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Different neural modifications underpin PTSD after different traumatic events:
an fMRI meta-analytic study.
Maddalena Boccia1,2*, Simonetta D’Amico3, Filippo Bianchini1,2, Assunta Marano3,
Anna Maria Giannini2, Laura Piccardi1,3
1 Neuropsychology Unit, IRCCS Fondazione Santa Lucia of Rome, Italy
2!Department of Psychology, “Sapienza” University of Rome, Italy
3 Department of Life, Health and Environmental Sciences, L’Aquila University, Italy
*Corresponding author
Maddalena Boccia
Department of Psychology,
“Sapienza” University of Rome
Via dei Marsi, 78
00185 Rome (Italy)
maddalena.boccia@uniroma1.it
tel. +390651501547
fax. +390651501213
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Abstract
Post-traumatic stress disorder (PTSD) is an anxiety condition that can develop after
exposure to trauma such as physical or sexual assault, injury, combat-related trauma,
natural disaster or death. Although an increasing number of neurobiological studies
carried out over the past 20 years have allowed clarifying the neural substrate of
PTSD, the neural modifications underpinning PTSD are still unclear. Here we used
activation likelihood estimation meta-analysis (ALE) to determine whether PTSD has
a consistent neural substrate. We also explored the possibility that different traumatic
events produce different alterations in the PTSD neural network. In neuroimaging
studies of PTSD, we found evidence of a consistent neural network including the
bilateral insula and cingulate cortex as well as the parietal, frontal and limbic areas.
We also found that specific networks of brain areas underpin PTSD after different
traumatic events and that these networks may be related to specific aspects of the
traumatic events. We discuss our results in light of the functional segregation of the
brain areas involved in PTSD.
Keywords: PTSD; fMRI; ALE meta-analysis
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1.!Introduction
Post-traumatic stress disorder (PTSD) is an anxiety condition that can develop after
exposure to trauma such as physical or sexual assault, injury, combat-related trauma,
natural disaster or death, but also after witnessing or indirect exposure, by learning
that a close relative or close friend was exposed to trauma, or in the course of
professional duties (American Psychiatric Association, 2013). PTSD is a complex
syndrome with pathognomonic symptomatology that includes the following: re-
experiencing of trauma-related aspects (events), avoidance of trauma-related
situations, hyperarousal and emotional numbing, together with poor concentration and
difficulty explicitly recalling aspects of the traumatic event (American Psychiatric
Association, 2013). Mild cognitive deficits are also observed in PTSD, such as
impoverished autobiographical memory for positive events (Harvey et al., 1998;
Mcnally et al., 1995) and attentional and working memory deficits (Vasterling et al.,
1998; 2002). Furthermore, electrophysiological studies found that PTSD is associated
with enhanced processing of trauma-related stimuli (Karl et al., 2006). Over the past
twenty years the neurobiological mechanisms underlying PTSD have been studied
extensively in both human and animal models and have led to significant findings
(Pitman et al., 2012). First, we will review the main neuropsychological and
neurobiological findings in PTSD. Then, we will carry out a meta-analysis on fMRI
studies of PTSD using activation likelihood estimation (ALE) (Eickhoff et al. 2009)
to verify the existence of consistent neural modifications in PTSD. We also explored
the possibility that different traumatic events produce different neural alterations in
the neural network of PTSD, by means of single ALE meta-analyses. For easiness of
exposition the introduction will be divided into subheadings.
1.1.!Neuropsychological and neurobiological aspects of PTSD
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Neuroimaging studies have brought to light important findings regarding the neural
substrates of PTSD. Most of these studies examined the structural brain changes
related to PTSD symptomatology (Karl et al., 2006; Kitayama et al., 2005). The most
common finding of these studies concerns the lower volume of the hippocampus
(Bremner et al., 1995; Gurvits et al., 1996; Stein et al., 1997; Kitayama et al., 2005;
Smith, 2005; Karl et al., 2006) and the ventromedial prefrontal cortex (vmPFC)
(Kasai et al., 2008). As these structures are respectively involved in declarative
episodic memory and in recalling extinction of fear conditioning, it has been
hypothesized that their structural changes have a crucial role in maintaining two
pathognomonic symptoms of PTSD: a deficit in using contextual cues in the
environment and a deficit in maintaining extinction of conditioned emotional
responses once traumatic learning is no longer relevant (Pitman et al., 2012).
