photon emission computerizedtomography (SPECT) in a resting state, found that 15alcoholics with antisocial personality disordershowed significantly reduced frontal regional cere-bral blood flow (rCBF) compared to 4 alcoholics withother personality disorders and 10 nonalcoholiccontrols. Intrator et al. (1997), using SPECT, showedthat 8 drug-abusing psychopaths compared to 9non-psychopaths had increased rCBF bilaterally infronto-temporal regions during the processing ofemotional words (see also Hirono, Mega, Dinov,Mishkin, & Cummings, 2000 below). Soderstrom,Tullberg, Wikkelsoe, Ekholm, & Forsman (2000),


also using SPECT, found reduced blood flow in bothfrontal and temporal lobes of 21 individuals convic-ted of impulsive violent offences. Using magneticresonance spectroscopy, Critchley et al. (2000) foundlower prefrontal concentrations of N-acetyl aspartateand creatine phosphocreatine in 10 mildly retardedrepetitively violent offenders compared to controls.

These studies have been very variable with respectto subject population (e.g., murderers, violentschizophrenics, drug-abusing psychopaths) andmeasure of frontal functioning (blood flow, glucose,N-acetyl aspartate) and it should be noted thatsample sizes are generally small. However, the factthat they all observe anterior, frontal deficits in as-sociation with violent, aggressive, antisocial beha-vior suggests that frontal dysfunction is a broadpredisposition to generalized antisocial and violentbehavior. Frontal deficits are not universally found,however; at least two studies (Seidenwurm, Pounds,Globus, & Valk, 1997, using PET in a non-activation,eyes open, resting state, and Raine et al., 2001ausing fMRI to a working memory challenge task)have failed to find frontal deficits. Furthermore, it isclear that the prefrontal cortex is but one of a num-ber of brain structures implicated in neural circuitsunderlying violence (Davidson et al., 2000). Never-theless, the overall body of brain imaging researchclearly implicates frontal dysfunction in violentoffenders.

In our own research, we found reduced prefrontalglucose metabolism in 41 murderers compared to 41age, sex, and schizophrenia matched normal con-trols (Raine, Lencz, Bihrle, Lacasse, & Collette,1997). Furthermore, these deficits particularlycharacterized affective, impulsive murderers as op-posed to predatory, instrumental murderers (Raineet al., 1998b). Nevertheless, three important ques-tions remain unanswered from this increasinglylarge body of research. First, are frontal deficitsspecific to selected populations of institutionalizedoffenders, or are they also found in communitysamples of violent offenders? Second, do violent off-enders have a physical, structural deficit in thisregion of the brain? Third, are prefrontal structuraland functional deficits found in psychopathic formsof antisocial behavior?

Prefrontal structural deficits in adult antisocialindividuals

Findings from a recent structural MRI study provideanswers to these questions above. Twenty-one indi-viduals recruited from the community with a diag-nosis of antisocial personality disorder (APD) andhigh psychopathy scores were shown to have an 11%reduction in the volume of gray matter in the pre-frontal cortex, compared to both normal controls anda substance dependence control group (Raine et al.,2000). The APD group also showed lower autonomicactivity (both skin conductance and heart rate)

during a social stressor task in which subjects had toprepare and give a speech about their worst faults.As argued by Damasio (2000), this is a task that isparticularly well suited to eliciting secondary emo-tions such as shame, guilt, and embarrassment,which are thought to be mediated by the ventrome-dial prefrontal cortex. In a logistic regression inwhich the Antisocial group was compared to Con-trols, the three prefrontal and autonomic variables(prefrontal gray/whole brain, heart rate, skin con-ductance) predicted 50.8% of the variance and pre-dicted group membership with an accuracy of76.9%.

These results are consistent with findings on pa-tients with neurological disorders in both single case(Damasio, 1994) and group studies (Damasio, Tra-nel, & Damasio, 1990; Stuss & Benson, 1986). Thisresearch demonstrates that those who have sufferedsignificant damage to the prefrontal region of thebrain proceed to acquire an antisocial, psychopath-ic-like personality. These patients also show auto-nomic arousal and attention deficits to sociallymeaningful events (Damasio, 1994, Damasio et al.,1990), a finding consistent with the role played bythe prefrontal cortex in modulating emotion, arou-sal, and attention (Stuss & Benson, 1986; Davidson,1993). These patients have major structural deficitsto the prefrontal cortex, and the relevance of suchfindings to the majority of antisocial, psychopathicindividuals in both society and prison could bequestioned. The fact that antisocial, psychopathic-like individuals drawn from society also show asubtle but significant volume reduction in theprefrontal cortex (Raine et al., 2000) supports therelevance of these neurological studies for under-standing antisocial behavior in society.

