A Systematic Review and Meta-Analysis of Magnetic Resonance Imaging Measurement of Structural Volumes in Posttraumatic Stress Disorder

Psychiatry Research: Neuroimaging 232 (2015) 1–33
Contents lists available at ScienceDirect
Psychiatry Research: Neuroimaging

journal homepage: www.elsevier.com/locate/psychresns
Review article
A systematic review and meta-analysis of magnetic resonance imaging

measurement of structural volumes in posttraumatic stress disorder
Daniel C.M. O'Doherty a,n, Kate M. Chitty a, Sonia Saddiqui b, Maxwell R. Bennett a,
Jim Lagopoulos a
a
Brain and Mind Research Institute, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia
b
Faculty of Human Sciences, Macquarie University, Sydney, Australia
art ic l e i nf o a b s t r a c t
Article history: Posttraumatic stress disorder (PTSD) is a debilitating condition associated with mild to moderate
Received 10 January 2014 cognitive impairment and with a prevalence rate of up to 22% in veterans. This systematic review and
Received in revised form quantitative meta-analysis explore volumetric differences of three key structural brain regions
15 November 2014
(hippocampus, amygdala and anterior cingulate cortex (ACC)), all of which have been implicated in
Accepted 8 January 2015
Available online 30 January 2015
dysfunction of both salience network (SN) and default mode network (DMN) in PTSD sufferers. A
literature search was conducted in Embase, Medline, PubMed and PsycINFO in May 2013. Fifty-nine
Keywords: volumetric analyses from 44 articles were examined and included (36 hippocampus, 14 amygdala and
MRI nine ACC) with n ¼ 846 PTSD participants, n ¼520 healthy controls (HCs) and n ¼624 traumatised
Posttraumatic stress disorder
controls (TCs). Nine statistical tests were performed for each of the three regions of interest (ROIs),
Hippocampus
measuring volume differences in PTSD subjects, healthy and traumatised controls. Hippocampal volume
Amygdala
Anterior cingulate cortex was reduced in subjects with PTSD, with a greater reduction in the left hippocampus. A medium effect
size reduction was found in bilateral amygdala volume when compared with findings in healthy
controls; however, no significant differences in amygdala volume between PTSD subjects and trauma-
exposed controls were found. Significant volume reductions were found bilaterally in the ACC. While
often well matched with their respective control groups, the samples of PTSD subjects composed from
the source studies used in the meta-analyses are limited in their homogeneity. The current findings of
reduced hippocampal volume in subjects with PTSD are consistent with the existing literature. Amygdala
volumes did not show significant reductions in PTSD subjects when compared with volumes in trauma-
exposed controls—congruous with reported symptoms of hypervigilance and increased propensity in
acquisition of conditioned fear memories—but a significant reduction was found in the combined left
and right hemisphere volume analysis when compared with healthy controls. Bilateral volume
reductions in the ACC may underpin the attentional deficits and inabilities to modulate emotions that
are characteristically associated with PTSD patients.
& 2015 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.1. Previous studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2. Hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.3. Amygdala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.4. Anterior cingulate cortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.5. Past meta-analyses: limitations and implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2. Method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
n
Corresponding author. Tel.: þ 61 2 93510714; fax: þ 61 2 93510652.
E-mail addresses: daniel.odoherty@sydney.edu.au (D.C.M. O'Doherty),
kate.chitty@sydney.edu.au (K.M. Chitty), sonia.saddiqui@mq.edu.au (S. Saddiqui),
maxwell.bennett@sydney.edu.au (M.R. Bennett),
jim.lagopoulos@sydney.edu.au (J. Lagopoulos).
http://dx.doi.org/10.1016/j.pscychresns.2015.01.002
0925-4927/& 2015 Elsevier Ireland Ltd. All rights reserved.
2 D.C.M. O'Doherty et al. / Psychiatry Research: Neuroimaging 232 (2015) 1–33
2.1. Characteristics of studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

2.2. Literature search and inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.3. Statistical tests used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.1. Hippocampus volume – study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.1.1. PTSD vs. healthy controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1.2. PTSD vs. traumatised controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1.3. PTSD vs. healthy controls þtraumatised controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.2. Amygdala volume – study characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4.1. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Appendix A. 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Appendix B. 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Appendix C. 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Appendix D. 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
1. Introduction dissociation and problems memory (Daniels et al., 2010; Lanius