Neuropsychological studies in patients with PTSD have demonstrated deficits in
specific cognitive domains which are compatible with the structural brain
modifications that occur in PTSD. Many studies investigated the association between
memory and PTSD and the majority found that PTSD patients performed worse than
controls (Vasterling and Brailey, 2005). Attentional deficits were also found in PTSD
patients (Vasterling et al., 2002; 1998) as were deficits in executive functioning,
especially for working memory (Brandes et al., 2002; Jenkins et al., 2000; Vasterling
et al., 1998; 2002), the presence of perseverations (Koenen et al., 2001), reduced
phonemic fluency (Bustamante et al., 2001) and semantic fluency (Gil, 1990). Other
neuropsychological domains, such as visuospatial processing (Gilbertson et al., 2001),
(Sullivan et al., 2003), language (Gurvits et al., 1993) and motor functioning (Gurvits
et al., 2002; Sullivan et al., 2003) were found spared in PTSD patients.
1.2.!Functional neuroimaging studies in PTSD
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Functional neuroimaging studies using both Positron Emission Tomography (PET)
and functional Magnetic Resonance Imaging (fMRI) shed more light on the neural
mechanisms underlying PTSD, supporting structural brain abnormalities and
neuropsychological findings. Etkin and co-workers (Etkin and Wager, 2007) found
that a common brain mechanism subtends anxiety disorders and normal fear and that
PTSD is particularly related to functional alterations at the level of the cingulate
cortex and vmPFC. Commonly fMRI and PET studies of PTSD had shown altered
activity in the amygdala, vmPFC, cingulate cortex, hippocampal and insular cortex
(Pitman et al., 2012).
Different experimental paradigms were developed in functional neuroimaging studies
to assess the neural correlates of PTSD. For example, several studies assessed the
functional neural correlates of PTSD in relation to specific cognitive functions by
using tasks that tap on different cognitive domains, for example, working memory
with an n-back task (Shaw et al., 2002), declarative episodic memory with encoding
and retrieval of words (Chen et al., 2009) or executive functioning with a go no-go
task (Falconer et al., 2008). Some other studies directly tested emotional processing
using an affective priming task (Mazza et al., 2012) or presenting affective pictures
(Ekman, 1993). And other investigations directly tested the processing of traumatic
pictures above (Hou et al., 2007; Morey et al., 2008) and below (Sakamoto et al.,
2005) the cognitive threshold. Still others adopted trauma-related sounds by means of
auditory stimulation (Pissiota et al., 2002). A study by Geuze and co-workers (Geuze
et al., 2007) tested pain processing directly using individual temperature threshold.
Britton and co-workers (Britton et al., 2005) used personalized scripts for each
participant before the scans that recalled individual memories about the trauma.
Finally, many studies used Shin and co-workers’ method (Shin et al., 1997) in which
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participants are asked to mentally generate trauma-related images (Shin et al., 1999;
Lanius et al., 2002; 2003; 2004; 2005; 2007). All of these studies included PTSD
patients and a control group of no-PTSD participants. In some studies patients with
PTSD had experienced different traumatic events (Falconer et al., 2008; Lanius et al.,
2003; 2004; 2007; Shaw et al., 2002; Sakamoto et al., 2005) and in others all
participants had experienced the same specific trauma, for example, a natural disaster
(Mazza et al. 2012; Chen et al., 2009; Hou et al., 2007) or physical or sexual abuse
(Lanius et al., 2002; 2005; Shin et al., 1999). In others participants were all veterans
who had experienced combat-related trauma (Pissiota et al., 2002; Britton et al., 2005;
Morey et al., 2008; Geuze et al., 2007). Besides investigating common functional
abnormalities in PTSD, it is also important to determine whether trauma-related
neural modifications are present. This, in turn, is important for developing therapeutic
approaches for PTSD. Indeed, it would help identify the neural mechanisms
subtending PTSD that arise from different events. It can be hypothesized that since
different therapeutic approaches tap on different aspects of PTSD some might be
better than others for treating specific trauma-related symptoms. For example,
Exposure Therapy (Rauch et al., 2012) might be better for coping with deficits in
maintaining the extinction of conditioned emotional responses and processing
contextual cues, and Cognitive Therapy (Polak et al., 2012) for coping with avoidance
of trauma-related situations, etc. A neuroimaging approach could elucidate specific
trauma-related mechanisms in the functional domain. Due to the increasing number of
neuroimaging studies of PTSD, it is possible to test the hypothesis that PTSD is
functionally segregated from different traumatic events using a meta-analytic
approach.