The specific subregion of the prefrontal cortex thatis structurally impaired in antisocial and aggressiveindividuals is still open to question. Data based onacquired damage to the prefrontal cortex in the formof gross lesions in civilians (Damasio, 1994) anddamage incurred through warfare in soldiers (Graf-man et al., 1996) implicate the ventromedial andorbitofrontal sub-regions. Alternatively, impair-ments to the dorsolateral region, which is criticallyinvolved in cognitive flexibility and response per-severation, cannot be ruled out because recidivisticantisocial behavior can be conceptualized asperseverative, unmodifyable behavior in the face of arepeatedly punished response. Future research innon-neurological antisocial populations using ana-tomical MRI and segmentation of gray matter withinthe prefrontal cortex is critically needed to resolvethis issue.

What are the mechanisms and processes throughwhich prefrontal and autonomic deficits could pre-dispose to antisocial personality disorder? There areat least three routes. First, patients with prefrontaldamage fail to give anticipatory autonomic responsesto choice options that are risky, and make bad

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choices even when they are aware of the more ad-vantageous response option (Bechara, Damasio,Tranel, & Damasio, 1997). This inability to reasonand to take appropriate decisions in risky situationsis likely to contribute to the impulsivity, rule-breaking, and reckless, irresponsible behavior thatmake up four of the seven traits of DSM-IV antisocialpersonality disorder. Second, the prefrontal cortex ispart of a neural circuit that plays a central role infear conditioning and stress responsivity (Hugdahl,1998; Frysztak & Neafsey, 1991). Poor conditioningis theorized to be associated with poor consciencedevelopment (Raine, 1993), and individuals who areless autonomically responsive to aversive stimulisuch as social criticism during childhood would beless susceptible to socializing punishments, andhence become predisposed to antisocial behavior.Experiments have repeatedly confirmed that anti-social groups show poor fear conditioning (Raine,1993). Third, the prefrontal cortex is involved in theregulation of arousal (Dahl, 1998; Hellige, 1993),and as outlined earlier, deficits in autonomic andcentral nervous system arousal in antisocials havebeen viewed as facilitating a stimulation-seeking,antisocial behavioral response to compensate forsuch underarousal.

Frontal deficits in antisocial children

Brain imaging and neurological studies, combinedwith the substantial neuropsychological and EEGliterature on antisocial and criminal behavior (Vola-vka, 1995; Raine, 1993), place beyond reasonabledoubt the fact that there is a link between prefrontaldeficits and antisocial, violent behavior in adults.But are these same links found in children? And isthere evidence that damage to the prefrontal regionof the brain actually causes antisocial, aggressivebehavior in children?

The question of whether there are links betweenprefrontal structural/functional deficits and anti-social behavior in children would be most directlyanswered by imaging research. Although there is agrowing literature on other externalizing disorderssuch as hyperactivity, which inconsistently impli-cates frontostriatal systems (Filipek, 1999), thereappears to have been no studies conducted on con-duct disorder, aggression, or antisocial behavior inchildren (although see Amen and Carmichael, 1997,for a report of increased anterior medial frontal bloodflow as assessed by SPECT in sixty-four 6–17-year-olds with oppositional defiant disorder but lacking inconduct disorder). Instead, one must turn to tradi-tional neuropsychological studies to answer thequestion of functional deficits in antisocial children.

Reviews of this evidence in child and adolescentsamples indicate that antisocial behavior is charac-terized by neuropsychological impairments (Moffitt,1993; Raine, 1993). More specifically, Moffitt (1990,1993) has argued that antisocial children and

delinquents specifically have a deficit with respect toexecutive functions, i.e., self-regulation and inhibi-tory control, concept-formation, abstract reasoning,problem-solving behavior, flexible behavior respon-sive to external contingencies, sustained attention,planning, and organization. The frontal cortex is thebrain structure that has been most consistently im-plicated in executive function deficits, although itshould be noted that executive function deficits donot always go hand-in-hand with frontal structuraldeficits. While Teicher and Golden (2000) argue thatevidence for executive function deficits in antisocialchildren is variable, a recent meta-analysis of exe-cutive dysfunction and antisocial behavior by Mor-gan and Lilienfeld (2000) shows significant effectsizes (Cohen’s d) of .40 for conduct disorder and .86for juvenile delinquency, thus supporting Moffitt’sposition. There is debate, however, as to whetherthese effects are carried entirely by comorbid atten-tion-deficit disorder in antisocial children (e.g., seeClark, Prior, & Kinsella, 2000), or whether executivefunction deficits exist in aggressive children aftercontrolling for hyperactivity (see e.g., Seguin, Bou-lerice, Harden, Tremblay, & Pihl, 1999). On balance,it seems likely that (a) conduct disordered childrencomorbid for attention-deficit disorder have theseverest executive functional deficits; (b) conductdisordered children without attention-deficit have aless strong, but significant form of executive functiondeficits; (c) evidence for executive function deficitssupports the notion of frontal lobe deficits in anti-social children.