et al., 2010). To our knowledge, this is the first meta-analysis that
Posttraumatic stress disorder (PTSD) is a debilitating condition explores volumetric differences in all three brain regions involved
characterised by flashbacks, hyperarousal, hypervigilance, emotional in both the SN and DMN with the current number of studies.
numbing, mood lability, insomnia and avoidance of potentially trigger-
ing situations (DSM-IV; American Psychiatric Association, 1994). PTSD 1.1. Previous studies
has also been associated with mild to moderate cognitive impairment,
most notably, reduced concentration and difficulties associated with The pathophysiology of PTSD is characterised by a heightened
learning and memory (Bremner et al., 1993; Yehuda et al., 1995; sensitivity to certain stimuli perceived to be threatening, followed by
Vasterling et al., 1998, 2002). In the general population, lifetime inability to extinguish the resulting fear (Garfinkel and Liberzon,
prevalence of PTSD across the Western world ranges from 1.9% to 2009). Elucidating the neurobiology and neurocircuitry of PTSD
6.8% ( Kessler et al., 2005; Australian Bureau of Statistics, 2007; constitutes an essential step in informing the detection and treatment
Wittchen et al., 2011). War veterans are typically more susceptible to of the disorder. To this end, significant efforts are focussed on
PTSD, with rates as high as 19–22% being reported in Vietnam, and determining why only a proportion of trauma-affected individuals
Iraq and Afghanistan war veterans (Dohrenwend et al., 2006; Seal et go on to develop PTSD symptoms. Early studies have hypothesised an
al., 2009). Among people who are not former combatants, PTSD may association between PTSD and atrophy in the hippocampus, amygdala,
develop following exposure to severe trauma (e.g., abuse during and the prefrontal cortex (Karl et al., 2006). The link between PTSD
childhood) and/or threat to life. Given its prevalence and the wide- and stress responses (Davis, 1992; McEwen, 1995; LeDoux, 2000) has
ranging negative effects on behaviour, mood and cognition, PTSD underscored the role of the amygdala and hippocampus, in particular,
represents a significant public health concern for the wider popula- although all three ROI are critical for normal fear extinction and the
tion, as well as highly susceptible groups such as returning combatants regulation of emotions (Chen et al., 2012). Studies conducted into
(Childress et al., 2013). amygdala and hippocampal atrophy in association with other psy-
The current meta-analysis seeks to expand on previous work chiatric disorders such as depression (Siegle et al., 2003; Campbell et
that has explored volumetric differences of brain regions known to al., 2004) and anxiety (Milham et al., 2005) have demonstrated
be associated with PTSD, by examining the following three key decreased volume. In relation to PTSD, attenuated recruitment of
areas implicated in PTSD: hippocampus, amygdala and anterior these structures (Vogt et al., 2003) and reduced volume have been
cingulate cortex (ACC). Previous meta-analyses have focused on reported, but findings from extant research have not been conclusive.
one or two of the brain regions examined here; however all three Numerous studies undertaken within the past decade have attem-
of these regions of interest (ROIs) have implicated in dysfunction pted to identify associations between specific brain regions linked to
of both the salience network (SN) and default mode network PTSD, with the aim of discovering if volumetric differences are present
(DMN) function in PTSD sufferers (Hughes and Shin, 2011; Sripada in people with PTSD. Functional magnetic resonance imaging (fMRI)
et al., 2012) and therefore warrant a combined investigation. The studies have identified increased activation of the hippocampus,
SN is involved in monitoring salient events and controlling amygdala and ACC in stress paradigms carried out on subjects with
behavioural responses (Seeley et al., 2007). Disruptions in the SN PTSD. All three ROIs are posited to play important roles in normal fear
have been shown to correlate with PTSD symptoms such as extinction and the regulation of memories (Herry and Garcia, 2002;
anxiety and problems with emotional processing during stressful Myers and Davis, 2007). As such, many studies have sought to test the
events (Patel et al., 2012). The DMN has been shown to be engaged association between the morphological characteristics of these ROIs
when an individual is performing inwardly focused or self- and the presence of PTSD.
referential tasks such as planning or memory recollection Some researchers speculate that hyper-response in the amygdala,
(Buckner et al., 2008). Abnormalities in the DMN associated with in relation to stimuli perceived to be threatening, is either exacerbated
the onset of PTSD have been linked to symptoms such as or the result of attenuated top-down inhibition by the pregenual ACC
D.C.M. O'Doherty et al. / Psychiatry Research: Neuroimaging 232 (2015) 1–33 3
and/or the hippocampus (Bremner et al., 1999; Liberzon et al., 1999; ors suggest that exposure to trauma may be associated with
De Bellis et al., 2000; Rauch et al., 2000, 2006). diminished hippocampal volume in both PTSD and non-PTSD
It remains that there has been significant variability across subjects, due to findings which show no difference in volume in
studies. Even among the research that focuses on a particular ROI, trauma-exposed PTSD sufferers and those without PTSD (Winter
the literature invariably consists of studies that use different and Irle, 2004). Other factors found to be related to the smaller
imaging modalities, different techniques for measurement, differ- hippocampal volumes were length of time since trauma (Villarreal
ent tools for diagnosing PTSD, and heterogeneous groups of et al., 2002) and severity of trauma (Gurvits et al., 1996; Bremner
subjects with different histories of trauma (Smith, 2005). Given et al., 1997; Winter and Irle, 2004).
this wide variation, meta-analysis represents a useful technique by Other studies have reported no significant volumetric differ-
which to provide clarity (Woon et al., 2010) and to measure and ences (Stein et al., 1997; De Bellis et al., 1999, 2002; Bonne et al.,
quantify the significance of volumetric differences (or lack thereof) 2001; Carrion et al., 2001; Schuff et al., 2001; Fennema-Notestine
reported across studies. To date, 11 meta-analyses have been et al., 2002; Pederson et al., 2004; Golier et al., 2005; Freeman
conducted to look into ROIs and their association with PTSD. et al., 2006; Jatzko et al., 2006; Yehuda et al., 2007). Interestingly,
Seven looked at hippocampal volume (Kitayama et al., 2005; the twin study by Gilbertson et al. (2002) reported reduced
Smith, 2005; Woon and Hedges, 2008, 2011; Hedges and Woon, hippocampal volumes in former combatants with severe PTSD
2010; Woon et al., 2010; Rodrigues et al., 2011), three looked at the compared with controls that had not been exposed to trauma, but
amygdala (de-Almeida et al., 2012; Woon and Hedges, 2008, also found no significant differences when this severe PTSD group
2009), while two studies investigated multiple structures of the was compared with former combatants who had less severe PTSD.
brain implicated in the development and maintenance of PTSD However, the study also found no significant difference in hippo-
(Karl et al., 2006; Kuhn and Gallinat, 2013). campal volume within identical twin pairs with and without PTSD,
lending credence to earlier studies reporting that smaller hippo-
1.2. Hippocampus campal volume may be a premorbid risk factor for the develop-
ment of PTSD.
The role played by the hippocampus in memory processing
(Squire et al., 2004; Brewin et al., 2007; Apfel et al., 2011) and the 1.3. Amygdala
regulation of the hypothalamic–pituitary–adrenocortical (HPA)
axis (Buchanan et al., 2004) makes this a key region in examining While the hippocampus has been the subject of major focus in
possible structural abnormalities associated with PTSD, given that determining if structural characteristics of brain anatomy are
memory impairment is a core feature of PTSD. associated with PTSD, fewer studies have examined the role of
Animal studies on rodents (McEwen et al., 1992; Sunanda et al., the amygdala and its relation to the disorder. Findings from fMRI
1995; Magarinos et al., 1996; Sapolsky, 1996; Gould et al., 1998; studies into amygdala activation in PTSD (Rauch et al., 2000;
McEwen, 2000b; Stewart et al., 2005) and primates (Sapolsky et al., Bremner, 2003; Hendler et al., 2003; Shin et al., 2004a, 2005;
1990) have suggested an association between stress and structural Lanius et al., 2006; Williams et al., 2006; Etkin and Wager, 2007;
changes observed in the hippocampus. Damage to the hippocampus is Morey et al., 2009) have provided theoretical support for further
postulated to occur as the result of prolonged, stress-related gluco- investigation into amygdala volumetric changes. The amygdala has
corticoid and glutamate neurotoxicity, or due to brain-derived neuro- been postulated to play a role in the pathophysiology of PTSD
trophic factor (BDNF) changes (Magarinos and McEwen, 1995; Smith (Bremner et al., 1997; Bonne et al., 2001; Wignall et al., 2004;
et al., 1995; Sapolsky, 2000; Moghaddam, 2002; Abrous et al., 2005; Pavlisa et al., 2006) since it is integral in the regulation of memory
Bennett and Lagopoulos, 2014), that eventually causes atrophy, cell of stressful and traumatic events, behaviour and emotion (Dolan,
death and inhibits neurogenesis (McEwen, 2000a; Sapolsky, 2000), 2007), and in fear conditioning and generalisation ( LaBar et al.,
with higher levels of stress hormone leading to greater levels of 1998; Pape and Pare, 2010; Dunsmoor et al., 2011). Successful
neurotoxicity. learned fear extinction is dependent upon N-methyl-d-aspartate
In human studies, it remains inconclusive whether hippocampal (NMDA) receptors in the amygdala. Lower levels of NMDA thus
volume loss occurs as a result of PTSD (Bremner, 1999) or whether impair the function of the amygdala in extinguishing fear (Myers
premorbid hippocampal volume loss merely places an individual at a and Davis, 2007). The outcome of animal stress models and human
higher risk of developing PTSD (Gilbertson et al., 2002). studies into neuronal architecture in the amygdala has provided
Since Bremner's 1995 finding of decreased hippocampal further support for the amygdala's association with PTSD. Animal
volume in PTSD in veterans as compared with controls, numerous models involving fear conditioning have demonstrated volumetric
other studies have produced similar results (Gurvits et al., 1996; changes in the basolateral complex of the amygdala (BLA) (Yang
Bremner et al., 1997, 2003; Villarreal et al., 2002; Hedges et al., et al., 2008), increased arborisation, and the growth of dendritic
2003; Lindauer et al., 2004; Shin et al., 2004b; Vythilingam et al., spines in the extended amygdala (Vyas et al., 2002, 2003, 2004;
2005; Emdad et al., 2006; Li et al., 2006; Bonne et al., 2008; Roozendaal et al., 2009). Altered fear learning and stress beha-
Bossini et al., 2008; Felmingham et al., 2009; Apfel et al., 2011; viours have also been observed in the BLA of rats following lesions
Zhang et al., 2011). Meta-analyses (Kitayama et al., 2005; Smith, induced to this area. Finally, human studies have demonstrated
2005; Karl et al., 2006) similarly reported hippocampal atrophy in heightened fear response and fear conditioning in PTSD patients
PTSD-afflicted subjects compared with healthy controls (HCs). A (Schmahl et al., 2002; Shin et al., 2006), as well as increased
meta-analysis by Kitayama et al. (2005) reported reduced volume glucocorticoid response to stress (Hartley et al., 2011). These
bilaterally in the hippocampus, which was supported by a sub- findings support both heightened activation and morphological
sequent meta-analysis by Smith (2005) that examined 13 struc- changes of the amygdala (e.g. decreased volume) being associated
tural studies of adult PTSD and also found an overall reduction in with PTSD (Ganzel et al., 2008). However, as is the case in
bilateral hippocampal volumes. More recently, a meta-analysis by volumetric studies examining the role of the hippocampus in
Karl et al. (2006) found reduced volumes in the right and left PTSD, findings across studies concerning amygdala volume are
hippocampi in PTSD subjects compared with controls who had not also equivocal (Karl et al., 2006; Woon and Hedges, 2009).
been exposed to trauma. Additionally, the volume of the left Early volumetric studies into the amygdala have reported both
hippocampus was smaller among the PTSD subjects when com- insignificantly larger volumes (Bremner et al., 1997) and smaller
pared with trauma-exposed subjects without PTSD. Auth- volumes (Gurvits et al., 1996). More recent studies have produced
similar, inconclusive results. When including only homogenous As with the hippocampus and amygdala, previous studies of the
groups from the larger meta-analysis population of research ACC in PTSD (using PET, fMRI and magnetic resonance spectroscopy)
subjects, Karl et al. (2006) reported smaller left amygdala volume have found anomalous ACC engagement in PTSD subjects compared
in subjects with PTSD than in healthy controls who had not with subjects without PTSD. Typically, the ACC demonstrated hypo-
experienced trauma, as well as in controls who had experienced activity when compared with subjects without PTSD (Bremner et al.,
trauma, but had not developed PTSD. Findings from Woon and 1999, 2004; Shin et al., 2001; Lanius et al., 2003; Yang et al., 2004).
Hedges (2009) also indicated smaller volume differences in the left Similar to findings from neuroimaging studies examining ACC activa-
amygdala of PTSD subjects compared with healthy controls that tion and function, different volumetric measurement techniques
had not been exposed to trauma. Conversely, larger left amygdala (i.e. manual tracing, voxel-based analysis and automated segmenta-
volume was reported in subjects with PTSD compared with tion) have been used to investigate ACC morphometry in PTSD, and
healthy controls (Pavlisa et al., 2006). The study by Kuo et al. the various techniques have yielded similar findings of reductions in
(2012), which involved a large homogenous sample of subjects grey matter. Lending support for the ACC's function and effect in
suffering chronic and severe PTSD, also reported larger amygdala emotional regulation and fear conditioning, smaller ACC volume was
volume among the PTSD group. In yet other studies, no significant detected (Cohen et al., 2006) even in the absence of a PTSD diagnosis.
differences in amygdala volume have been reported between PTSD Cohen et al. used automated segmentation in measuring ACC volumes
patients and control subjects (Gurvits et al., 1996; Bonne et al., in subjects who reported early life stressors and found reduced grey
2001; Lindauer et al., 2004; Wignall et al., 2004). Morey et al. matter volume (GMV). In terms of architectural anomalies, changes in
(2012) determined that trauma dose and the chronicity of PTSD ACC dendritic growth have also been observed in PTSD subjects
did not have an effect on amygdala volume and that having a following stress tests (Wellman, 2001; Radley et al., 2004). The
smaller amygdala did not increase the risk of developing PTSD. meta-analysis conducted by Karl et al. (2006) found significantly
Even where volumetric differences have been reported in reduced ACC volume in PTSD subjects compared with trauma-
different subregions of the amygdala in PTSD-afflicted subjects exposed controls. Woodward et al.'s (2006a) study, which used the
(Pavlisa et al., 2006; Rogers et al., 2009), it is perhaps prudent to manual tracing method, observed smaller ACC volumes in PTSD
consider the potential limitations of past studies. For example, Karl subjects compared with controls. Chen et al. (2006), using a morpho-
et al.'s (2006) wider sample of subjects included adolescent data logical VBM analysis, found reduced left ACC volume in subjects with
from a number of papers by De Bellis et al. (1999, 2001b, 2002) in PTSD. Rauch et al. (2003) reported smaller ACC volumes in PTSD
order to examine the moderating effects of age on ROI volumes. subjects compared with non-PTSD subjects who were trauma-
The inclusion of paediatric data in neural morphological studies is exposed. The volumetric difference found by Rauch et al. was recorded
potentially problematic given the growth and development typi- in the pregenual ACC, while the volumetric difference found by
cally occurring in the brains of children and adolescents (Sisk and Yamasue et al., (2003) in their voxel-based morphometry study was
Foster, 2004; Hedges et al., 2007; Whitford et al., 2007). Addition- located in the dorsal ACC. Interestingly, using voxel-based analysis,
ally, Karl et al. also included a group of subjects without PTSD Kasai et al. (2008) found smaller ACC volume in combat-exposed
diagnosis, but who suffered intrusive recollections. Other limita- twins with PTSD when compared with twins that had not been
tions of these meta-analyses include methodological issues such exposed to combat, as well as when compared with combat-exposed
as small sample sizes, differences in rating systems, different twins with and without PTSD. These findings implicate pregenual ACC
scanner specifications, different statistical tests and trauma het- atrophy as a morphological characteristic resulting from PTSD, rather
erogeneity. The inconsistency across findings from these studies than as a pre-existing risk factor for PTSD.
may in part be attributed to these methodological differences. While volumetric studies of the ACC in association with PTSD have
more conclusively demonstrated grey matter atrophy than similar
studies conducted on the hippocampus and amygdala, some studies
1.4. Anterior cingulate cortex (Rauch et al., 1996; Shin et al., 1997; Liberzon et al., 1999; Zubieta et al.,
1999; Lanius et al., 2004) have found hyperactivation of the ACC,
The third area implicated in the neurocircuitry and pathophy- rather than hypoactivation. Given this, and the inherent heterogeneity
siology of PTSD is the anterior cingulate cortex (ACC) which among neuroimaging studies of PTSD involving the ACC, meta-analysis
includes the dorsal, rostral and ventral subdivisions (Vogt et al., remains a logical and useful method by which to elucidate the
1992; Bush et al., 1998; Whalen et al., 1998). Investigation into the association between ACC morphology and PTSD.
role the ACC assumes in the anatomy of fear conditioning and
PTSD is especially interesting given the numerous neuroimaging
studies that have demonstrated associations between ACC activa- 1.5. Past meta-analyses: limitations and implications
tion and volume in PTSD subjects.
Positron emission tomography (PET) and fMRI studies have A previous meta-analysis examining volumes in the current ROIs
indicated that the ACC is involved in the regulation of negative included PTSD subjects that were under the age of 18 at time of
feedback of the HPA during emotional distress (Kitayama et al., scanning (Karl et al., 2006). Karl et al. included PTSD subjects from
2006), behavioural inhibition (Menon et al., 2001; Kerns et al., studies performed by De Bellis et al. (1999, 2001a, 2002) on children
2004) and the regulation of emotion (Ochsner et al., 2002). The aged 5–17 years. While these studies represent a small proportion of
prevailing theory with regard to the role of the ACC in PTSD is that the total number of the studies included in this meta-analysis, the
PTSD symptoms occur as the result of amygdala hyperactivity (in inclusion of paediatric data could lead to uncertain conclusions due to
response to stimuli perceived to be threatening) and a correspond- the differences between adult brain development and that of subjects
ing failure of the ACC (Yamasue et al., 2003) to inhibit this undergoing puberty (Hedges et al., 2007).
response (Shin et al., 2001; Murphy et al., 2003; Damsa et al., The mixing of both healthy control and trauma control groups is a
2005; Rauch et al., 2006; Kasai et al., 2008). Animal stress studies further issue that has influenced past meta-analyses. A meta-analysis
have provided further support for this putative role, demonstrat- by Smith (2005), which examined PTSD bilateral hippocampal reduc-
ing changes to ACC dendritic architecture and the implication of tions, combined studies using PTSD–healthy control comparisons with
impaired or altered ACC functioning in rodents (Radley et al., studies using PTSD/trauma-exposed control comparisons. This is likely
2004; Cerqueira et al., 2005a, 2005b; Radley et al., 2006) and in to be a result of the previous limited number of studies investigating
primates (Mathew et al., 2003). specific brain regional volumes in PTSD.
Table 1
All studies participant characteristics and ROI.
Subjects
Study ROI PTSD Healthy controls Traumatised control
N M/F Age Mean time since trauma Comorbidity N M/F Age N M/F Age
1 Apfel et al. (2011) Hippocampus 41 32/9 42.17 9.6 410 years Sub-A 95 81/14 46.4 7 9.6 64 58/6 44.47 9.6
2 Bonne et al. (2001) Amygdala/Hippocampus 10 3/7 33.7 7 8.9 6 months NR – – – 27 15/12 29.8 710.1
D.C.M. O'Doherty et al. / Psychiatry Research: Neuroimaging 232 (2015) 1–33