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In this study we aimed to provide evidence that consistent neural substrates underlie
PTSD. Basing on previous findings, which found evidence for consistent structural
brain modifications in PTSD patients (Kitayama et al., 2005; Karl et al., 2006), we
expected to find also consistent functional modifications in these patients.
Furthermore, we explored the possibility that different traumatic events produce
different neural alterations in the neural network of PTSD. To pursue this aim, we
performed an Activation likelihood estimation (ALE) analysis, which allows for
coordinate-based meta-analyses of neuroimaging data (Fox et al., 2014). We selected
studies that provided activation foci derived from the direct comparison between
people with PTSD and healthy controls. This will allow assessing the role of the
traumatic events, overcoming the limitations of the single study approach, such as
small sample size, adopted paradigm, low reliability and logical subtraction, which is
sensitive only to differences between conditions.
2.!Method
2.1.!Studies/samples
Using the BrainMap database (www.brainmap.org), 16 papers reporting 55 individual
experiments (815 subjects) with a total of 351 activation foci were obtained. Inclusion
criteria for papers were: 1) use of functional magnetic resonance imaging (fMRI) or
positron emission tomography (PET), 2) inclusion of coordinates of activation foci,
either in Montreal Neurological Institute (MNI) or Talairach reference space, 3)
inclusion of peak activations derived from comparisons between patients diagnosed
with PTSD and healthy age-matched controls.
All selected studies were included in the general ALE meta-analysis, but only studies
that controlled for the traumatic event (i.e. sexual/physical abuse, combat-related
trauma and natural disaster) were included in further analyses on the role of the
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traumatic event. Thus, we found i) 13 individual experiments (113 subjects) with a
total of 100 foci in the studies in which the traumatic event was sexual/physical abuse,
ii) 16 individual experiments (366 subjects) with a total of 130 foci in the studies
investigating combat-related trauma (PTSD participants were veterans), iii) 9
individual experiments (105 subjects) with a total of 38 foci in the studies in which
the traumatic event was a natural disaster (see table 1).
---Insert Table 1 about here---
2.2.!Activation likelihood estimation (ALE) analysis
Activation likelihood estimation (ALE) was performed on activation-location
coordinates from selected studies. Actually, a great advantage of ALE meta-analysis
is that the tables of coordinates routinely reported by neuroimaging studies are its
input data (Fox et al., 2014). ALE models the uncertainty in localization of activation
foci using Gaussian distribution (Fox et al., 2014) and analyzes the probability that a
voxel will contain at least one of the activation foci; it is calculated at each voxel and
results in a thresholded ALE map. In other words, ALE assesses the overlap between
foci by modeling the probability distributions centered at the coordinates of each one
(Eickhoff et al., 2009).
First, we performed a general ALE analysis to determine whether a consistent neural
substrate of PTSD was found across neuroimaging studies regardless of the kind of
traumatic event. Then, we determined whether there were specific neural
modifications in relation to the type of trauma by carrying out three ALE analyses of
i) sexual/physical abuse PTSD (SP); ii) combat-related trauma PTSD (CR); and iii)
natural disaster PTSD (ND). Data from studies that failed to explicitly report the
traumatic event or did not control for the type of trauma were excluded from these
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analyses.