While structural brain imaging studies of conductdisordered children are lacking, there are studies ofthe behavioral sequelae that follow head injuries inchildren. Overwhelmingly, these studies find thatconduct disorder and externalizing behavior prob-lems are common after head trauma (Hux, Bond,Skinner, Belau, & Sanger, 1998; Max et al., 1998;Butler, Rourke, Fuerst, & Fisk, 1997; Mittenberg,Wittner, & Miller, 1997). It is also clear that somechildren develop internalizing rather than external-izing behavior problems after head injury (e.g., Maxet al., 1998), while others remain relatively unaffec-ted. When the problem is approached from the otherdirection, by looking at base rates of head injury indelinquents and non-delinquents, rates are not toodissimilar, but parents of delinquent children aremuch more likely to report that behavior problemsbegan to develop after head trauma compared toparents of non-delinquents (Hux et al., 1998).

Studies of children with lesions to the prefrontalcortex early in life lend further evidence to the viewthat head (and therefore brain) trauma can directlylead to antisocial and aggressive behavior. Anderson,Bechara, Damasio, Tranel, and Damasio (1999)reported on two cases (one female, one male)who suffered selective lesions to the prefrontalcortex in the first 16 months of life (bilateralpolar and ventromedial in the female, and right


polar-medial- dorsal in the male). Both showed earlyantisocial behavior that progressed into delinquencyin adolescence and criminal behavior in adulthood,and included impulsive aggressive and nonaggressiveforms of antisocial behavior. Both had autonomicdeficits, poor decision-making skills, and deficits onlearning from feedback. Pennington and Bennetto(1993) report on nine other cases of children sufferingfrontal lesions in the first 10 years of life. They notedthat all nine suffered behavioral problems after theinjuries, with 7 of the 9 being conduct disordered,and the remaining two exhibited either impulsive,labile, behavior or uncontrollable behavior. Thesecases when taken together strongly suggest thatdamage to the prefrontal cortex can directly lead toantisocial, aggressive, and criminal behavior.

Developmental processes, frontal functions,and antisocial behavior

Brain imaging, neuropsychological, and neurologicalstudies all suggest that damage or dysfunction to theprefrontal cortex is a significant predisposition toantisocial behavior. These findings are based pre-dominantly on studies focusing on children andadolescents, or adults up to the mid-30s, but there isalso recent evidence that aggression and antisocialbehaviour in elderly demented patients is particu-larly associated with deficits to the anterior andfrontal regions of the brain (Hirono et al., 2000;Miller, Darby, Benson, & Cummings, 1997; Megaet al., 2000). Combined with studies showing thatdamage to the prefrontal cortex in the beginning oflife produces antisocial and aggressive behavior, andimaging studies showing correlations between viol-ent offending and reduced prefrontal structure/function in early to mid-adulthood, they togethermake a compelling case for the notion that prefrontaldeficits can cause antisocial and aggressive behaviorthroughout the lifespan.

Adequate theories of antisocial and violent be-havior need to explain why criminal offending peaksin the late teens, a phenomenon that has been called‘at once the most robust and least understoodempirical observation in the field of criminology’(Moffitt, 1993, p. 675). The adolescent-limited per-spective of Moffitt (1993) in which social norms makeantisocial, rebellious behavior during adolescence anormative but transient phenomenon is one per-suasive account. It is argued here that a prefrontaldysfunction theory of crime can also contribute inpart to understanding this crime–age relationship.Prior to adolescence, children live in a relativelystructured environment where complex, life-chan-ging planning and decision making is not the norm.In contrast, late adolescence is a stage in life whereenormous social demands are being placed on therapidly growing teenager, a load that calls on re-sources of the frontal cortex and its associated exe-cutive functions. Such adolescents need to regulate,

control, and inhibit a growing sex drive, deal withthreats and challenges to their social status thatarise within their peer groups, and plan and organizefor a future career. They need to sustain increasingattention to school performance in order to maximizecareer prospects. Those leaving school at 18 for a jobin the real world lose the social structure and sup-port systems that they have grown used to, and mustadapt their behavior to the more variable contin-gencies, incentives, and disincentives that driveeconomic life. In addition, they must plan and de-velop strategies for attracting a partner (or choosingbetween possible partners), and they may need tomake early parenting decisions. Throughout thisperiod, they must evaluate and assess competinglife-course strategies and engage in complex decisionmaking. At the same time the normative rebelliousspirit and antisocial behavior that have character-ized most adolescence (Moffitt, 1993) must be in-hibited and suppressed in order to succeed in lifeand make way for new, more adaptive behavioralstrategies.

