200 II. BIOLOGICAL  FOuNDATIONS
the term amygdala  to refer to the “extended 
amygdala,” which also includes the neigh -
boring bed nucleus of the stria terminalis, 
which appears to be particularly important 
for maintaining vigilance in response to pro -
longed or uncertain threat [Shackman et al., 
2016].)
A number of (fMRI studies in adults indi -
cate that neuroticism is positively associated 
with amygdala activation during a range 
of tasks involving threatening, uncertain, 
or ambiguous stimuli (Everaerd, Klumpers, 
Wingen, Tendolkar, & Fernández, 2015; 
Hyde, Gorka, Manuck, & Hariri, 2011; 
Schuyler et al., 2014; Somerville, Whalen, 
& Kelley, 2010). Other studies have not 
detected the link between amygdala activa -
tion and neuroticism (Servaas et al., 2013), 
and it is possible that the relation between 
amygdalar function and neuroticism is con -
tingent on other variables. For example, in 
one fMRI study, neuroticism was associated 
with an increase in amygdalar response to 
fearful faces, but only during an acute stress 
induction (Everaerd et al., 2015). This is con -
sistent with findings that individuals high in 
neuroticism are especially prone to negative 
affect under stressful conditions (Shackman 
et al., 2016). In another fMRI study, neu -
roticism was negatively associated with the 
rate of decline in amygdalar activation fol -
lowing presentation of an aversive stimulus, 
rather than with the initial level of amygda -
lar activation (Schuyler et al., 2014). Others 
have found that the relation is moderated by 
social support (Hyde et al., 2011), or is re -
stricted to a specific region of the amygdala 
(Somerville et al., 2010). Clearly, further 
research in large samples is necessary. One 
large study of youth ( N = 875) found that 
neuroticism was associated positively with 
cerebral blood flow in the amgydala while 
at rest (Kaczkurkin et al., 2016).
In structural MRI, several studies of 
adults indicate positive associations be -
tween neuroticism and amygdalar volume 
(Barrós-  Loscertales et al., 2006; Iidaka et 
al., 2006; Koelsch, Skouras, & Jentschke, 
2013), but others have indicated no associa -
tion (Cherbuin et al., 2008; De  Young et al., 
2010; Fuentes et al., 2012; Liu et al., 2013). 
Perhaps the most likely explanation of this 
inconsistency is that the true effect size is 
small, requiring very large samples to yield consistent findings. In a study of over 1,000 
people, neuroticism was weakly, but posi -
tively, correlated with the volume of both 
amygdala and hippocampus, r ≈ .1 (Holmes 
et al., 2012). To detect a correlation of .1 
with 80% power requires a sample of 783.
The hippocampus abuts and influences 
the amygdala and is particularly implicated 
in conflict detection and anxiety (Gray & 
McNaughton, 2000). In a meta-  analysis, 
neuroticism was positively associated 
with hippocampal activation during fear 
learning—  that is, learning to predict pun -
ishments from environmental cues (Servaas 
et al., 2013). Several PET studies have also 
found a link between resting-  state hippo -
campal activity and neuroticism (Gray & 
McNaughton, 2000; Sutin, Beason-  Held, 
Dotson, Resnick, & Costa, 2010). The link 
between the hippocampus and neuroticism 
was even supported by a PET study of 238 
rhesus monkeys, in which anxious tempera -
ment predicted metabolic activity in the hip -
pocampus (Oler et al., 2010). The greater 
hippocampal volume and activation asso -
ciated with neuroticism may increase the 
detection of uncertainty and potential goal 
conflicts (Gray & McNaughton, 2000).
One important target of amygdalar out -
put is the hypothalamus, which forms the 
top of the hypothalamic–  pituitary–  adrenal 
(HPA) axis that controls the body’s response 
to stress. The HPA response begins with the 
release of corticotropin-  releasing hormone 
(CRH) from the paraventricular nucleus of 
the hypothalamus and ends with the release 
of the stress hormone cortisol from the adre -
nal glands. In both adults and children, neu -
roticism is positively associated with cortisol 
levels (Garcia-  Banda et al., 2014; Gerritsen 
et al., 2009; G. Miller, Cohen, Rabin, Skon -
er, & Doyle, 1999; Nater, Hoppman, & 
Klumb, 2010; Polk, Cohen, Doyle, Skoner, 
& Kirschbaum, 2005; Schmidt, Fox, Rubin, 
Sternberg, & Gold, 1997; Tyrka et al., 2010; 
but see K. Miller et al., 2016, for a large 
study that found an association with extra -
version and not neuroticism). The chronic 
stress associated with neuroticism may be 
responsible for some of its more diffuse neu -
ral correlates, because an overabundance of 
cortisol potentiates excitotoxic cell death in 
neurons. In other words, stress can damage 
the brain. This may explain why neuroti -