3 Bonne et al. (2008) Hippocampus 22 3/19 36.0 7 10.4 410 years MDD/GA 22 3/19 35.8 7 10.4 – – –
4 Bossini et al. (2008) Hippocampus 34 13/21 37.97 710.5 43 years – 34 13/21 37.82 710.7 – – –
5 Bremner et al. (1995) Hippocampus 26 26M 46.0 7 1.8 410 years MDD/BP/GA/Sub-A 22 22M 44.57 7.3 – – –
6 Bremner et al. (1997) Amygdala/Hippocampus 17 12/5 40.17 5.7 410 years MDD/BP/GA/Sub-A 17 12/5 42.4 7 7.3 – – –
7 Bremner et al. (2003) Hippocampus 10 10F 35.0 7 6.0 410 years MDD/GA/Sub-A 11 11F 38.0 7 7.0 12 12F 32.0 78.0
8 Chen et al. (2006) ACC/Hippocampus 12 8/4 34.56 7 4.91 o 1 year – – – – 12 8/4 33.25 7 5.27
9 Chen et al. (2012) ACC 10 10M 40.8 7 6.8 o 1 year – 20 20M 37.6 77.0 – – –
10 Corbo et al. (2005) ACC 14 6/8 33.36 7 12.06 o 6 months – 14 6/8 33.29 7 12.31 – – –
11 Driessen et al. (2000) Amygdala/Hippocampus 12 12F 29.9 7 6.0 NR BPD – – – 9 9F 29.3 76.7
12 Eckart et al. (2011) ACC 20 20M 36.2 7 7.7 410 years MDD 13 13M 29.0 7 7.2 19 19M 34.17 9.9
13 Emdad et al. (2006) Hippocampus 23 23M 38.65 7 6.23 45 years MDD 17 17M 37.88 78.58 – – –
14 Felmingham et al. (2009) ACC/Hippocampus 21 NR NRa 45 years MDD – – – 17 NR NRa
15 Fennema-Notestine et al. (2002) Amygdala/Hippocampus 11 11F 33.5 7 10.3 NR NR 17 17F 35.3 7 12.5 11 11F 35.4 7 9.6
16 Freeman et al. (2006) Hippocampus 10 10M 79.6 7 3.2 410 years MDD 6 6M 80.8 7 3.5 10 10M 79.8 72.8
17 Gilbertson et al. (2002) Amygdala/Hippocampus 12 12M 53.17 3.3 410 years MDD/Sub-A – – – 23 23M 51.8 72.3
18 Golier et al. (2005) Hippocampus 14 5/9 70.5 7 5.6 410 years MDD 20 13/7 71.4 76.4 13 6/7 68.5 7 7.3
19 Jatzko et al. (2006) Hippocampus 15 13/2 48.2 712.2 410 years MDD 15 13/2 47.9 7 12.9 – – –
20 Kitayama et al. (2006) ACC 8 1/7 43.0 7 7.0 NR MDD 13 1/12 37.0 78.0 – – –
21 Kuo et al. (2012) Amygdala 42 42M 49.5 78.6 410 years MDD – – – 45 45M 44.57 7.3
22 Landre et al. (2010) Amygdala/Hippocampus 17 17F 24.9 7 4.8 410 years MDD 17 17F 24.7 7 4.6 – – –
23 Lindauer et al. (2004) Amygdala/Hippocampus 14 8/6 35.4 7 11.2 43 years MDD – – – 14 8/6 36.9 710.1
24 Lindauer et al. (2005) Amygdala/Hippocampus 18 8/10 39.6 7 9.0 43 years MDD – – – 14 8/6 36.9 710.1
25 Morey et al. (2012) Amygdala/Hippocampus 99 79/20 38.4 7 9.9 48 years MDD – – – 102 86/16 37.5 7 10.6
26 Pavic et al. (2007) Hippocampus 15 15M 41.0 75.37 49 years – 15 15M 41.0 7 5.37 – – –
27 Pederson et al. (2004) Hippocampus 17 17F 24.8 7 5.2 410 years MDD 17 17F 23.8 7 5.6 17 17F 26.8 76.6
28 Rauch et al. (2003) ACC 9 9F 51.7 7 1.9 410 years MDD – – – 9 9F 52.0 71.9
29 Rocha-Rego et al. (2012) ACC 16 7/9 43.3 7 5.78 43 years MDD – – – 16 7/9 44.97 6.60
30 Rogers et al. (2009) Amygdala/Hippocampus 9 5/4 44.56 7 15.96 410 years MDD – – – 16 10/6 44.44 7 13.60
31 Schmahl et al. (2009) Amygdala/Hippocampus 10 10F 28.50 7 6.06 410 years BPD/Sub-A/MDD – – – 15 15F 29.337 7.29
32 Schuff et al. (2001) Hippocampus 18 18M 51.2 7 2.5 NR MDD/Sub-A 19 19M 51.8 7 3.2 – – –
33 Shu et al. (2013) Hippocampus 11 2/9 36.3 7 12.9 o 1 year MDD 11 2/9 35.3 7 11.4 – – –
34 Stein et al. (1997) Hippocampus 21 21F 32.0 7 6.3 410 years MDD 21 21F 30.2 7 6.4 – – –
35 Villarreal et al. (2002) Hippocampus 12 2/10 43.0 7 9.3 410 years MDD 10 10F 44.07 11.4 – – –
36 Vythilingam et al. (2005) Hippocampus 14 8/6 35.0 7 9.0 410 years MDD/Sub-A 23 9/20 34.0 7 10.0 23 15/8 35.0 7 7.0
37 Wang et al. (2010) Hippocampus 17 17M 41.0 712.0 410 years MDD/Sub-A – – – 19 19M 38.0 715.0
38 Weniger et al. (2008) Amygdala/Hippocampus 10 10F 32.0 7 7.0 410 years BPD/MDD 25 25F 33.0 7 7.0 – – –
5
Most previous meta-analyses have focused on the volume
34.30 7 5.37
56.0 7 3.5b
differences between PTSD subjects and controls in the hippocam-
36.7 7 3.9c
41.0 7 11.0
65.17 9.9
pal or amygdala regions—with the exception of the meta-analysis
NRd
of Karl et al. (2006), which included some additional structures
Traumatised control
Age
–
such as the ACC. Recent studies exploring the disruption of the
salience network (SN) and default mode network (DMN) found
25Mb
23Mc
15M
16M
10M
NRd
M/F
participants with PTSD showed reduced functional connectivity

–
between areas of the DMN brain regions including the rostral ACC
624
and hippocampus (Bluhm et al., 2009; Sripada et al., 2012).
48
28
15
16
10
N
The DMN has been implicated in mental explorations that are self-
referential such as remembering, exploring hypothetical social inter-
29.0 7 10.0
41.0 7 17.0
actions, and thoughts of future events pertaining to self (Buckner et al.,

2008). Disruption in DMN functioning could therefore cause inter-
Age
ference in PTSD sufferers' ability to mentally prepare for self-refere-

–
–
–
–
Healthy controls
ntial future events before and while they experience them.