The prefrontal cortex bears the burden of thismagnified cognitive load that requires multiple exe-cutive functions – sustained attention, behavioralflexibility to changing contingencies, working mem-ory, self-regulation and inhibition, abstract decisionmaking, planning and organization. Yet the pre-frontal cortex is relatively late to mature and thisprocessing load occurs at a time when this structureis still developing, with myelination of the frontalcortex continuing into the early 20s and even 30s. Aminority of individuals with early damage or dys-function of the prefrontal cortex would be particu-larly likely to suffer an information overload duringthis time period, resulting in further dysfunction ofthe prefrontal cortex, less regulatory control, andfurther, life-long, antisocial behavior. Others with anintact but particularly late-maturing prefrontal cor-tex may be antisocial during childhood and adoles-cence, but with further maturation of the frontallobes in early adulthood may eventually discontinuetheir antisocial behavior. Others may have frontaldysfunction, but may be protected from antisocialbehavior by having more social support or fewersocial-transitional demands placed on them. Yetanother group of late-onset offenders (Hamalainen &Pulkkinen, 1996; Ishikawa & Raine, 2001) may notevidence antisocial behavior until early adulthoodwhen life stressors at this time overload a prefrontalcortex with latent functional impairments.

In summary, the fact that children, adolescents,adults, and elderly patients with prefrontal deficitsare characterized by antisocial, aggressive behaviormakes a compelling lifespan case for a prefrontaldysfunction theory of antisocial, aggressive beha-vior. It is hypothesized that the social and executivefunction demands of late adolescence place anoverload on the late-developing prefrontal cortex,giving rise to prefrontal dysfunction and a lack of

424 Adrian Raine

inhibitory control over antisocial, aggressive beha-vior at this age. This prefrontal overload is hypo-thesized to be particularly likely in individuals withdevelopmental delays in prefrontal maturation or inhyperactive children with pre-existing prefrontaldeficits. Furthermore, persistence into adulthood ofantisocial behavior is thought to be especially likelyin those who have suffered head trauma and whichmay prevent a maturational catch-up of the pre-frontal cortex in adulthood.

Early health factors

The question of whether brain deficits exist in anti-social, violent individuals is no longer a useful one. Itis now beyond doubt that brain deficits contribute insome way to antisocial and aggressive behavior. Themore important question concerns ‘What early fac-tors can significantly increase the probability that agrowing child will suffer impaired brain functioningand consequent antisocial behavior?’. This sectionbriefly outlines early health factors that may con-tribute to brain impairment, and consequentlyautonomic dysregulation and antisocial/aggressivebehavior.

Birth complications

Several studies have shown that babies who sufferbirth complications are more likely to develop con-duct disorder, delinquency, and commit impulsivecrime and violence in adulthood when other psy-chosocial risk factors are present. Specifically, ob-stetric factors interact with psychosocial risk factorsin relation to adult violence. Raine, Brennan, andMednick (1994) prospectively assessed birth com-plications and maternal rejection at age 1 year in4,269 live male births in Copenhagen, Denmark.Birth complications significantly interacted withmaternal rejection of the child in predicting violentoffending at age 18 years. Only 4% of the sample hadboth birth complications and maternal rejection, butthis small group accounted for 18% of all the violentcrimes committed by the entire sample.

This finding from Denmark has been replicated inseveral other studies. Piquero and Tibbetts (1999), ina prospective longitudinal study of 867 males andfemales from the Philadelphia Collaborative Perina-tal Project, found that those with both pre/perinataldisturbances and a disadvantaged familial environ-ment were much more likely to become adult violentoffenders. Pregnancy complications interacted withpoor parenting in predicting adult violence in a largeSwedish sample (Hodgins, Kratzer, & McNeil, 2001).Similarly, perinatal risk interacted with being anonly child in raising the odds of adult violent off-ending by a factor of 4.4 in a sample of 5,587 Fin-nish males (Kemppainen, Jokelainen, Jaervelin,Isohanni, & Raesaenen, 2001). On the other hand,

no interaction between perinatal insult and familyadversity was found for a smaller sample of Germanchildren (N ¼ 322) where outcome was restricted tofollow-up at age 8 years (Laucht et al., 2000).