We performed paired contrast analyses to directly compare the effects of the trauma
([SP>CR]; [CR >SP]; [CR >ND]; [ND> CR]; [SP>ND]; [ND>SP]). These contrast
analyses allowed highlighting voxels whose signal was greater in the first than the
second condition.
By means of meta-analytic connectivity modeling (MACM), which allows for
assessing the functional connectivity of specific brain regions (Robinson et al., 2010),
we investigated the functional connectivity of a brain region that emerged as more
highly involved in PTSD after physical/sexual abuse than combat-related trauma.
The ALE meta-analysis was performed using GingerALE 2.1.1 (brainmap.org) with
MNI coordinates (Talairach coordinates were automatically converted into MNI
coordinates by GingerALE.). According to Eickhoff et al.’s (Eickhoff et al., 2009)
modified procedure, the ALE values of each voxel in the brain were computed and a
test was performed to determine the null distribution of the ALE statistic of each
voxel. The FWHM value was automatically computed because this parameter is
empirically determined (Eickhoff et al., 2009). The thresholded ALE map was
computed using p values from the previous step and a False Discovery Rate (FDR) at
the 0.05 level of significance (Tom Nichol’s FDR algorithm). Moreover, a minimum
cluster size of 200 mm3 was chosen. A cluster analysis was performed on the
thresholded map. The ALE results were registered on an MNI-normalized template
(brainmap.org) using Mricro
(http://www.mccauslandcenter.sc.edu/mricro/index.html).
3.!Results
3.1.!General ALE: evidence that PTSD has a common neural network
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The general ALE meta-analysis showed consistent activations across neuroimaging
studies of PTSD at the level of the bilateral anterior cingulate cortex (ACC), middle
cingulate cortex (MCC) and right posterior cingulate cortex (PCC). We also found
consistent activations in the bilateral medial frontal gyrus, specifically at the level of
the orbitofrontal cortex (mOFC), middle frontal gyrus and left insula (Ins). At the
level of the middle temporal lobe we found clusters of activation at the level of the
right hippocampus (HC) and parahippocampal gyrus (PHG); on the lateral face of the
temporal lobe we found activation of the bilateral superior temporal gyrus (STG).
Finally, we found activation of the claustrum and specific thalamic nuclei (see Table
2 and Figure 1).
---Insert table 2 about here---
---Insert figure 1 about here---
3.2.!ALE analysis on PTSD due to physical and sexual abuse
The ALE analysis of neuroimaging studies that assessed PTSD in patients who had
experienced physical and sexual abuse showed clusters of activation in the bilateral
ACC and MCC, precuneus (pCU), superior occipital gyrus (SOG) and middle frontal
gyrus (Figure 2A).
---Insert figure 2 about here---
3.3.!ALE analysis of PTSD due to combat-related trauma
The ALE analysis of neuroimaging studies that assessed PTSD in veterans with
combat-related trauma showed clusters of activation in the bilateral HC, ACC and
STG. We also found activations in the right inferior frontal gyrus (IFG), medial and
middle frontal gyrus, inferior parietal lobule (IPL) and pCU. Sub-nuclear activations
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were found at the level of the left caudate nucleus (CN), claustrum, globus pallidus
and right claustrum and putamen (Figure 2B).
3.4.!ALE analysis of PTSD caused by natural disaster
The ALE analysis of neuroimaging studies that assessed PTSD caused by natural
disasters showed clusters of activation in the right superior frontal gyrus (SFG) and
STG, left middle frontal gyrus and bilateral PHG (Figure 2C).
3.5.!Contrast analyses
The only T contrast that showed suprathreshold activation was [SP>CR], which
showed clusters of voxels that were more activated by SP than CR at the level of the
bilateral MCC (Figure 3A). No suprathreshold clusters were revealed by the other T
contrasts ([CR >SP], [CR>ND], [ND>CR], [SP>ND] and [ND>SP]), suggesting that
the neural areas involved in PTSD from these types of events partially overlap.
3.6.!Functional connectivity of the MCC
Thus, we assessed the functional connectivity of the MCC by means of MACM.