The SN has been associated with homoeostatic regulation and
15M
M/F
9/2
interoception, as well as autonomic and reward processing (Dose-

–
–
–
–
nbach et al., 2007; Seeley et al., 2007; Menon, 2011). Disruptions in the
520
15
11
SN have been linked to anxiety (Paulus, 2007; Paulus and Stein, 2010).
N
–
–
–
Within the SN, two ROIs associated with PTSD—the ACC and the
amygdala—have been shown to be hypoactive and hyperactive,
respectively (Shin and Handwerger, 2009; Hughes and Shin, 2011),
Comorbidity
MDD/Sub-A
MDD/Sub-A
MDD/Sub-A
with disrupted connection between the DMN and SN potentially

contributing to the mechanisms that result in PTSD symptoms.
Thus, any disruption to the equilibrium between the SN and the
–
–
DMN is likely to result in hypervigilance and hyperarousal, which are

often observed in patients with PTSD. Any study attempting to shed
Mean time since trauma
light on the volumetric abnormalities in PTSD subjects when com-

pared with either healthy or trauma-affected controls would need to
examine the differences in volumes of the brain regions involved in
the DMN and the SN, as both are suspected of playing a role in
410 years
410 years
410 years
o2 years
o1 year
o1 year
PTSD maintenance—specifically the hippocampus, the amygdala and

the ACC.
¼Gender and mean age for this subgroup of veterans with or without alcoholism were not reported.
40.80 7 6.83
42.0 7 10.0
2. Method
53.5 7 2.6b
37.0 7 5.7c
43.0 7 9.0
60.6 7 7.0
This meta-analysis has been organised into distinct sections, each of which
NRd
Age
analyses a separate ROI. Each section concludes with its own summary, and all
sections are reviewed in Section 4.
38Mb
13Mc
15M
10M
17M
NRd
M/F
9/6
2.1. Characteristics of studies

PTSD
15
15
51
27
17
10
846
N
In total we examine 59 studies across the three ROIs (36 hippocampus, 14 amygdala
and nine ACC) with n¼ 846 PTSD participants, n¼520 healthy controls and n¼624
Amygdala/Hippocampus
traumatised controls (TCs). All subjects were aged 18 years or older at the time of the
MRI scan, and the mean time since trauma for the majority of PTSD subjects was over 10
years (see Table 1 for details; included studies comprised (Bremner et al., 1995, 1997,
2003; Stein et al., 1997; Driessen et al., 2000; Bonne et al., 2001, 2008; Schuff et al.,
Hippocampus
Hippocampus
Hippocampus
Hippocampus
2001; Fennema-Notestine et al., 2002; Gilbertson et al., 2002; Villarreal et al., 2002;
Rauch et al., 2003; Lindauer et al., 2004, 2005; Pederson et al., 2004; Wignall et al.,
2004; Winter and Irle, 2004; Corbo et al., 2005; Golier et al., 2005; Vythilingam et al.,
ACC
ROI
2005; Chen et al., 2006, 2012; Emdad et al., 2006; Freeman et al., 2006; Jatzko et al.,
2006; Kitayama et al., 2006; Woodward et al., 2006a, 2006b; Pavic et al., 2007; Yehuda
et al., 2007; Bossini et al., 2008; Weniger et al., 2008; Felmingham et al., 2009; Rogers
et al., 2009; Schmahl et al., 2009; Landre et al., 2010; Wang et al., 2010; Apfel et al., 2011;
¼ Subjects aged matched to controls.
Eckart et al., 2011; Zhang et al., 2011; Kuo et al., 2012; Morey et al., 2012; Rocha-Rego
Woodward et al. (2006b)
Woodward et al. (2006a)
et al., 2012; Shu et al., 2013).

BPD¼ borderline personality disorder.
Winter and Irle (2004)
Some studies did not supply comorbidity data of subjects (i.e. bipolar disorder
Wignall et al. (2004)
Yehuda et al. (2007)
MDD¼ major depressive disorder.
(BP), major depressive disorder (MDD), substance abuse), but where reported, this
Zhang et al. (2011)
information is available in Table 1.

¼Persian Gulf Cohort.
Articles were included if they were structural MRI studies that reported volumetric
Sub-A ¼substance abuse.
data on one or more of the selected ROIs. Articles were excluded if they contained
GA ¼ Generlised Anxiety.
¼ Vietnam Cohort.
subjects under the age of 18 or did not have nZ10 PTSD subjects, with a few notable
BP¼ bipolar disorder.
Table 1 (continued )
Study
exceptions (Rauch et al., 2003; Kitayama et al., 2006; Rogers et al., 2009).
NR¼ Not Reported.
2.2. Literature search and inclusion criteria

Subjects
d
b
a
c
39
40
41
42
43
44
A literature search was conducted in Embase, Medline, PubMed and PsycINFO in