The Copenhagen sample of 4,269 was reassessedfor violence outcome at age 34 years (Raine, Bren-nan, & Mednick, 1997). The results indicate that thebiosocial interaction previously observed holds forviolent but not non-violent criminal offending. Fur-thermore, the interaction was found to be specific tomore serious forms of violence and not threats ofviolence. The interaction held for early onset but notlate onset violence, and was not accounted for bypsychiatric illness in the mothers. Rearing in apublic care institution in the first year of life andattempt to abort the fetus were the key aspects ofmaternal rejection found to interact with birth com-plications in predisposing to violence. In a more de-tailed assessment of a random 10% of this sample,those with both early neuromotor deficits (includingbirth complications) and unstable family environ-ments had higher rates of teenage behavior problemsand adult criminal and violent offending compared tothose with only social or biological risk factors(Raine, Brennan, Mednick, & Mednick, 1996). Thebiosocial group with both sets of risk factors ac-counted for 70.2% of all violence committed by theentire cohort.

Birth complications such as anoxia (lack of oxy-gen), forceps delivery, and pre-eclampsia (hyperten-sion leading to anoxia) are thought to contribute tobrain damage, and they may be just one of a numberof early sources of brain dysfunction observed inchild and adult antisocial groups. On the otherhand, as indicated above, birth complications maynot by themselves predispose to crime, but insteadmay require the presence of negative environmentalcircumstance to trigger later adult crime and viol-ence. Furthermore, while they are likely to contrib-ute to prefrontal damage, their effects would not bespecific to this brain area but would impact onmultiple brain sites, including the hippocampus.

Minor physical anomalies

Minor physical anomalies (MPAs) have been associ-ated with disorders of pregnancy and are thought tobe a marker for fetal neural maldevelopment towardsthe end of the first three months of pregnancy. Assuch, they may be viewed as an indirect marker ofabnormal brain development. MPAs are relativelyminor physical abnormalities consisting of suchfeatures as low-seated ears, adherent ear lobes, anda furrowed tongue. While MPAs may have a geneticbasis, they may also be caused by environmentalfactors acting on the fetus such as anoxia, bleeding,and infection (Guy, Majorski, Wallace, & Guy, 1983).

Minor physical anomalies have also been found tocharacterize pre-adult antisocial behavior and tem-perament. Paulus and Martin (1986) found more


MPAs in aggressive and impulsive pre-school boys,while Halverston and Victor (1976) also found higherlevels of MPAs in boys showing problem behaviors inelementary school. MPAs have even been linked topeer aggression as early as age 3 years (Waldrop,Bell, McLaughlin, & Halverson, 1978). AlthoughMPAs have generally characterized behavior disor-ders in children drawn from the normal population(see Pomeroy, Sprafkin, & Gadow, 1988 for a review),at least one study failed to observe a link betweenMPAs and conduct disorder within a mixed group ofemotionally disturbed children (Pomeroy et al.,1988).

Mednick and Kandel (1988) studied MPAs, as-sessed by an experienced pediatrician, in a sample of129 12-year-old boys. MPAs were found to be relatedto violent offending as assessed nine years laterwhen subjects were aged 21 years, though not toproperty offenses without violence. However, whensubjects were divided into those from unstable, non-intact homes versus those from stable homes, abiosocial interaction was observed. MPAs only pre-dicted violence in those individuals raised in un-stable home environments. Similarly, Brennan,Mednick, and Raine (1997), in a study of 72 maleoffspring of psychiatrically ill parents, found thatthose with both MPAs and family adversity had es-pecially high rates of adult violent offending. Thisinteraction was confirmed by Pine, Shaffer, Schon-feld, and Davies (1997) who found that MPAs in7-year-olds combined with environmental risk inpredisposing to conduct disorder at age 17. Thesefindings are similar to those on birth complicationsreported above: thus the presence of a negativepsychosocial factor is required to ‘trigger’ the biolo-gical risk factor, and in both cases the effects arespecific to violent offending. In a study confirmingspecificity of MPAs to violence, Arseneault, Tremb-lay, Boulerice, Seguin, and Saucier (2000) found thatMPAs assessed at age 14 predicted violent delin-quency at age 17 in 170 males, but not to nonviolentdelinquency. In this study, effects were independentof family adversity.