MACM showed patterns of functional connectivity of the MCC, especially at the
level of the frontal, parietal and limbic lobes (Figure 3B). In detail, we found clusters
of activation in the frontal lobe at the level of the bilateral precentral gyrus, left
medial frontal gyrus and right IFG. At the level of the limbic lobe we found
activations of the right ACC and MCC and bilateral PHG. Furthermore, at the level of
the parietal lobe we found activation of bilateral postcentral gyrus, left paracentral
gyrus and right IPL, and in the temporal lobe we found activation in the left STG. We
also found bilateral activation of the insula. At the sub-lobar level, we found
activations of the bilateral claustrum, the basal ganglia, especially the bilateral globus
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pallidus and right putamen. At the level of the thalamus, we found activation in the
right medial dorsal nucleus and left ventral lateral nucleus.
---Insert Figure 3 about here---
4.!Discussion
The aim of the present ALE meta-analysis was to find evidence of a consistent PTSD
neural substrate. We also wanted to determine whether functional segregation exists
for different traumatic events in this network of areas.
PTSD is the only major mental disorder with a known cause, that is, an event that
threatens one’s physical integrity or that of others and induces a response of intense
fear, helplessness or horror (Pitman et al., 2012). Although different studies have
found common neural mechanisms underpinning PTSD symptomatology, including
intrusive memories of the traumatic event, avoidance of reminders of it, emotional
numbing and hyperarousal (Pitman et al., 2012), no previous study has assessed the
effect of different traumatic events on the brain mechanisms underlying PTSD.
Clinical trials suggest that different traumatic events interact with individual factors
(such as personality, gender and genetic factors) and lead to different physical and
behavioral outcomes as well as a different prevalence of PTSD (Husarewycz et al.,
2014; Perrin et al., 2013; Ditlevsen and Elklit, 2012; Santiago et al., 2013).
4.1.!The common neural substrates of PTSD
Our first aim was to find evidence of a consistent neural substrate of PTSD. Our
results clearly demonstrate that PTSD has a common neural substrate regardless of
the type of traumatic event. This neural substrate includes a network of brain areas
that span from the parietal to the frontal lobe and also include the limbic structures
and cingulate cortex. Most of these brain areas are frequently reported in
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neuroimaging studies of PTSD and are hypothesized to play complementary roles in
maintaining the PTSD symptomatology, such as fear conditioning of trauma-related
stimuli and failing to recall fear extinction (Pitman et al., 2012). In particular, models
of the human neural network of PTSD posit that the ventromedial prefrontal cortex
fails to inhibit the amygdala, whose hyperactivation leads to an increase in the fear
response, impaired extinction of traumatic memories and deficits in emotion
regulation (Elzinga and Bremner, 2002; Rauch et al., 2006). In our meta-analysis we
found that PTSD patients, unlike healthy controls, showed higher activation of the
MCC and ACC, structures, which have been hypothesized to be the human
homologue of animals’ prelimbic cortex, a brain region that facilitates the expression
of conditioned fear (Morrow et al., 1999; Herry et al., 2010; Milad and Quirk, 2012).
We also found hyperactivation of the bilateral insula, which has been repeatedly
associated with severity of PTSD symptoms (Simmons et al., 2008). The insular
cortex is involved in monitoring internal body states, thus in perceiving feelings from
the body, stress levels, mood and disposition (Craig, 2002). It also seems to be
involved in several anxiety disorders (Etkin and Wager, 2007). In PTSD, insula
hyperactivation could be due to interception of the increased arousal associated with
the trauma-related stimuli. In addition to the hyperactivation observed in the cingulate
cortex and insula, we also observed hyperactivation of a set of frontal areas mainly
located at the level of the dorsal medial prefrontal cortex. These regions have been
frequently associated with emotional conflict (Etkin et al., 2006), emotional arousal
(Taylor et al., 2003), autonomic activity (Critchley, 2005) and anticipation of aversive
events (Kalisch et al., 2005). All of these alterations are frequently reported in PTSD
and the set of dorsal medial prefrontal areas we found in the present meta-analysis
could be involved in the maintenance of PTSD-related symptoms, such as higher
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emotional arousal, emotional conflict, dysfunction of autonomic activity and, above
all, anticipation of aversive events strictly connected with the avoidance of trauma-
associated stimuli.