May 2013 using the following keywords: (i) “posttraumatic stress disorder”, (ii) “PTSD”,
combined with the following subcategory keywords: (iii) “magnetic resonance imaging”, in PTSD subjects, while a positive score is indicative of a volume increase within the
(iv) “MRI”, (v) “hippocampus”, (vi) “amygdala”, and (vii) “anterior cingulate cortex”. same ROI. Standardized mean differences were reported with Hedges' correction
Studies were selected if: (1) they were in vivo MRI studies; (2) the patient group had for small samples (Hedges and Olkin, 1985) using 95% confidence intervals. Hedges'
a DSM-based diagnosis of PTSD and was compared with either a healthy or traumatised effect size (“g”) was interpreted in the same way as Cohen's d: 0.2 ¼small;
control group that had not developed PTSD; (3) one or more of the following ROIs were 0.5 ¼medium; and 0.8 ¼large (Cohen, 1988).
included: hippocampus, amygdala, or anterior cingulate cortex; (4) participants were 18 Heterogeneity was reported using Q-statistic, and I2 was used to index
years or older at time of scan; and (5) the study was in English (or translated). The significant heterogeneity of effect sizes. I2 of 0.25, 0.50, and 0.75 denoted small,
majority of articles included had a sample size in each subject groupZ10, with the moderate, and high levels of heterogeneity, respectively (Higgins and Thompson,
exceptions of Kitayama et al., 2006 (eight PTSD subjects; 13 healthy controls), Rauch 2002). Alpha was set to 0.10 to test for heterogeneity as this procedure typically
et al., 2003 (nine PTSD subjects; nine traumatised controls) and Rogers et al., 2009 (nine lacks power (Higgins et al., 2003). Where heterogeneity was present, the covariates
PTSD subjects; 16 traumatised controls). Where any two or more studies included the “mean age of PTSD subjects” and “mean time since trauma” were examined as
same or overlapping patient populations, only the study with the larger sample size was potential effect modifiers. A mixed effects model (unrestricted maximum like-
included in the analysis. lihood) meta-regression was conducted to determine if there were any correlations
with observed Hedges' g results and mean age of PTSD subjects. Data for mean time
since trauma were not found to be normally distributed; thus, it was deemed
2.3. Statistical tests used inappropriate to run a meta-regression for this covariate (Thompson and Higgins,
2002). Publication bias was assessed using the fixed effect regression Eggers' Test
For this meta-analysis we conducted nine statistical tests measuring volume (Egger et al., 1997).
differences in PTSD subjects, healthy controls (HCs) and traumatised controls (TCs)
for each of the three ROIs (hippocampus, amygdala and ACC): (1) PTSD vs. HC,
combined left and right volume; (2) PTSD vs. HC, left volume; (3) PTSD vs. HC, right
volume; (4) PTSD vs. TC, combined left and right volume; (5) PTSD vs. TC, left
volume; (6) PTSD vs. TC, right volume; (7) PTSD vs. HC þTC, combined left and right 3. Results
volume; (8) PTSD vs. HC þ TC, left volume; (9) PTSD vs. HC þTC, right volume.
The inclusion of a combined healthy control and trauma control (HC þ TC) For each of the three examined ROI, effect sizes for studies are
condition in each ROI analysis is to provide an additional analysis with which to
contrast against the individual and separate healthy and traumatised control
grouped into the following three categories; (1) PTSD vs. healthy
analyses. A combined HC þTC analysis becomes especially useful in the case of controls (HC); (2) PTSD vs. trauma-exposed controls (TC); and
the ACC analyses, where the number of studies (and therefore the number of (3) PTSD vs. healthy and trauma exposed controls (HC and TC).
subjects and controls) is limited.
Where a study compared PTSD subjects with both healthy and traumatised
controls, only the traumatised controls were included in tests 7, 8 and 9, to avoid
duplication of sample populations. 3.1. Hippocampus volume – study characteristics
As the present study has accumulated data from past research performed by
researchers using different populations, a common effect size was not assumed.
Consequently, mean effect sizes were calculated with the random-effects model. In Thirty-six studies with a hippocampal ROI published between
the random-effects model, each study is weighted by the inverse of its variance, 1995 and 2013 were identified by our search as matching the
which includes both within-studies variance and the estimate of between-studies inclusion criteria. The total number of PTSD subjects included in
variance (Borenstein et al., 2009). these studies was n¼ 676, with n¼ 460 healthy controls and
This meta-analysis was conducted using Comprehensive Meta-analysis soft-
ware (Version 2.2.046) developed by Biostat (Borenstein et al., 2011). Effect sizes
n ¼487 traumatised controls. An overview of participant charac-
were standardized mean differences in volume between PTSD patients and healthy teristics from the selected hippocampus studies is detailed
or traumatised controls. A negative score indicates a reduction in volume of the ROI in Table 1 and Appendix A.
Fig. 1. Pooled studies investigating combined left and right hippocampal volumes.
3.1.1. PTSD vs. healthy controls volume, τ2 ¼0.218, p¼0.177; PTSD vs. HCþTC, right volume, τ2 ¼0.56,
This analysis included 22 studies (see Fig. 1(A) and Appendix p¼ 0.315. The data were not found to be normally distributed for the
Figs. A1–A3). Significant reductions in the left (Hedges' g ¼ 0.473, mean age of PTSD subjects in PTSD vs. TC right, PTSD vs. HC left and
95% CI: 0.664 to 0.282, p o0.001), right (Hedges' g ¼ 0.516, right combined, PTSD vs. TC left and right combined, PTSD vs. HCþ TC
95% CI: 0.734 to 0.298, p o0.001), and combined left and right left and right combined volumes, and thus it was inappropriate to run
hippocampal volumes (Hedges' g¼ 0.495, 95% CI: 0.629 to a meta-regression for these analyses (Thompson and Higgins, 2002).
0.361, po 0.001) were found in the PTSD group compared with
the healthy control group. Heterogeneity was significant in all 3.2. Amygdala volume – study characteristics
analyses (see Appendix D).
Fourteen studies with an amygdala ROI published between
3.1.2. PTSD vs. traumatised controls 1997 and 2012 were identified by our search as matching the
This analysis included 21 studies (see Fig. 1(B) and Appendix inclusion criteria. The total number of PTSD subjects included in
Figs. A4–A6). Significant reductions in left (Hedges' g ¼ 0.412, these studies was n ¼296, with n ¼110 healthy controls and
95% CI: 0.731 to 0.094, p o0.05), right (Hedges' g¼ 0.341, n¼ 276 traumatised controls. An overview of participant charac-
95% CI: 0.586 to 0.097, p o0.01), and combined left and right teristics from the selected amygdala studies is detailed in Table 1
hippocampal volumes (Hedges' g ¼ 0.370, 95% CI: 0.552 to and Appendix B.
the trauma-exposed control group. Heterogeneity was significant
3.2.1. PTSD vs. healthy controls
in all analyses (see Appendix D).
This analysis included six studies (see Fig. 2(A) and Appendix
Figs. A10–A12). No significant reductions were found in the left
3.1.3. PTSD vs. healthy controlsþtraumatised controls (Hedges' g¼ 0.605, 95% CI: 1.328 to 0.119, p ¼0.101), right
This analysis included 36 studies (see Fig. 1(C) and Appendix (Hedges' g ¼ 0.418, 95% CI: 1.097 to 0.261, p ¼0.228), amygdala
Figs. A7–A9). Significant reductions in left (Hedges' g ¼ 0.447, volumes. However, a reduction was found in the combined left and
95% CI: 0.662 to 0.231, p o0.001), right (Hedges' g¼ 0.415, right volume analysis (Hedges' g¼ 0.508, 95% CI: 0.982 to
95% CI: 0.599 to 0.231, po 0.001), and combined left and right 0.033, p o0.05). Heterogeneity was significant in all analyses
hippocampal volumes (Hedges' g ¼ 0.429, 95% CI: 0.558 to (see Appendix D).
the combined healthy and trauma-exposed control groups. Het-
erogeneity was significant in all analyses (see Appendix D). 3.2.2. PTSD vs. traumatised controls
Significant reductions were found in all hippocampal analyses This analysis included 10 studies (see Fig. 2(B) and Appendix
comparing PTSD subjects with both healthy and trauma-exposed Figs. A13–A15). No significant reductions were found in the left
control groups. A medium effect size was seen in reductions of both (Hedges' g¼ 0.076, 95% CI: 0.356 to 0.205, p ¼0.596), right
left and right volumes in the PTSD vs. HC group, with the right (Hedges' g¼ 0.053, 95% CI: 0.358 to 0.252, p ¼ 0.734), or
hippocampal hemisphere volume showing a slightly larger reduction combined left and right amygdala volumes (Hedges' g ¼ 0.042,
than the left (Hedges' g right¼ 0.516 vs. Hedges' g left¼ 0.473). 95% CI: 0.238 to 0.154, p ¼0.673) in the PTSD group compared
This asymmetry was reversed in the PTSD vs. TC group, with the left with the trauma-exposed control group. Heterogeneity was sig-
hippocampal hemisphere volume showing a greater reduction than nificant in all analyses (see Appendix D).
the right (Hedges' g left¼ 0.412 vs. Hedges' g right¼ 0.341).
Differences in hemisphere volume reductions were not carried 3.2.3. PTSD vs. healthy controls þtraumatised controls
through with significance to the combined HC and TC comparison This analysis included 14 studies (see Fig. 2(C) and Appendix
group. A meta-regression testing the covariate “mean age of PTSD Figs. A16–A18). No significant reductions were found in the left
subjects” found no significant results; PTSD vs. HC, left volume, (Hedges' g ¼ 0.268, 95% CI: 0.620 to 0.083, p ¼0.135), right
τ2 ¼0.56, p¼0.315; PTSD vs. HC, right volume, τ2 ¼0.113, p¼0.445; (Hedges' g¼ 0.243, 95% CI: 0.571 to 0.086, p¼ 0.148), or
PTSD vs. TC, left volume, τ2 ¼0.334, p¼0.295; PTSD vs. HCþTC, left combined left and right amygdala volumes (Hedges' g¼ 0.227,
Fig. 2. Pooled studies investigating combined left and right amygdala volumes.
95% CI: 0.456 to 0.002, p¼ 0.052) in the PTSD group compared trauma-exposed control group. Heterogeneity was significant in
with the combined healthy trauma-exposed control groups. Het- the left and combined left and right analyses (see Appendix D).
erogeneity was significant in all analyses (see Appendix D).
The only analysis reporting a significant reduction or increase
3.2.6. PTSD vs. healthy controls þtraumatised controls
in amygdala volume was the PTSD vs. HC combined left and right
This analysis included nine studies (see Fig. 3(C) and Appendix
volume group with a medium effect size (Hedges' g ¼ 0.508, 95%
Figs. A25–A27). Significant reductions in left (Hedges' g ¼ 0.833,
CI: 0.982 to 0.033, p o0.05). This is indicative of the varied
95% CI: 1.289 to 0.377, po 0.001), right (Hedges' g ¼ 0.507,
results of studies investigating amygdala volumes in PTSD subjects
95% CI: 0.775 to 0.239, po 0.001), and combined left and right
and possibly a symptom of the large clinical heterogeneity in the
ACC volumes (Hedges' g ¼ 0.697, 95% CI: 0.963 to 0.430,
current available literature. Whilst not significant, the PTSD vs. HC
po 0.001) were found in the PTSD group compared with the
group comparison did trend towards an asymmetrically larger
combined healthy and trauma-exposed control groups. Hetero-
reduction in the left amygdalae (Hedges' g left ¼ 0.605 vs.
geneity was significant in the left and combined left and right
Hedges' g right ¼ 0.418). A meta-regression testing the covariate
analyses (see Appendix D).
“mean age of PTSD subjects” found no significant results; PTSD vs.
Significant reductions were found in all ACC analyses compar-
HC, left volume, τ2 ¼0.601, p ¼0.811; PTSD vs. HC right volume,
ing PTSD subjects with both healthy and trauma-exposed control
τ2 ¼ 0.523, p ¼0.484, PTSD vs. HC, left and right combined volume,
groups, except for the PTSD vs. HC left volume group. The effect
τ2 ¼ 0.600, p ¼0.761; PTSD vs. TC, left volume, τ2 ¼0.004, p ¼0.078,
size of the PTSD vs. TC left ACC volume reduction was large
PTSD vs. TC, right volume, τ2 ¼0.054, p¼ 0.352, PTSD vs. HC þTC,
(Hedges' g¼ 0.987, 95% CI: 1.498 to 0.476, po 0.001), and
left volume, τ2 ¼ 0.375, p ¼0.708, PTSD vs. HC þTC, right volume,
also showed substantial asymmetry when compared with the
τ2 ¼ 0.264, p ¼0.334; PTSD vs. HC þTC, left and right combined
right ACC volume (Hedges' g left¼ 0.987 vs. Hedges' g
volume, τ2 ¼0.333, p¼ 0.492. The data were not found to be
right ¼ 0.524). This asymmetrical trend was still present when
normally distributed for the mean age of PTSD subjects in PTSD
PTSD subjects were compared with the combined healthy and
vs. TC left and right combined volumes, and thus it was inap-
trauma-exposed control groups (Hedges' g left¼ 0.833 vs.
propriate to run a meta-regression for this analysis (Thompson
Hedges' g right ¼ 0.507). The bias towards a greater reduction
and Higgins, 2002).
of left ACC volume is likely the result of the study by Chen et al.
(2006) only reporting on the left ACC with a strong effect size
3.2.4. PTSD vs. healthy controls (Hedges' g ¼ 1.991)—this combined with the small sample of
This analysis included four studies (see Fig. 3(A) and Appendix available studies could explain the slight skewing of results. Under
Figs. A19–A21). No significant reductions in the left (Hedges' 10 studies provided “mean age of PTSD subjects” covariate data in
g ¼ 0.573, 95% CI: 1.287 to 0.141, p¼ 0.116) ACC volume were all ACC analyses except in the cases of PTSD vs. TC left and right
found. However, reductions were found in the right (Hedges' combined and PTSD vs. HC þTC left and right combined volume.
g ¼ 0.678, 95% CI: 1.326 to 0.030, p o0.05), and combined However, data were not found to be normally distributed for the
left and right ACC volumes (Hedges' g¼ 0.616, 95% CI: 1.071 to mean age of PTSD subjects in PTSD vs. TC left and right combined
0.161, p o0.01) in the PTSD group compared with the healthy volumes, and thus it was inappropriate to run a meta-regression
control group. Heterogeneity was significant in the left and for these analyses (Thompson and Higgins, 2002).
combined left and right analyses (see Appendix D).
4. Discussion
3.2.5. PTSD vs. traumatised controls
This analysis included six studies (see Fig. 3(B) and Appendix The current findings of reduced hippocampal volume in sub-
Figs. A22–A24). Significant reductions in left (Hedges' g ¼ 0.987, jects with PTSD are consistent with the existing literature, with a
95% CI: 1.498 to 0.476, p o0.001), right (Hedges' g ¼ 0.524, greater reduction being found in the left hippocampus. This
95% CI: 0.816 to 0.232, p o0.001), and combined left and right conclusion is in contrast to the mixed results of studies investigat-
ACC volumes (Hedges' g¼ 0.772, 95% CI: 1.064 to 0.480, ing volume in the amygdala, which did not show significant
p o0.001) were found in the PTSD group compared with the differences between PTSD subjects and trauma-exposed controls,
Fig. 3. Pooled studies investigating combined left and right ACC volumes.
but did find a medium effect size reduction in bilateral volume excitotoxicity (Sheline, 2000; Reul and Nutt, 2008). Glial cells are
when compared with healthy controls. also involved in the production of glial cell line-derived neuro-
It should be noted that while our findings present evide- trophic factor (GDNF), which has been found to have a role in the
nce supporting structural changes in the three main ROIs, the survival of midbrain neurons (Lin et al., 1993).
mechanisms underpinning these observed volume changes are still The role of a sustained increased level of glucocorticoids
open to greater levels of uncertainty. involved in stress-related excitotoxicity has been well documented
Adding to the problem of correctly identifying the genesis of in relation to hippocampal and ACC GMV atrophy (Arborelius
observed volumetric changes is the effect of Axis I and II comorbidity et al., 1999; Tata and Anderson, 2010), but differences in the
as well as substance abuse often reported in PTSD subjects. Axis I plasticity of these structures compared with the amygdala in the
comorbidity, commonly reported as major depressive disorder (MDD), context of PTSD recovery have been less explored. The neuropil of
is the confound most frequently encountered in PTSD studies—32 out the hippocampus, in particular, has been found to be more capable
of the 44 studies included in this meta-analysis reported MDD of recovery from atrophy, compared with the ability of the
comorbidity. This prevalence presents a frequent issue in determining amygdala (in particular, the BLA) to recover from stress-related
the true changes in ROI volumes attributable to PTSD alone, as MDD dendritic hypertrophy (Vyas et al., 2002, 2004; Adamec et al.,
has been well documented to show volumetric reductions, particularly 2012). These differences in structural aptitude to return to their
in the hippocampus (Sheline et al., 1996; Bremner et al., 2000; Vakili pre-trauma volumes once glutamate homoeostasis has been
et al., 2000). Eight of the studies included in the current analysis chose restored add to the difficulty in developing successful PTSD
to exclude PTSD subjects with MDD symptoms. However, as they are treatments.
spread across multiple ROIs, they do not include a large enough Each of these cellular pathways to GMV changes has a sub-
number of subjects to permit a separate analysis that would avoid the stantial body of evidence supporting its involvement in PTSD-
MDD confound and identify its contributing effects to volumetric related atrophy and hypertrophy. Future studies exploring
changes. mechanisms of action may find that there are a range of combina-
Further complicating the problem, PTSD is also highly comor- tions, instead of a single style or combination, that reflect a
bid with substance abuse, borderline personality disorder (BPD), spectrum of PTSD development types and forms of maintenance
generalised anxiety (GA) and bipolar disorder (BP). Twelve studies (i.e., single or multi-incident trauma).
included PTSD subjects with comorbid substance abuse, two with Some studies investigating volumetric structural changes raise the
BPD, four with GA, and two with BP. Four studies had subjects with issue of genetic influences being a predetermined risk factor for GMV
at least three comorbid disorders (see Table 1). reductions associated with PTSD. A recent study that used combat-
While it is good practise to account for and remove all possible exposed monozygotic twins with and without PTSD to investigate ACC
confounds when conducting a meta-analysis, the pervasiveness of volumes (Kasai et al., 2008) concluded that GMV reductions in limbic
Axis I and II comorbidity in PTSD, especially MDD, suggests that and paralimbic structures were acquired due to stress-induced PTSD-
the two disorders may be linked and may necessitate a joint related loss, rather than any genetic or familial risk factors.
analysis in order to elucidate the core mechanisms involved in The intrusive recollection of traumatic events associated with
observed volume transitions. PTSD—commonly known as flashbacks during waking hours and
Potential cellular mechanisms resulting in PTSD-related grey nightmares when sleeping—has been associated with volumetric
matter volume (GMV) changes can be broken into three main reductions in the hippocampus and related disruptions in memory
categories, as follows: (i) fluctuations in synaptic spine density on (Squire, 1992; Eichenbaum, 2000; Brewin et al., 2009, 2010).
different-order dendrites (dendritic remodelling), (ii) reduction in A model developed by Brewin et al. (1996, 2010) and Brewin
BDNF resulting in impaired neurogenesis, and (iii) glial dysfunc- (2001) explains PTSD flashbacks in terms of two types of hippo-
tion and loss resulting in an impaired glutamate–glutamine cycle. campal dependant memory, as follows: (i) contextual representa-
Synaptic spine density fluctuations in cortical regions asso- tional memory, which provides context to memories during
ciated with PTSD have been most often examined using animal retrieval, and (ii) sensation-based representational memory, which
models. A recent study examining stress-induced GMV loss in is involved in the emotional recollections of an event. The model
rodents (Kassem et al., 2013) found a linear relationship between suggests that flashbacks occur when sensation-based representa-
changes in ACC and hippocampal GMV and cumulative changes of tional memory is activated by either an environmental cue or
dendritic volume. This finding builds upon previous animal internal thought, without the corresponding contextual represen-
dendritic studies (Magarinos et al., 1996; Gould et al., 1998; tational memory – causing PTSD sufferers to experience the
Radley et al., 2006; Chen et al., 2010) and suggests that GMV emotional memory out of context, and propelling them into a
reductions observed in humans afflicted by PTSD may have a hypervigilant state.
similar dendritic basis. A similar model explored in animals by Rudy (2009), Rudy et al.
BDNF has been shown to be one of the most active neurotro- (2002, 2004) and Rudy and O’Reilly (1999) also suggests that
phins involved in neurogenesis, and has a neuroprotective effect failures in hippocampal encoding of traumatic events result in
against glutamate excitotoxicity ( Nibuya et al., 1995, 1996; Vaidya flashbacks. In this model the hippocampus is responsible in the
et al., 1999; Almeida et al., 2005). Reduced levels of BDNF in creation of memories during a traumatic event, and correctly
structures related to PTSD have been found to correlate to an encoding multiple conjunctive cues (e.g., visual, aural, odour)
impairment of neurogenesis, and subsequent GMV atrophy during a conditioned fear response. Flashbacks are the result of
(Sapolsky, 2000; Sala et al., 2004). one or more of these conjunctive cues being recalled outside the
Glial cell dysfunction or reduction is another suspected context of the original conditioned fear event.
mechanism of GMV atrophy in PTSD. Glial cells are necessary for Both these models involve reduced hippocampal function
the regulation of glutamate throughout the brain – especially the associated with reduced neuronal and dendritic related atrophy
synaptic cleft – via conversion of glutamate into glutamine using found in PTSD patients following traumatic events. Each model
the enzyme glutamine synthetase. Any dysfunction and/or loss of can be used to explain the flashbacks experienced in PTSD in terms
glial cells results in an impaired glutamate–glutamine cycle of hippocampal dysfunction—either in memory encoding or retrie-
potentially subjecting any afflicted brain structure to glutamate val—as triggered by external environmental cues or internal
thoughts. As both models involve heightened states of emotion such as attention and working memory, while disengaging other
and fear elements, the amygdala is also implicated, and our systems not important to a current task (Menon and Uddin, 2010).
observed comparatively small changes in amygdala volume (with Enhanced activity in the anterior insula has been reported in PTSD
the associated hypervigilance) additionally fit within each model. fMRI studies ( Paulus and Stein, 2006; Shin and Liberzon, 2009;
Whether flashbacks, memory dysfunction and associated hip- Lanius et al., 2011), and is thought to be involved in valuing a
pocampal volume reductions are a result of PTSD or a pre-existing stimulus in terms of how it might affect the body state.
trait in some sufferers, increasing their susceptibility to develop- In a dysfunctional SN postulated to occur in PTSD, the anterior
ment of the disorder has been explored in monozygotic twin insula is primed to over-value stimuli as potential threats (Paulus
studies (Gilbertson et al., 2002, 2007). These twin studies found and Stein, 2006), contributing to classical PTSD hypervigilance
that subjects with PTSD had hippocampal volumes on par with symptoms. To date, however, only a limited number of PTSD
their non-PTSD siblings, and that both had significantly smaller studies have examined volumes of the anterior insula (Kasai
hippocampal volumes compared with trauma-exposed controls et al., 2008; Nardo et al., 2010). Future longitudinal studies should
and their non-exposed siblings. While these twin studies provide seek to examine volumes of the ROIs involved in the SN model of
evidence that pre-existing lower hippocampal GMV represents a PTSD (hippocampus, amygdala, ACC—along with other key areas
vulnerability to developing PTSD after exposure to trauma, more such as the anterior insula) and their ratios within the same
studies (preferably longitudinal) are required before a strong subjects compared with controls.
causal link can be confirmed.
Both the amygdala and hippocampus are identified as regions
of interest in PTSD due to their role in the processing and
coordination of traumatic memories and perception (Rolls, 1996; 4.1. Limitations
Kensinger and Corkin, 2004) and in salience network (SN) pro-
cesses. SN function within the brain is in the assessment of salient Although often well matched with their respective control groups,
external stimuli and pertinent sensory data (Seeley et al., 2007; the samples of PTSD subjects in the source studies used in this meta-
Menon and Uddin, 2010). Impaired functioning in the SN can analyses are limited in their homogeneity. Many of the subjects differ
result in dysfunctional processing of stimuli, autonomic arousal, in age, trauma type (e.g. combat exposure or civilian accident), trauma
cognition and behaviour regulation. duration, trauma severity, and age of symptom onset. Interpretation of
Our finding of reductions in ACC volumes fits the SN model, the volumetric changes reported also must be tempered by considera-
and due to its role in fear extinction and its moderating effect on tion of the potential confounding factors of Axis I and II comorbidity,
the amygdala, suggests that dysfunction of the ACC may have a substance abuse of subjects, and medication usage often associated
larger role in PTSD symptoms and severity than previously with a diagnosis of PTSD.
suspected. As disruption of the SN in PTSD is associated with The small number of studies that examined ACC volume (nine
volume reduction and hypoactivation of the ACC (Rauch et al., studies in the current meta-analysis) leads to a high level of
2006), the current and previous mixed findings in relation to heterogeneity and limits the generalisation of the results found.
amygdala volumes may be explained in relation to an impairment The relative paucity of ACC studies also necessitated the inclusion
of the top-down processing of a correctly functioning SN. of two studies (Kitayama et al., 2006; Rauch et al., 2003) that had
The top-down processing of the SN may explain why PTSD only eight and nine PTSD subjects rather than the preferred
sufferers are more prone to being affected by certain types of minimum of 10. A third study containing only nine PTSD subjects
triggers, e.g., trauma (Cohen and Servan-Schreiber, 1992) that may was also included, as it explored both the amygdala and hippo-
result in a selective dominance of traumatic memory networks campus ROIs—and also had close to double the number of subjects
(McFarlane et al., 2002). These memory networks are primed to as traumatised controls (16:9).
respond in a particular way due to a neural network bias in the As with previous meta-analyses elucidating the current ROIs,
way a trigger is perceived and processed (Hoffman and the lack of a standardised best practice of methodological image
McGlashan, 1993). The nature of the trauma may not be as critical acquisition and variance between ROI-tracing protocols also con-
as the way it is processed by the neural network and the particular tribute to the issue of identifying a suitably sized homogeneous
effect this processing has on an individual's memory and percep- study group.
tion (McFarlane et al., 2002). Further to this, impairment within While it is recognised that the statistical heterogeneity scores
the DMN has also been suggested as a contributing factor to PTSD (I2) for each analysis are high, they are considered acceptable as
symptoms, in conjunction with dysfunctional SN (Lanius et al., intra-study groups are clinically and methodologically homoge-
2011; Patel et al., 2012). This cascading, inter- and intra-network neous across subjects and controls. In the future, as more volu-
dysfunction may account for the range of PTSD symptoms experi- metric ROI PTSD studies are published, it may be possible to
enced by sufferers, along with the discrepancies in the results of further narrow the inclusion criteria and reduce the effects of
studies examining amygdala volumes. Rather than amygdala clinical heterogeneity.
volume itself being a biomarker and predictor of PTSD suscept-
ibility and severity, recent results suggest the pre- and post-
morbid ratio between the ACC and the amygdala might be
indicative of SN dysfunction within PTSD.
An additional region involved in SN function is the anterior Appendix A1
insula. The anterior insula has been found to co-activate with the
ACC and is involved in engaging higher order control processes See Table A1.
Fig. A1. Pooled studies investigating left hippocampal volumes in PTSD subjects vs. healthy controls..
Fig. A2. Pooled studies investigating right hippocampal volumes in PTSD subjects vs. healthy controls..
Fig. A3. Pooled studies investigating combined left and right hippocampal volumes in PTSD subjects vs. healthy controls..
Fig. A4. Pooled studies investigating left hippocampal volumes in PTSD subjects vs. trauma exposed controls..
Fig. A5. Pooled studies investigating right hippocampal volumes in PTSD subjects vs. trauma exposed controls..
Fig. A6. Pooled studies investigating combined left and right hippocampal volumes in PTSD subjects vs. trauma exposed controls..
Fig. A7. Pooled studies investigating left hippocampal volumes in PTSD subjects vs. healthyþ trauma exposed controls..
Fig. A8. Pooled studies investigating right hippocampal volumes in PTSD subjects vs. healthyþ trauma exposed controls..
Fig. A9. Pooled studies investigating combined left and right hippocampal volumes in PTSD subjects vs. healthyþ trauma exposed controls..
Fig. A10. Pooled studies investigating left amygdala volumes in PTSD subjects vs. healthy controls..
Fig. A11. Pooled studies investigating right amygdala volumes in PTSD subjects vs. healthy controls..
Fig. A12. Pooled studies investigating combined left and right amygdala volumes in PTSD subjects vs. healthy controls..
Fig. A13. Pooled studies investigating left amygdala volumes in PTSD subjects vs. trauma exposed controls..
Fig. A14. Pooled studies investigating right amygdala volumes in PTSD subjects vs. trauma exposed controls..
Fig. A15. Pooled studies investigating combined left and right amygdala volumes in PTSD subjects vs. trauma exposed controls..
Fig. A16. Pooled studies investigating left amygdala volumes in PTSD subjects vs. healthyþ trauma exposed controls..
Fig. A17. Pooled studies investigating right hippocampal volumes in PTSD subjects vs. healthy þ trauma exposed controls..
Fig. A18. Pooled studies investigating combined left and right amygdala volumes in PTSD subjects vs. healthy þ trauma exposed controls..
Fig. A19. Pooled studies investigating left ACC volumes in PTSD subjects vs. healthy controls..
Fig. A20. Pooled studies investigating right ACC volumes in PTSD subjects vs. healthy controls..
Fig. A21. Pooled studies investigating combined left and right ACC volumes in PTSD subjects vs. healthy controls..
Fig. A22. Pooled studies investigating left ACC volumes in PTSD subjects vs. trauma exposed controls..
Fig. A23. Pooled studies investigating right ACC volumes in PTSD subjects vs. trauma exposed controls..
Fig. A24. Pooled studies investigating combined left and right ACC volumes in PTSD subjects vs. trauma exposed controls..
Fig. A25. Pooled studies investigating left ACC volumes in PTSD subjects vs. healthy þtrauma exposed controls..
Fig. A26. Pooled studies investigating right ACC volumes in PTSD subjects vs. healthy þtrauma exposed controls..
Fig. A27. Pooled studies investigating combined left and right ACC volumes in PTSD subjects vs. healthy þtrauma exposed controls..
Table A1
Hippocampal studies participant characteristics.
Subjects
Study PTSD Healthy controls Traumatised control
N M/F Age Mean time since trauma N M/F Age N M/F Age
1 Apfel et al. (2011) 41 32/9 42.17 9.6 410 years 95 81/14 46.4 7 9.6 64 58/6 44.4 79.6
2 Bonne et al. (2001) 10 3/7 33.77 8.9 6 months – – – 27 15/12 29.8 7 10.1
3 Bonne et al. (2008) 22 3/19 36.0 7 10.4 410 years 22 3/19 35.8 710.4 – – –
4 Bossini et al. (2008) 34 13/21 37.977 10.5 43 years 34 13/21 37.82 7 10.7 – – –
5 Bremner et al. (1995) 26 26M 46.0 7 1.8 410 years 22 22M 44.5 7 7.3 – – –
6 Bremner et al. (1997) 17 12/5 40.17 5.7 410 years 17 12/5 42.4 7 7.3 – – –
7 Bremner et al. (2003) 10 10F 35.07 6.0 410 years 11 11F 38.0 7 7.0 12 12F 32.0 7 8.0
8 Chen et al. (2006) 12 8/4 34.56 7 4.91 o1 year – – – 12 8/4 33.257 5.27
9 Driessen et al. (2000) 12 12F 29.9 7 6.0 NR – – – 9 9F 29.3 7 6.7
10 Emdad et al. (2006) 23 23M 38.65 7 6.23 45 years 17 17M 37.88 7 8.58 – – –
11 Felmingham et al. (2009) 21 NR NRa 45 years – – – 17 NR NRa
12 Fennema-Notestine et al. (2002) 11 11F 33.57 10.3 NR 17 17F 35.3 712.5 11 11F 35.47 9.6
13 Freeman et al. (2006) 10 10M 79.6 7 3.2 410 years 6 6M 80.8 7 3.5 10 10M 79.8 7 2.8
14 Gilbertson et al. (2002) 12 12M 53.17 3.3 410 years – – – 23 23M 51.8 7 2.3
15 Golier et al. (2005) 14 5/9 70.57 5.6 410 years 20 13/7 71.4 7 6.4 13 6/7 68.57 7.3
16 Jatzko et al. (2006) 15 13/2 48.27 12.2 410 years 15 13/2 47.9 7 12.9 – – –
17 Landre et al. (2010) 17 17F 24.97 4.8 410 years 17 17F 24.7 74.6 – – –
18 Lindauer et al. (2004) 14 8/6 35.47 11.2 43 years – – – 14 8/6 36.9 7 10.1
19 Lindauer et al. (2005) 18 8/10 39.6 7 9.0 43 years – – – 14 8/6 36.9 7 10.1
20 Morey et al. (2012) 99 79/20 38.4 7 9.9 48 years – – – 102 86/16 37.5 7 10.6
21 Pavic et al. (2007) 15 15M 41.0 7 5.37 49 years 15 15M 41.0 7 5.37 – – –
22 Pederson et al. (2004) 17 17F 24.87 5.2 410 years 17 17F 23.8 7 5.6 17 17F 26.8 7 6.6
23 Rogers et al. (2009) 9 5/4 44.56 7 15.96 410 years – – – 16 10/6 44.447 13.60
24 Schmahl et al. (2009) 10 10F 28.50 7 6.06 410 years – – – 15 15F 29.337 7.29
25 Schuff et al. (2001) 18 18M 51.2 7 2.5 NR 19 19M 51.8 73.2 – – –
26 Shu et al. (2013) 11 2/9 36.3 7 12.9 o1 year 11 2/9 35.3 711.4 – – –
27 Stein et al. (1997) 21 21F 32.0 7 6.3 410 years 21 21F 30.2 7 6.4 – – –
28 Villarreal et al. (2002) 12 2/10 43.0 7 9.3 410 years 10 10F 44.0 7 11.4 – – –
29 Vythilingam et al. (2005) 14 8/6 35.07 9.0 410 years 23 9/20 34.0 7 10.0 23 15/8 35.07 7.0
30 Wang et al. (2010) 17 17M 41.0 7 12.0 410 years – – – 19 19M 38.0 7 15.0
31 Weniger et al. (2008) 10 10F 32.0 7 7.0 410 years 25 25F 33.0 77.0 – – –
32 Wignall et al. (2004) 15 9/6 43.0 7 9.0 o1 year 11 9/2 29.0 7 10.0 – – –
33 Winter and Irle (2004) 15 15M 42.0 7 10.0 o2 years 15 15M 41.0 7 17.0 15 15M 41.0 7 11.0
34 Woodward et al. (2006b) 27 NRb NRb 410 years – – – 28 NRb NRb
35 Yehuda et al. (2007) 17 17M 60.6 7 7.0 410 years – – – 16 16M 65.1 79.9
36 Zhang et al. (2011) 10 10M 40.80 7 6.83 o1 year – – – 10 10M 34.30 7 5.37
676 460 487
NR¼ Not Reported.