Nicotine during pregnancy

The effect of fetal exposure to alcohol in increasingrisk for conduct disorders is well known (e.g., Fast,Conry, & Loock, 1999; Olsen et al., 1997; Streiss-guth et al., 1999), but recently a spate of studies hasestablished beyond reasonable doubt a significantlink between smoking during pregnancy and laterconduct disorder and violent offending. A number ofthese studies are impressive in terms of their size,the prospective nature of data collection, long-termoutcome, and control for third factors. Rantakallio,Laara, Isohanni, and Moilanen (1992) found that theoffspring of mothers who smoked were twice as likelyto have a criminal record by age 22 in a sample of5,966. Brennan, Grekin, and Mednick (1999), using

a birth cohort of 4,169 males, found a twofold in-crease in adult violent offending in the offspring ofmothers who smoked 20 cigarettes a day. Rasanen etal. (1999) again found a twofold increase of violentcriminal offending in the offspring of women whosmoked during pregnancy. Weissman, Warner,Wickramaratne, and Kandel (1999) found a fourfoldincrease in conduct disorder in boys of mothers whosmoked 10 cigarettes a day during pregnancy, whileWakschlag et al. (1997) found more than a fourfoldincrease in conduct disorder in the offspring ofmothers who smoked 10 cigarettes a day. Fergusson,Woodward, and Horwood (1998) also found a doub-ling of risk for conduct disorder in the offspring ofmaternal smokers, while Day, Richardson, Golds-chmidt, and Cornelius (2000) found an increase of6 points in behavior problems in three-year-oldsexposed to smoking during the third trimester.

Importantly, a number of the above studies havecontrolled for many third factors that could accountfor the smoking–antisocial relationship. Low SES,low maternal education level, mother’s age at birth,family size, poor childrearing behaviors, bad par-enting, obstetric complications, birth weight, familyproblems, parental psychiatric diagnoses, offspringsmoking, and other drug use during pregnancy werecontrolled for in one or more of the above studies.One important third factor, criminality and anti-social personality in the parents, was controlled forin the studies of Brennan et al. (1999), Weissman etal. (1999), and Wakschlag et al. (1997), althoughHill, Lowers, Locke-Wellman, and Shen (2000) foundno relation between maternal smoking and conductdisorder after controlling for parental antisocialpersonality disorder. Taken together with the dose–response relationship also established in several ofthe studies, these findings suggest (but do not prove)a causal relationship between smoking duringpregnancy and later antisocial and violent behavior.

Some interaction effects were observed betweensmoking and other factors. For example, Brennanet al. (1999) found a much stronger link betweensmoking during pregnancy and adult violent off-ending in those who had suffered delivery compli-cations – there was no such link in those lackingdelivery complications. Rasanen et al. (1999) simi-larly found interaction effects between birth compli-cations and teenage pregnancy, single-parent family,unwanted pregnancy, and developmental motorlags. Combined with other interaction effects forbirth complications and MPAs noted above, theseinteraction effects for nicotine support a biosocialinteraction conceptual framework for understandingbiology–antisocial relationships (Raine et al., 1997b)and underline the need to test for interaction effectsin future studies.

Maternal smoking during pregnancy may be animportant contributory factor to the brain deficitsthat have been found in adult offenders. Animalresearch has clearly demonstrated the neurotoxic

426 Adrian Raine

effects of two constituents of cigarette smoke – carb-on monoxide (CO) and nicotine (see Olds, 1997 for adetailed review). Prenatal nicotine exposure, even atrelatively low levels, disrupts the development of thenoradrenergic neurotransmitter system (Levin,Wilkerson Jones, Christopher, & Briggs, 1996), andinterferes with neuronal development in the cere-bellum which in turn is implicated in cognitivefunctioning. Similarly, CO has been found to damagethe basal ganglia, cerebral cortex, and cerebellarcortex, as well as decrease levels of norepinephrine.

These effects of smoking exposure on noradren-ergic neurotransmitter functioning may be of par-ticular significance in the context of autonomicdeficits in antisocial individuals outlined earlier.Reduction of noradrenergic functioning caused bysmoking would be expected to disrupt sympatheticnervous system activity, consistent with evidenceoutlined earlier for reduced sympathetic arousal inantisocial individuals (Raine, 1996). Furthermore,when pregnant rats are exposed to nicotine at thelevels found in human smokers, the offspring showan enhancement of cardiac M2-muscarinic cholin-ergic receptors, receptors that inhibit autonomicfunctions (Slotkin, Epps, Stenger, Sawyer, & Seidler,1999). This would help explain the well-replicatedfinding of low resting heart rate in antisocial indi-viduals outlined above (Raine, 1993). Further evi-dence supporting this perspective is the finding thatbeta-adrenergic agonists that increase cognitiveperformance in normal rats fail to have such effectson nicotine-exposed rats (Levin, Briggs, Christopher,& Rose, 1993), again indicating disruption of thisneurotransmitter system that regulates both auto-nomic and cognitive functions.