We also found hippocampal hyperactivation in PTSD patients. The role of the
hippocampus in PTSD has not yet been established. Indeed, some studies reported
hippocampal hypoactivation (Bremner et al., 2003) and others, hippocampal
hyperactivation (Shin and Liberzon, 2010). Structural brain imaging findings
demonstrate smaller hippocampal volume in PTSD patients (Kitayama et al., 2005).
The hippocampal cortex is involved in declarative episodic memory and its lesioning
produces the well-known medial temporal lobe amnesia (Milner, 2005; Bohbot and
Corkin, 2007). The Multiple Trace Theory (MTT), which is one of the latest theories
on the role of the hippocampus in declarative memory, posits that a new trace is
formed in the hippocampus every time a certain memory is recollected; thus, older
memories become more resistant to hippocampal damage or become semantic and
independent from the hippocampus (Moscovitch et al., 2005; 2006). According to the
MTT, the hippocampal hyperactivation we found in PTSD may be due to the
recurrence of intrusive memories about the traumatic event. Indeed, this is frequently
reported by patients and considered one of the pathognomonic symptoms of PTSD
(Pitman et al., 2012). We also found consistent activation across neuroimaging studies
of PTSD at the level of the parietal lobe, in particular the right IPL. This region was
recently found to be involved in pain and force processing (Misra and Coombes,
2014). In light of this recent finding, and also considering evidence of a hippocampal-
parietal memory network (Vincent et al., 2006), IPL seems to be the part of the PTSD
neural network that is involved in remembering the pain experienced during the
trauma. This confirms what already emerged in Karl and co-workers’ (Karl et al.,
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2006) meta-analysis of structural brain imaging. These authors posited that the
hippocampus could be crucial in the neuropathology of PTSD because of its
connections with the parietal lobe.
Finally, we found evidence for consistent modifications of the thalamic activation in
PTSD patients. It is widely known that thalamus plays a crucial role in consciousness
(Damasio, 1999) and in the interaction between attention and arousal (Portas et al.,
1998), other than serving as the main synaptic relay station for sensory information
(Kandel et al., 1991). Its alteration in PTSD patients may reflect their altered
conscious experience (Lanius et al., 2005) as well as hyperarousal and attentional
deficits usually observed in these patients.
Unlike previous studies (Rauch et al., 2000; Shin et al., 2004; Protopopescu et al.,
2005; Hopper et al., 2007; Simmons et al., 2011; Rabinak et al., 2011; Sripada, et al.,
2012), we failed to find amygdalar hyperactivation in PTSD patients. Amygdala is
notoriously difficult to image due to its susceptibility to artifact and its small volume
(Hayes et al., 2012). Actually, amygdalar activation often results only using a less
stringent spatial extent in the whole brain analysis or leading region of interest
analyses (Hayes et al. 2012). Furthermore, amygdalar hyperactivation in PTSD
frequently results from the direct comparison between PTSD patients and healthy age-
matched controls who were not exposed to trauma, disappearing when PTSD patients
are compared with trauma-exposed controls, who experienced trauma without
developing PTSD (see for examples, Hou et al., 2007; Lanius et al., 2003; 2004;
2007). Accordingly, amygdalar hyperactivation has been recently found to be related
more generally to trauma exposure (Patel et al., 2012).