a
Subjects aged matched to controls.
b
Gender and mean age for this subgroup of veterans with or without alcoholism were not reported.
Appendix B1 Appendix C1
See Table B1. See Table C1.
Table B1
Amygdala studies participant characteristics.
Subjects
1 Bonne et al. (2001) 10 3/7 33.7 7 8.9 6 months – – – 27 15/12 29.8 7 10.1
2 Bremner et al. (1997) 17 12/5 40.17 5.7 4 10 years 17 12/5 42.4 7 7.3 – – –
3 Driessen et al. (2000) 12 12F 29.9 7 6.0 NR – – – 9 9F 29.3 7 6.7
4 Fennema-Notestine et al. (2002) 11 11F 33.5 7 10.3 NR 17 17F 35.3 712.5 11 11F 35.47 9.6
5 Gilbertson et al. (2002) 12 12M 53.17 3.3 4 10 years 23 23M 51.8 72.3 23 23M 51.8 7 2.3
6 Kuo et al. (2012) 42 42M 49.57 8.6 4 10 years – – – 45 45M 44.5 77.3
7 Landre et al. (2010) 17 17F 24.9 7 4.8 4 10 years 17 17F 24.7 74.6 – – –
8 Lindauer et al. (2004) 14 8/6 35.4 7 11.2 4 3 years – – – 14 8/6 36.9 7 10.1
9 Lindauer et al. (2005) 18 8/10 39.6 7 9.0 4 3 years – – – 14 8/6 36.9 7 10.1
10 Morey et al. (2012) 99 79/20 38.4 7 9.9 4 8 years – – – 102 86/16 37.5 7 10.6
11 Rogers et al. (2009) 9 5/4 44.56 7 15.96 4 10 years – – – 16 10/6 44.447 13.60
12 Schmahl et al. (2009) 10 10F 28.50 7 6.06 4 10 years – – – 15 15F 29.337 7.29
13 Weniger et al. (2008) 10 10F 32.0 7 7.0 4 10 years 25 25F 33.0 77.0 – – –
14 Wignall et al. (2004) 15 9/6 43.0 7 9.0 o 1 year 11 9/2 29.0 7 10.0 – – –
296 110 276
NR¼ Not Reported.