Nutrition

Although deficiency in nutrition itself has been rarelystudied in relation to childhood aggression, severalstudies have demonstrated the effects of relatedprocesses, including food additives, hypoglycemia,and more recently cholesterol, on human behavior(Rutter et al., 1998; Raine, 1993; Fishbein & Pease,1994). In addition, some studies have shown asso-ciations between over-aggressive behavior and vita-min and mineral deficiency (Breakey, 1997;Wereback, 1995). Furthermore, one study (Rosen,1996) claimed that nearly a third of a population ofjuvenile delinquents (mostly males) showed evidenceof iron deficiency. Nevertheless, these findings re-main both conflicting and controversial (Rutter et al.,1998).

One intriguing and important study illustrates thepotentially causal role of malnutrition as early aspregnancy in predisposing to antisocial behavior.Towards the end of World War II when Germany waswithdrawing from Holland, they placed a foodblockade on the country that led to major foodshortages and near-starvation in the cities and

towns for several months. Women who were preg-nant at this time were exposed to severe malnutritionat different stages of pregnancy. The male offspringof these women were followed up into adulthood toascertain rates of antisocial personality disorder,and were compared to controls who were not ex-posed to malnutrition. The adult offspring of preg-nant women who suffered significant nutritionaldeficits during the first and/or second (but not third)trimester of pregnancy had 2.5 times the rates ofantisocial personality disorder compared to controls(Neugebauer, Hoek, & Susser, 1999).

There is also initial evidence for relationships be-tween zinc and protein deficiency and aggression inanimals (Tikal, Benesova, & Frankova, 1976; Halas,Reynolds, & Sandstead, 1977). There is extensiveexperimental evidence in animals that the offspringof rats fed a diet containing marginal levels of eitherzinc or protein throughout pregnancy and lactationshowed impaired brain development (Oteiza, Hurley,Lonnerdal, & Keen, 1990; Bennis-Taleb, Remacle,Hoet, & Reusens, 1999). In humans, zinc deficiencyin pregnancy has been linked to impaired DNA, RNA,and protein synthesis during brain development,and to congenital brain abnormalities (Pfeiffer &Braverman, 1982; King, 2000). The amygdala, whichalso shows abnormal functioning in PET imaging ofviolent offenders (Raine, Buchsbaum, & LaCasse,1997c; Raine et al., 1998b; Davidson et al., 2000) isdensely innervated by zinc-containing neurons(Christensen & Frederickson, 1998), and males witha history of assaultive behavior have been found tohave lower zinc relative to copper ratios in their bloodcompared to non-assaultive controls (Walsh, Isaac-son, Rehman, & Hall, 1997). While prenatal zincsupplementation trials have failed to documentconsistent effects, initial data suggest a beneficialeffect of prenatal zinc supplementation on infants’neurobehavioural development (Shah & Sachdev,2001). Furthermore, smoking during pregnancy,which is also associated with violence in the off-spring, can impair the transportation of zinc fromthe mother to her fetus (King, 2000).

Protein provides essential amino acids for the ra-pid growth of fetal tissue, and protein deficiency hasbeen recently linked to antisocial behavior problems.For example, malnutrition at age 3 years (includingprotein deficiency) has recently been associated withincreased externalizing behavior problems at ages 8,11 and 17 years (Liu, Raine, Venables, Dalais, &Mednick, 2002). Furthermore, positron emissiontomography (PET) studies of violent offenders haverevealed deficits to the prefrontal cortex and corpuscallosum (Raine et al., 1997c; Volkow et al., 1995).Of interest, too, is the finding that the offspring ofrats fed a low-protein diet during pregnancy show aspecific impairment to the corpus callosum (Wain-wright & Stefanescu, 1983) and reduction in DNAconcentration in the forebrain (Bennis-Taleb et al.,1999). Consequently, protein and zinc deficiency


may both contribute to the brain impairments shownin violence offenders, which in turn are thought topredispose to violence, although the empirical basisfor such a conclusion requires further substanti-ation from future studies.

Future research and intervention implications

Despite the progress that has been made in recentyears in identifying biological risk factors for anti-social and aggressive behavior, there are still majorlacunae in this knowledge base. Which of these riskfactors are specific to aggression and violence, andwhich reflect a more general predisposition to anti-social behavior? Are there specific biological corre-lates of reactive versus proactive aggression,life-course persistent versus adolescent limitedantisocial behavior, and hyperactive versus non-hyperactive subgroups of antisocial children? Whatbiological factors protect against the development ofantisocial and aggressive behavior? Are biologicalrisk factors for antisocial behavior in childrenattributable to genetic or environmental processes?These are just some of the central questions thatneed urgent attention in future studies. For example,it has been suggested that affective, impulsiveaggression may be more clearly linked to frontalimpairments (Ishikawa & Raine, 2001), but conclu-sive statements cannot be drawn due to the lack ofsufficient empirical data.

