 8. The Neurobiology of Personality  201
cism is negatively related to global measures 
of brain volume (Bjørnebekk et al., 2013; 
Jackson, Balota, & Head, 2011; Knutson, 
Momenan, Rawlings, Fong, & Hommer, 
2001; Liu et al., 2013).
Various cortical regions regulate the sub -
cortical defensive systems we described ear -
lier, and several of these have been linked 
to neuroticism. One of these is the insula, 
or insular cortex, a part of the frontal lobe 
hidden behind the temporal lobe. The insula 
acts as a hub integrating interoceptive, emo -
tional, and cognitive information (Chang, 
Yarkoni, Khaw, & Sanfey, 2012). Neuroti -
cism has been found to predict greater blood 
flow to the insula at rest (Kaczkurkin et al., 
2016), and also insular activity in anticipa -
tion of losing $5 (Wu et al., 2014).
Another cortical region linked to neu -
roticism and emotion regulation is in me -
dial prefrontal cortex (mPFC) and adjacent 
ACC (Etkin, Egner, & Kalisch, 2011). The 
study with over 1,000 participants we cited 
earlier reported that neuroticism was associ -
ated with lower cortical thickness in this re -
gion (Holmes et al., 2012). Smaller studies, 
yet still with hundreds of participants, have 
produced mixed results for this region (Bjør -
nebekk et al., 2012; Riccelli et al., 2017), but 
this is exactly what one should expect if the 
effect size ( r = .1) estimated by Holmes et al. 
(2012) is accurate. Other studies have found 
that neuroticism is associated with both 
structural and functional connectivity be -
tween mPFC and amygdala (Cremers et al., 
2010; Davey et al., 2015; Jalbrzikowski et 
al., 2017). The ability of this region of cor -
tex to influence the amygdala may be crucial 
for the regulation of negative affect.
A third region of the PFC linked to neu -
roticism is the dorsolateral prefrontal cor -
tex (dlPFC), which appears to play a role in 
top-down regulation of negative affect in 
response to cues of potential threat. Under 
conditions of uncertain threat, lower levels 
of dlPFC–  amygdala functional connectivity 
have been associated with higher neuroti -
cism in children and anxious temperament 
in rhesus monkeys (Birn et al., 2014), sug -
gesting that the influence of this circuit on 
neuroticism is evolutionarily conserved. 
A large study of brain-  damaged patients 
showed that lesions to the dlPFC (as op -
posed to other regions) were associated with increased neuroticism, further supporting 
this region’s regulatory role (Forbes et al., 
2014).
All of the systems implicated in neu -
roticism are modulated by serotonin, and 
recent fMRI studies show that potent se -
rotonin agonists, such as psilocybin and 
3,4-methylenedioxy- methamphetamine 
(MDMA) (which reduce or completely abol -
ish subjective ratings of anxiety and fear), 
attenuate amygdalar reactivity to negative 
stimuli during the period of acute drug ef -
fects (Bedi, Phan, Angstadt, & De Wit, 
2009; Kraehenmann et al., 2015, 2016). 
Several lines of evidence implicate varia -
tion in serotonergic function in neuroti -
cism. Selective serotonin reuptake inhibitors 
(SSRIs), which increase serotonergic func -
tion by blocking its removal from synapses, 
are commonly used to treat anxiety and 
depression, and SSRI-  induced reductions in 
symptoms of these disorders are mediated 
by declines in neuroticism over the course of 
treatment (Du, Bakish, Ravindran, & Hrdi -
na, 2002; Quilty, Meusel, & Bagby, 2008; 
Tang et al., 2009). Further, a recent meta- 
analysis shows that neuroticism is the per -
sonality trait that changes most following 
SSRI treatment (Roberts et al., 2017). PET 
studies (albeit in small samples) have found 
neuroticism to be associated with variation 
in serotonin receptor or transporter binding 
(Frokjaer et al., 2008; Takano et al., 2007; 
Tauscher et al., 2001). One study using a 
pharmacological probe to assess partici -
pants’ typical level of serotonergic function 
revealed that it was negatively associated 
with a standard questionnaire measure of 
neuroticism (Flory, Manuck, Matthews, & 
Muldoon, 2004). Interestingly, this study 
also assessed mood daily for a week and 
found that lower serotonergic function 
was associated with the absence of positive 
mood from day to day rather than the pres -
ence of negative mood.
Despite these converging lines of evidence, 
the link between serotonin and neuroticism 
appears complex, and much uncertainty re -
mains. SSRIs are not effective in a substan -
tial percentage of depressive patients, and a 
week-long course of SSRIs has been dem -
onstrated to increase,  rather than decrease, 
neural reactivity to emotionally negative 
stimuli in people high in neuroticism (Di 