Table C1
ACC studies participant characteristics.
Subjects
1 Chen et al. (2006) 12 8/4 34.56 7 4.91 o 1 year – – – 12 8/4 33.257 5.27
2 Chen et al. (2012) 10 10M 40.8 7 6.8 o 1 year 20 20M 37.6 7 7.0 – – –
3 Corbo et al. (2005) 14 6/8 33.367 12.06 o 6 months 14 6/8 33.297 12.31 – – –
4 Eckart et al. (2011) 20 20M 36.2 7 7.7 4 10 years 13 13M 29.0 7 7.2 19 19M 34.17 9.9
5 Felmingham et al. (2009) 21 NR NRa 4 5 years – – – 17 NR NRa
6 Kitayama et al. (2006) 8 1/7 43.0 7 7.0 NR 13 1/12 37.0 7 8.0 – – –
7 Rauch et al. (2003) 9 9F 51.7 7 1.9 4 10 years – – – 9 9F 52.0 7 1.9
8 Rocha-Rego et al. (2012) 16 7/9 43.3 7 5.78 4 3 years – – – 16 7/9 44.9 7 6.60
9 Woodward et al. (2006a) 51 38Mb 53.5 7 2.6b 4 10 years – – – 48 25Mb 56.0 7 3.5b
13Mc 37.0 7 5.7c 23Mc 36.7 7 3.9c
161 60 121
NR¼ Not Reported.

