Short fused? associations between white matter connections, sex steroids, and aggression across adolescence

INTRODUCTION

Extreme forms of aggression pose a threat to both individuals and society. Higher than normal levels of aggression have been linked to psychopathological conditions including conduct disorder, oppositional defiant disorder and antisocial personality disorder [Matthys et al., 2013]. Studying the underlying etiology of individual differences in aggression is, therefore, of critical importance for understanding this often destructive behavior.

Aggression can be defined as overt behavior to deliberately inflict harm to others, objects or one‐self [Anderson and Bushman 2002]. Aggression comes in different forms and includes “inhibited” aggression (e.g., hostility), aggressive emotions (e.g., anger), and “disinhibited” aggressive behavior (e.g., physical and verbal aggression [Anderson and Bushman, 2002]. Even though aggressive behavior is complex and involves an intricate interplay between the individual and environment, social scientific research has shown that aggressive behavior is often associated with low impulse control, anger, and decreased capacity of regulating emotions [Anderson and Bushman, 2002; Dodge, 2006].

Neuroimaging studies in adults have shown that aggressive tendencies involve an imbalance between heightened reactivity in motor and subcortical areas dedicated to motivation [Hermans et al., 2008; Pawliczek et al., 2013], paralleled by relative low regulatory capacities of the prefrontal brain areas (for review see [Coccaro et al., 2011]). This imbalance may point to suboptimal brain communication between cortical and subcortical brain areas that could represent a neural predisposition for aggressive behavior (e.g., [Hofman and Schutter, 2012; Schutter and Harmon‐Jones, 2013]. Indeed, abnormalities in white matter integrity within subcortico‐frontal and fronto‐temporal connections were reported in adolescents with conduct disorder [Haney‐Caron et al., 2014; Sarkar et al., 2013], as well as in adult psychopathic offenders [Hoppenbrouwers et al., 2013]. Interestingly, the integrity of white matter pathways between cortical and subcortical brain areas increases from childhood into adolescence [Brouwer et al., 2012; Ladouceur et al., 2012; Lebel and Beaulieu, 2011; Simmonds et al., 2013]. The increase in subcortico‐cortical white matter quality has been proposed as a possible mechanism by which cognitive control over motivational tendencies grows during this transition period [Peper et al., 2013a]. As a result of the increase in quality of the white matter tracts between subcortical, frontal, and temporal brain regions, it is not unreasonable to assume that aggressive tendencies will decrease with age.

In addition, there is now evidence showing that the sharp rise in the sex steroid hormones testosterone and estradiol may account for changes in brain development and aggression during adolescence (for reviews see [Blakemore et al., 2010; Peper and Dahl, 2013]).

Relatively early pubertal development and enhanced testosterone and estradiol levels, compared to same aged peers, have been associated with decreased behavioral control [de Water et al., 2013; Hemphill et al., 2010] and lowered brain connectivity [Klapwijk et al., 2013; Peper et al., 2013a]. It can therefore be argued that if sex steroids influence white matter connectivity, then increased sex steroid production during puberty may result in decreases in structural connectivity and increase aggressive tendencies.

In this study, we examined the association between sex steroids, aggressive traits, and white matter connections between frontal, temporal, and subcortical brain areas in a large normative group of participants between 8 and 25 years. We hypothesized that with age increasing white matter integrity of frontal‐temporal‐subcortical connections is associated with decreases in aggressive tendencies. We further anticipated that higher endogenous levels of sex steroid hormones suppresses this effect, in such a way that higher levels of sex steroids decrease white matter integrity in the frontal‐temporal‐subcortical network and contributes to aggression.

MATERIALS AND METHODS

RESULTS

DISCUSSION

In a community‐based sample of 258 participants between 8 and 25 years, we examined the associations between sex steroid hormone effects on aggression and white matter connections within a fronto‐temporal‐subcortical network. We hypothesized that with age, white matter integrity within subcortico‐frontal‐temporal connections would increase paralleled by a decrease in aggressive traits. Moreover, we expected that a higher sex steroid level suppresses this effect, in such a way that higher levels of sex steroids would relate to lower white matter integrity and increase aggression.

In line with our expectations, we replicated earlier findings of increased white matter integrity with chronological age [Asato et al., 2010; Lebel and Beaulieu 2011; Lebel et al., 2012; Simmonds et al., 2013]. Moreover, above and beyond age‐related effects on white matter, our results indicate that a higher testosterone level relates to lower white matter integrity within a subcortico‐frontal‐temporal network (i.e., lower FA in girls and higher MD in boys and girls). These results fit with earlier neuroimaging studies in adults, reporting less functional and structural connectivity between frontal and subcortical brain areas with higher levels of testosterone [Peper et al., 2013a; van Wingen et al., 2010; Volman et al., 2011]. Indeed, our data suggest that adolescent increases in testosterone in girls and—to a lesser extent—in boys is associated with decreased structural connectivity between subcortical and frontal and temporal brain areas. It should nevertheless be noted, that the associations between testosterone and DTI‐metrics did not survive correction for multiple comparisons. Therefore, the interpretation of these data should be with caution and warrants replication. Estradiol levels were not related to white matter integrity.