4.2.!The trauma-related neural networks
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Our second aim was to find evidence of functional neural segregation of different
types of traumatic events in PTSD. We found that a specific network of areas,
including the MCC and ACC, pCU and middle frontal gyrus, is associated with PTSD
after physical or sexual abuse (SP). In particular, MCC was found to be more
activated by SP than CR trauma. As reported above, it has been hypothesized that the
cingulate cortex is the human homologue of the prelimbic cortex, which has been
found to facilitate the expression of conditioned fear in animals. It seems to play a
crucial role in PTSD. In any case, because of its selective involvement in SP trauma
some feasible considerations must be made about its functional role in PTSD
symptomatology. The cingulate cortex is related to pain processing (Vogt, 2005), with
functional specialization in its subregions depending on different factors such as fear
avoidance (anterior MCC), unpleasantness (posterior ACC) and skeletomotor
orientation to the noxious stimuli (posterior MCC). The anterior MCC was also found
to be equally involved in pain processing and motor control (Misra and Coombes,
2014). Our results suggest that after SP trauma PTSD produces neural alterations at
the level of the neural network involved in pain processing. The fact that SP activates
MCC more than CR suggests the presence of a specific motor component in the
noxious aspect of the trauma in SP PTSD. We explored the functional connectivity
pattern of MCC in order to better understand its role in PTSD. We found that activity
in the MCC significantly correlated with that of the SMA, insula, amygdala, ACC,
SFG, MFG and thalamus. The finding that activity in the MCC correlates
significantly with activity in the SMA supports the possibility of a specific motor
component in the noxious aspects of the trauma in SP PTSD. Furthermore, its
connections with other structures such as the amygdala, ACC and insula suggest that
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this region also receives information about other aspects of PTSD, such as fear
(amygdala), sadness (ACC) and proprioceptive information (insula).
We also found a specific network of areas related to PTSD after combat-related
trauma (CR). This network includes the bilateral insula and IFG, ACC, PCC, SPL and
hippocampus. The ACC is known to be involved in emotional processing, especially
of sadness (Vogt, 2005), and (as mentioned above) the insular cortex is involved in
monitoring internal body states. The fact that CR PTSD patients showed higher
activation in these brain areas suggests that neural modifications related to this type of
trauma especially involve the neural correlates of emotional processing and
interoception. On the other hand, veterans also show increased activation in the
retrospenial cortex (especially in the PCC) and hippocampus. The retrosplenial cortex
is known to be involved in a wide range of cognitive functions, including episodic
memory, navigation, imagining and planning for the future (Vann et al., 2009; Boccia
et al., 2014). In particular, PCC is most likely involved in hippocampus-dependent
functions, because of their dense anatomical connections (Vann et al., 2009). In any
case, it seems that both of these areas are engaged in a process that is not purely
mnemonic but is crucial for memory (Vann et al., 2009). Hassabis and Maguire
(Hassabis and Maguire, 2007) hypothesized that the hippocampus-RSC network
allows scene construction, that is, the process of mentally generating and maintaining
a complex and coherent scene or event that is necessary for autobiographical memory,
navigation and thinking about the future. This model accounts for the PCC
hyperactivation we found in CR PTSD, especially for autobiographical memories, and
indicates that hippocampal and retrosplenial hyperactivation could be the neural
correlates of reminiscences associated with trauma.
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Finally, we found that a set of areas, including the bilateral PHG, right STG and SFG
and left middle frontal gyrus, was activated in ND PTSD. This is somewhat
surprising, because PHG is involved in scene perception (Epstein and Morgan, 2012)
and thus is frequently reported in studies of human spatial navigation (Boccia et al.,
2014). The neural alteration we observed in ND PTSD may have been due to the fact
that the natural disasters mostly involved the surrounding environment and familiar
places.
4.3.!Limitations
One of the major limits of the present study is the restricted number of studies, which
flaws the generalization of present results. Actually, it has to be noted that several
previous studies did not control for the type of traumatic event. Anyway, we would
highlight that meta-analyses, other than a quantitative review of neuroimaging
studies, may serve for hypothesis generation. In this light, results of our study, even if
with restrictions due to the limited number of studies, may serve a) to lay the
foundations for the hypothesis that different type of traumatic event may lead to
different neural modifications in PTSD and b) to establish the need to better control
for the type of traumatic event during fMRI investigations of PTSD.
5.!Conclusions and future directions
Overall, the results of the present meta-analysis indicate that a consistent neural
substrate underlies PTSD symptoms (Kitayama et al., 2005; Karl et al., 2006; Etkin
and Wager, 2007). Noteworthy, we found that different neural networks underpin
PTSD depending on the type of traumatic event. Indeed, we found that different types
of PTSD tap on different neural mechanisms according to functional specifications.