a
¼ Subjects aged matched to controls.
b
¼ Vietnam Cohort.
c
¼ Persian Gulf Cohort.
Appendix D1 Adamec, R., Hebert, M., Blundell, J., Mervis, R.F., 2012. Dendritic morphology of
amygdala and hippocampal neurons in more and less predator stress respon-
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Carvalho, R.F., Carvalho, A.P., Duarte, C.B., 2005. Neuroprotection by BDNF
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Hippocampus M.W., Schuff, N., Neylan, T.C., 2011. Hippocampal volume differences in Gulf
PTSD vs. HC left volume 21 31.82 20 37.14 p o0.05 War veterans with current versus lifetime posttraumatic stress disorder
PTSD vs. HC right volume 21 40.73 20 50.89 p o0.005 symptoms. Biological Psychiatry 69, 541–548.
PTSD vs. HC combined volume 44 73.41 43 42.79 p o0.005 Arborelius, L., Owens, M.J., Plotsky, P.M., Nemeroff, C.B., 1999. The role of
PTSD vs. TC left volume 18 59.37 17 73.05 p o0.001 corticotropin-releasing factor in depression and anxiety disorders. Journal of
PTSD vs. TC right volume 16 30.92 15 54.72 p o0.01 Endocrinology 160, 1–12.
PTSD vs. TC combined volume 37 92.03 36 61.97 p o0.001 Australian Bureau of Statistics, 2007. (Cat. no. 4326.0). In: ABS (Ed.), National
Survey of Mental Health and Wellbeing: Summary of Results, 2007. Australian
PTSD vs. HC þ TC left volume 31 85.60 30 66.51 p o0.001
Bureau of Statistics, Canberra.
PTSD vs. HC þ TC right volume 29 60.15 28 55.11 p o0.001
Bennett, M.R., Lagopoulos, J., 2014. Stress and trauma: BDNF control of dendritic-
PTSD vs. HC þ TC combined 65 149.84 64 58.62 p o0.001
spine formation and regression. Progress in Neurobiology 112, 80–99.
volume Bluhm, R.L., Williamson, P.C., Osuch, E.A., Frewen, P.A., Stevens, T.K., Boksman, K.,
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PTSD vs. HC left volume 6 28.42 5 82.41 p o0.001 connectivity in posttraumatic stress disorder related to early-life trauma.
PTSD vs. HC right volume 6 25.65 5 80.50 p o0.001 Journal of Psychiatry and Neuroscience 34, 187–194.
PTSD vs. HC combined volume 12 54.66 11 79.87 p o0.001 Bonne, O., Brandes, D., Gilboa, A., Gomori, J.M., et al., 2001. Longitudinal MRI study
PTSD vs. TC left volume 9 12.19 8 42.58 p o0.05 of hippocampal volume in trauma survivors with PTSD. The American Journal
PTSD vs. TC right volume 9 16.80 8 58.33 p o0.05 of Psychiatry 158, 1248–1251.
PTSD vs. TC combined volume 19 31.22 18 48.75 p o0.01 Bonne, O., Vythilingam, M., Inagaki, M., Wood, S., Neumeister, A., Nugent, A.C.,
PTSD vs. HC þTC left volume 13 45.73 12 75.95 p o 0.001 Snow, J., Luckenbaugh, D.A., Bain, E.E., Drevets, W.C., Charney, D.S., 2008.
PTSD vs. HC þTC right volume 13 41.27 12 73.35 p o0.001 Reduced posterior hippocampal volume in posttraumatic stress disorder.
PTSD vs. HC þTC combined 27 90.01 26 73.35 p o0.001 Journal of Clinical Psychiatry 69, 1087–1091.
volume Borenstein, M., Hedges, L.V., Higgins, J.P., Rothstein, H., 2011. Comprehensive Meta-
ACC Analysis: A Computer Program for Meta-Analysis, Comprehensive Meta-
Analysis, 2.2.046 ed. Biostat Inc., Englewood, NJ.
PTSD vs. HC left volume 4 10.21 3 70.62 p o0.05
Borenstein, M., Hedges, L.V., Higgins, J.P.T., Rothstein, H.R., (Eds) 2009. Front matter.
PTSD vs. HC right volume 3 4.18 2 52.15 p ¼0.124
Introduction to Meta-Analysis. John Wiley & Sons, Ltd., New York, pp.i–xxix.
PTSD vs. HC combined volume 7 14.53 6 58.71 p o0.05
Bossini, L., Tavanti, M., Calossi, S., Lombardelli, A., Polizzotto, N.R., Galli, R., Vatti, G.,
PTSD vs. TC left volume 6 13.60 5 70.59 p o 0.01 Pieraccini, F., Castrogiovanni, P., 2008. Magnetic resonance imaging volumes of
PTSD vs. TC right volume 5 4.42 4 32.15 p ¼0.352 the hippocampus in drug-naive patients with post-traumatic stress disorder
PTSD vs. TC combined volume 12 19.87 11 59.74 p o0.01 without comorbidity conditions. Journal of Psychiatric Research 42, 752–762.
PTSD vs. HC þTC left volume 9 24.91 8 71.90 p o0.001 Bremner, J.D., 1999. Does stress damage the brain? Biological Psychiatry 45,
PTSD vs. HC þTC right volume 7 6.90 6 27.58 p ¼0.352 797–805.
PTSD vs. HC þTC combined 27 33.02 26 60.63 p o0.001 Bremner, J.D., 2003. Functional neuroanatomical correlates of traumatic stress revisited
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Bremner, J.D., Narayan, M., Anderson, E.R., Staib, L.H., Miller, H.L., Charney, D.S.,
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A Systematic Review and Meta-Analysis of Magnetic Resonance Imaging Measurement of Structural Volumes in Posttraumatic Stress Disorder

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Psychiatry Research: Neuroimaging 232 (2015) 1–33

Contents lists available at ScienceDirect

Psychiatry Research: Neuroimaging

A systematic review and meta-analysis of magnetic resonance imaging

2.1. Characteristics of studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1. Introduction dissociation and problems memory (Daniels et al., 2010; Lanius

Study ROI PTSD Healthy controls Traumatised control

D.C.M. O'Doherty et al. / Psychiatry Research: Neuroimaging 232 (2015) 1–33

Most previous meta-analyses have focused on the volume

participants with PTSD showed reduced functional connectivity

actions, and thoughts of future events pertaining to self (Buckner et al.,

ference in PTSD sufferers' ability to mentally prepare for self-refere-

ntial future events before and while they experience them.

interoception, as well as autonomic and reward processing (Dose-

with disrupted connection between the DMN and SN potentially

DMN is likely to result in hypervigilance and hyperarousal, which are

light on the volumetric abnormalities in PTSD subjects when com-

PTSD maintenance—speciﬁcally the hippocampus, the amygdala and

2.1. Characteristics of studies

et al., 2012; Shu et al., 2013).

Yehuda et al. (2007)

MDD¼ major depressive disorder.

information is available in Table 1.

2.2. Literature search and inclusion criteria

A literature search was conducted in Embase, Medline, PubMed and PsycINFO in

Study PTSD Healthy controls Traumatised control

NR¼ Not Reported.

See Table B1. See Table C1.

Study PTSD Healthy controls Traumatised control

NR¼ Not Reported.

Study PTSD Healthy controls Traumatised control

NR¼ Not Reported.

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