Neural mechanisms underlying sex differences in aggression could potentially explain sexual dimorphism in neuropsychiatric disorders and improve dysregulated aggressive behavior

Structural and functional biomarkers of the insula subregions predict sex differences in aggression subscales. Haixia Long,Ming Fan, Qiaojun Li, Xuhua Yang, Yujiao Huang, Xinli Xu, Ji Ma, Jie Xiao, Tianzi Jiang. Human Brain Mapping, March 15 2022. https://doi.org/10.1002/hbm.25826

Abstract: Aggression is a common and complex social behavior that is associated with violence and mental diseases. Although sex differences were observed in aggression, the neural mechanism for the effect of sex on aggression behaviors remains unclear, especially in specific subscales of aggression. In this study, we investigated the effects of sex on aggression subscales, gray matter volume (GMV), and functional connectivity (FC) of each insula subregion as well as the correlation of aggression subscales with GMV and FC. This study found that sex significantly influenced (a) physical aggression, anger, and hostility; (b) the GMV of all insula subregions; and (c) the FC of the dorsal agranular insula (dIa), dorsal dysgranular insula (dId), and ventral dysgranular and granular insula (vId_vIg). Additionally, mediation analysis revealed that the GMV of bilateral dIa mediates the association between sex and physical aggression, and left dId–left medial orbital superior frontal gyrus FC mediates the relationship between sex and anger. These findings revealed the neural mechanism underlying the sex differences in aggression subscales and the important role of the insula in aggression differences between males and females. This finding could potentially explain sexual dimorphism in neuropsychiatric disorders and improve dysregulated aggressive behavior.

4 DISCUSSION

This study mainly investigated the association between sex, structure, and function of the insula and aggression subscales. We identified significant effects of sex on physical aggression, anger and hostility. Sex also influenced the GMV and FC of insula subregions. Even more striking, the GMV of the left dIa and right dIa mediated the association between sex and physical aggression, and the left dId–left ORBsupmed FC mediated the association between sex and anger, which may reveal the underlying neural mechanism of sex differences in aggression subscales.

The observed significant effect of sex on the physical aggression is consistent with previous studies that showed males tended to take physical aggression action more than females (Archer, 2004; Gerevich et al., 2007; Harris & Knight-Bohnhoff, 1996; Kalmoe, 2015; Sadiq & Shafiq, 2020). Additionally, we also found sex difference in hostility, that is, males having higher hostility than females, which is in line with a previous finding that males showed more hostility than females in Spanish and Japanese samples (Ramirez et al., 2001). These findings indicated that physical aggression may be associated with hostility. In addition, the higher anger scores in females than in males were also similar to the results in Isanzu and Buryats (Butovskaya et al., 2020). Additionally, an fMRI experiment of facial expressions also showed higher anger recognition levels in females than in males (Dores, Barbosa, Queiros, Carvalho, & Griffiths, 2020), which indicates their emotional dysregulation.

The insula is a heterogeneous brain region and is involved in various functions, such as emotion, cognitive control, attention, memory, perception, motor, and conscious awareness (Craig, 2009; Kurth, Zilles, Fox, Laird, & Eickhoff, 2010; Menon & Uddin, 2010; Uddin, Kinnison, Pessoa, & Anderson, 2014). This study used the Human Brainnetome Atlas to divide the insula into six subregions, including a dorsal anterior insula, a ventral anterior insula, a central region, a more ventral region, and two posterior subregions (Fan et al., 2016). In brief, the dorsal anterior insula is associated with cognitive function, the ventral anterior insula is associated with social–emotional tasks, and the mid-posterior insula is related to interoception, perception, somatosensation, pain, and motor (Chang, Yarkoni, Khaw, & Sanfey, 2013; Kelly et al., 2012; Kurth, Eickhoff, et al., 2010; Kurth, Zilles, et al., 2010; Uddin, Nomi, Hebert-Seropian, Ghaziri, & Boucher, 2017). Previous studies found that males exhibited significantly larger volumes across many cortex regions, including the insula, than females (Oz et al., 2021; Wierenga et al., 2014), which indicated sex differences in cortical development. Other studies have shown that sex affected the volumes of insula subregions. A related study demonstrated that males with posttraumatic stress symptoms had a larger volume of ventral anterior insula than females with posttraumatic stress symptoms, but this difference was not significant in control subjects (Klabunde et al., 2017). Another study found the larger GMV of the posterior insula in females than in males (Lotze et al., 2019). The inconsistent results of previous studies may be associated with different contexts of subjects and different locations of the insula. Therefore, our study investigated more fine-grained insula subregions based on the Brainnetome atlas and found that males showed the larger GMV of each insula subregion than females, which was partly consistent with previous studies and revealed sex difference in brain maturation, with cortex volume decreasing more in females than males during puberty (Vijayakumar et al., 2016; Wierenga et al., 2014).