These issues notwithstanding, what interventionimplications if any can be drawn from risk researchon autonomic arousal, prefrontal dysfunction, andearly health factors? First and foremost, the trans-lation of knowledge from risk research to preventresearch must be undertaken with prudence anddue circumspection. At the same time, it is also im-portant to ask how prevention and intervention re-search can be informed by knowledge of autonomicunderarousal, prefrontal deficits, and early healthrisk factors for antisocial behavior.

With respect to the physiological underarousal–antisocial link, if low arousal causes antisocial be-havior, increasing arousal may help reduce anti-social behavior. As outlined earlier, methylphenidateboth increases arousal and reduces conduct disor-der (Klein et al., 1997; Wachtel and de Wit, 1999). Analternative to drug therapy may be environmentalmanipulations. For example, there is initial evidencethat positive environmental manipulations are cap-able of producing long-term shifts in arousal andpsychophysiological information processing. In astudy in which children were randomly assigned toexperimental and control conditions and matched onearly psychophysiological functioning, a nutritional,physical exercise, and educational enrichment pro-gram from ages 3–5 years resulted in increasedpsychophysiological arousal and orienting at age 11years (Raine et al., 2001b). There have been some

initial reports of the possible efficacy of usingbiofeedback to increase physiological arousal inhyperactive children (Lubar, 1989), and it is con-ceivable that biofeedback training as part of a largermulti-modal treatment package could help to reduceantisocial and violent behavior in adolescents. Nev-ertheless, rigorous experimental studies on theefficacy of biofeedback on antisocial behavior arecurrently lacking and are needed before clinicalapplication is justified.

Findings that prefrontal brain deficits predisposeto antisocial and aggressive behavior suggest thatinterventions that tackle the source of brain deficitsmay be successful in reducing antisocial andaggressive behavior. One of the most promisingapproaches to reducing the impact of brain deficitslies in early health interventions (Liu & Raine, 1999).If factors such as smoking and malnutrition duringpregnancy cause antisocial behavior, then interven-tions aimed at reducing these should help reduceantisocial behavior. In this context, Olds et al.(1998), in a methodologically strong randomizedcontrolled trial, showed that an average of ninenurse home visitations during pregnancy, whichimproved the quality of pregnant mothers’ prenataldiet and reduced fetal exposure to smoking, alsoreduced offspring criminal and antisocial behavior15 years later. Similarly, Lally, Mangione, and Honig(1988) showed that advice to pregnant women ongood nutrition, health, and child-rearing lead to areduction in juvenile delinquency at age 15 years.These studies provide more support to the notionthat poor nutrition and smoking play a causal role inthe development of childhood aggression and thatearly attempts to reduce these risk factors can besuccessful in reducing antisocial behavior. In addi-tion, because birth complications have been linkedto adult violence, it is possible that providing betterantenatal and perinatal health care to poor mothersmay help reduce birth complications, and thusreduce violence. Stress management during preg-nancy could reduce pregnancy-induced hyperten-sion and hypoxia to the fetus. Breast-feeding duringthe postnatal period has also been shown to increasecognitive functioning in childhood, and this tooneeds to be further encouraged.

In addition to these prevention efforts, interventionprograms to reduce existing levels of antisocialbehavior may be more successful if they incorporatestrategies that tackle brain deficits. Safety educationprograms and programs that tackle physical abusemay be expected to reduce rates of head trauma (andthus brain dysfunction) in children. Cognitiveremediation programs that target executive func-tions may conceivably help to reduce antisocial andaggressive behavior in the subgroup of conduct dis-ordered children with prefrontal deficits.

In conclusion, biological factors clearly contributeto childhood antisocial and aggressive behavior. In-terventions to reduce such behavior in children are

428 Adrian Raine

likely to be maximally effective if they incorporatecomponents aimed at tackling the biological basis toantisocial behavior. At this point in time, evidencesuggests that early health intervention and preven-tion studies may provide the most effective way ofreversing biological deficits that predispose to anti-social and aggressive behavior in both children andadults.

Acknowledgments

This review was written with support from an Inde-pendent Scientist Award from NIMH (K02 MH01114-01).

Correspondence to

Adrian Raine, Department of Psychology, Universityof Southern California, Los Angeles, CA 90089-1061,USA; Email: [email protected]

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Manuscript accepted 7 January 2002

434 Adrian Raine

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