We also hypothesized that increased sex steroid hormone production—as opposed to general age effects—would relate to increased aggression. Indeed, age‐related decreases in aggression were demonstrated, but in girls only. In boys, aggressive traits did not change with age but were associated both with testosterone and to a larger extent to estradiol levels. That is, higher levels of testosterone in boys were related to higher disinhibited (physical) aggression. The association between testosterone and physical aggression in the current sample of normally developing boys is comparable to earlier studies carried out in clinical [Barzman et al., 2013; Popma et al., 2007; Scerbo and Kolko 1994; van Bokhoven et al., 2006] and healthy [Vermeersch et al., 2008a] adolescent samples. The association between estradiol and aggressive traits is less well established. Recently however, rapid effects of estradiol on aggressive behavior in rodents have been described [Laredo et al., 2014]. This study provides the first evidence for possible contributions of endogenous estradiol levels and aggressive traits in boys. However, our data do not suggest that this association is established through estradiol acting on the white matter connections we examined.

Surprisingly, in girls, higher testosterone was related to lower hostility. It should be noted that hostility is characterized by a cynical attitude, feelings of resentment, and mistrust of others [Miller et al., 1996] and has been associated with higher levels of social anxiety and depression [Asberg, 2013; Weiss et al., 2005]. Interestingly, our finding of higher endogenous testosterone relating to lower hostility adds evidence to the idea that testosterone has anxiolytic properties [van Honk et al., 2005]. Opposed to boys, estradiol was not associated with aggression in girls. To our knowledge, only one study has investigated the relation between female estradiol levels and aggressive behavior and found that a positive association, but only in the luteal phase of the menstrual cycle (i.e., around Day 14) [Vermeersch et al., 2008b]. In our study, postmenarcheal females were examined during the early follicular phase (i.e., Day 7), which could provide an explanation for the absence of an association between estradiol and aggressive behavior.

Interestingly, in adults [Pawliczek et al., 2013] and in extreme [Coccaro et al., 2011] forms of aggression have been associated with enhanced subcortical brain activity and reduced regulatory control by (pre)frontal and temporal brain areas. When directly relating white matter connectivity with aggression, we now for the first time provide evidence that in healthy children and adolescents the integrity of white matter connections between these brain areas is associated with aggressive tendencies. In particular, decreased connectivity relates to higher explicit' verbal aggression, while increased connectivity relates to higher “implicit” aggression (i.e., hostile thoughts). Thus, it can be speculated that although aggressive thoughts and feelings are subcortically generated [Davidson et al., 2000], the tendency to act on these thoughts and feelings (i.e., aggressive behavior) or to control these aggressive tendencies is partially regulated by white matter tracts between subcortico‐frontal and temporal connections. Although we found that verbal aggression was associated with lower structural connectivity, this association was neither age nor hormonally related, and may reflect a more stable trait across adolescence. In contrast, higher levels of hostility were linked to increased structural white matter connectivity and lower levels of testosterone, suggesting that implicit forms aggression are (partly) regulated at a hormonal and neuronal level. We could, however, not distinguish between LD and RD effects, as both measures seemed to contribute equally to the effects in MD. We, therefore, argue that the combination of all axonal properties (i.e., axonal diameter, myelination and axonal coherence) most likely seems to play a role in the decreased “integrity” of subcortico‐frontal‐temporal white matter, subsequently relating to aggressive traits. Although prior research has provided evidence for hemispheric asymmetries in aggressive tendencies [Hofman and Schutter, 2012], the present findings did not show intracortical differences in white matter connectivity between the left and right hemisphere. A possible explanation is that aggression may be better explained by interhemispheric connectivity rather than local intrahemispheric differences in white matter connectivity [Schutter and Harmon‐Jones, 2013].

Finally, it must be pointed out that the selected white matter pathways are not predefined tracts by white matter atlases. We preferred to select all anatomical connections between our regions of interest not to exclude relatively small white matter bundles that are not predefined by white matter atlases. It is highly likely however, that subcortico‐frontal tracts partly overlap with the uncinate fasciculus which is in agreement with the notion that the integrity of the UF is implicated in conduct disorder [Sarkar et al., 2013] and antisocial personality disorder [Haney‐Caron et al., 2014].

CONCLUSION

Our study suggests that the “integrity” of white matter connections within fronto‐temporal‐subcortical brain areas increases with age, but higher levels of testosterone might‐partially‐suppress this process by decreasing the integrity of connections. Lower white matter integrity within this network is subsequently associated with more disinhibited aggressive behavior, but with less inhibited aggression. Thus, distinct subtypes of aggression seem to be driven by different neural correlates. Our data add evidence to the general idea that aggressive tendencies are subcortically driven, but individuals with relatively high testosterone have lower structural connectivity within cortical control areas, resulting in a stronger tendency to act on these aggressive tendencies, as opposed to individuals who seem to be less short fused and more capable of regulating aggressive impulses.

Supporting information