In addition, we also found the mediation of bilateral dIa GMV on the association between sex and physical aggression. The dIa belongs to the anterior insula and is related to cognitive tasks, decision making, and awareness (Craig, 2009; Deen, Pitskel, & Pelphrey, 2011). The anterior insula, which is involved in the salience network, is associated with social cognition and evaluation, and is sensitive to social saliency (Achterberg et al., 2016; Achterberg et al., 2018; Cacioppo et al., 2013). In addition, prior studies found that 19% of the variance in callous-unemotional traits was explained by the GMV of the anterior insula in males, and callous-unemotional traits were related to physical aggression (Raschle et al., 2018; Wright, Hill, Pickles, & Sharp, 2019). The fMRI studies also showed an association between anterior insula and reactive aggression and motor impulsivity (Chester et al., 2014; Dambacher et al., 2015; Werhahn et al., 2020). Therefore, compared with females, males received more social salience stimuli because of greater GMVs of bilateral dIa, which led to more physical aggression.

On the other hand, this study investigated the effect of sex on the FC of insula subregions. First, we found males showing greater FC between dIa and some prefrontal and parietal cortex, such as ORBinf, ORBsupmed, PCUN, and PUT, which was similar to previous studies (Hong et al., 2014; Sie et al., 2019). Additionally, there was significantly increased dId–MTG FC, dId–ORBinf FC and dId–ORBsupmed FC in males compared with females in our study, and the core affected regions are consistent with Dai et al.'s study (Dai et al., 2018). In addition, vId_vIg showed increased FC with ORBinf.R and decreased connectivity with Cbe9.L and CUN.R in males rather than in females, while a previous study found that women have greater FC between the posterior insula and cerebellum crus I (Sie et al., 2019), which was associated with autonomic regulation (Beissner, Meissner, Bar, & Napadow, 2013). Other studies considered the insula as a whole and found significant sex differences in FC between the insula and prefrontal cortex and sensorimotor cortex, where men showed increased FC in the insula than women (Jin et al., 2019). The effect of sex on FC mainly focuses on the relationship between the insula and brain regions in the default mode network (DMN) (Buckner, Andrews-Hanna, & Schacter, 2008; Liu et al., 2010; Smith et al., 2009). Overall, compared with females, males demonstrated a stronger modulation of insula subregions in the DMN, while the modulation of vId_vIg on Cbe9 and CUN was weaker in males than in females for the compensation mechanism.

Moreover, correlation analysis and mediation analysis revealed the important role of left dId–left ORBsupmed FC in mediating the relationship between sex and anger. The dId belongs to the middle insula and is related to interoception, sensory perception, and somatosensation (Kelly et al., 2012; Kurth, Zilles, et al., 2010). The functional experiment showed that middle insula activity was associated with tolerance of anger expression (de Greck et al., 2012). Anger is a common experience during interpersonal communication, and some interpersonal conflict behaviors, such as unfair treatment and personal insults, may arouse anger (Averill, 1983; Baumeister, Stillwell, & Wotman, 1990; Gilam & Hendler, 2017). Moreover, anger is associated with emotion underregulation, and ORBsupmed is an important region of the emotion regulation network (Gilam & Hendler, 2017). Gilam et al.'s tDCS-fMRI study validated the role of the ventromedial prefrontal cortex (vmPFC) in anger regulation (Gilam et al., 2018). Another study demonstrated that mPFC activity was positively correlated with self-reported anger (Siep et al., 2019). Functional and effective connectivity analysis studies further illustrated that the FC of the mPFC and OFC was related to anger and proactive violence, and the effective connectivity among the insula, OFC and superior temporal gyrus was involved in anger processing (Eshel et al., 2021; Romero-Martinez et al., 2019; Seok & Cheong, 2019). It is interesting to note the mediation effect of FC between left dId and left ORBsupmed on the relationship between sex and anger. The negative correlation between left dId–left ORBsupmed FC and anger indicated that the greater FC the subjects had, the stronger emotional regulation they showed, leading to less anger. Therefore, males showed stronger emotion regulation and less anger than females.

There are several limitations in the present study. First, our study only included Chinese samples to avoid stratification artifacts. Previous studies have shown that cultural background may influence aggression behavior (Butovskaya et al., 2020; Hyde, 2014; Ramirez et al., 2001). Therefore, further studies in different populations are needed to clarify the effect of sex on aggression in different populations. Second, our study only investigated the effect of sex on aggression and related neural mechanisms. In fact, aggression is a very complex social behavior that is influenced by multiple factors, such as genetic or environmental factors. Thus, further studies are needed to assess the effects of other factors on aggression. Advanced studies using machine learning models are also needed to predict aggression based on images and behavior measures. Third, although the Brainnetome atlas has been validated to effectively define more fine-grained brain subregions and is consistent with other brain parcellation atlases (Fan et al., 2016), the impact of the potential interindividual variability of the insular subregions should also be investigated in further studies.