For example, SP PTSD is associated with neural alterations at the level of brain areas
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known to be involved in processing specific motor components of noxious stimuli
(MCC). And CR PTSD is associated with a network of brain areas known to be
involved in memory, emotional processing and interoception (HC, PCC, ACC and
insula). Finally, ND PTSD is associated with neural modifications in areas known to
be involved in environmental and space representation. This functional specialization
deserves some feasible considerations but it also requires further investigation. Our
results suggest the existence of trauma-specific dimensions that should be treated
specifically during PTSD therapy. In this light, our results also suggest the need for
greater control of trauma-related variables in PTSD studies, especially regarding
sample homogeneity. In any case, our results and the findings of previous
neuroimaging studies of PTSD do not allow excluding the role of pre-existing factors
in the development of PTSD. The next question that needs to be answered is whether
the neural alterations we found were an “effect” of PTSD or a “predictive” factor?
Further investigations are required to better clarify the role of the neural alterations
associated with PTSD.
Acknowledgements:
This research was supported by a grant from the Italian Association of Psychology
(AIP) to the Faculty of Psychology, University of L'Aquila, after the earthquake of
April 6, 2009 and ANIA Foundation.
No animal or human studies were carried out by the authors for this article and data
from previous studies were collected using Brainmap database.
Maddalena Boccia, Simonetta D’Amico, Filippo Bianchini, Assunta Marano, Anna
Maria Giannini and Laura Piccardi declare that they have no conflict of interest.
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Captions
Figure 1 – Brain regions that showed consistent activations across neuroimaging
studies of PTSD, which emerged from the ALE meta-analysis. A. Right hemisphere
B. Left hemisphere
Figure 2 – Results of single ALE analyses of different traumatic events. A. PTSD
neural network of patients who developed the syndrome after sexual or physical abuse
(SP); B. PTSD neural network of patients who developed the syndrome after combat-
related trauma (CR); C. PTSD neural network of patients who developed the
syndrome after natural disasters (ND).
Figure 3 – A. Regions that showed suprathreshold activations in contrast analysis
between SP and CR; B. Functional connectivity of the MCC specifically involved in
SP, which emerged from contrast analysis.
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Paper
N a
Studies b
PTSD event c
Single ALE d
fMRI Paradigm
Sakamoto et al. 2004
32
1
-
-
TR pictures, under perceptual threshold
Falconer et al. 2008
23
1
-
-
Go/No-Go Task
Lanius et al. 2003
10
3
-
-
Script-driven symptom provocation
Lanius et al. 2004
11
1
-
-
Script-driven symptom provocation
Lanius et al. 2007
11
9
-
-
Script-driven symptom provocation
Shaw et al. 2002
10
2
-
-
n-back task
Chen et al. 2009
24
1
Catastrophe
ND
Encoding and retrieval memory tasks
Mazza et al. 2012
20
1
Catastrophe
ND
Affective priming task
Hou et al. 2007
7
7
Catastrophe
ND
Symptom provocation paradigm/TR-STM
Lanius et al. 2002
7
3
Physical/Sexual
PS
Script-driven symptom provocation
Lanius et al. 2005
10
5
Physical/Sexual
PS
Script-driven symptom provocation
Shin et al. 1999
8
5
Physical/Sexual
PS
Script-driven imagery
Britton et al. 2005
16
6
Veterans
V
Script-driven imagery
Geuze et al. 2007
12
2
Veterans
V
Pain processing
Morey et al. 2008
39
6
Veterans
V
Emotional TR scenes
Pissiota et al. 2002
7
2
Veterans
V
TR sounds
Table 1 – Studies included in the general ALE meta-analysis. Notes. a Number of subjects; b Number of individual experiments reported; c Trauma event if detectable; d
Category in the single ALE analysis, if applicable. Notes. TR=Trauma related; STM=Short term memory
!
31!
Region
BAa
Hemb
Volumec
ALE valued
xe
y
z
Anterior Cingulate Gyrus
24
R
9672
0.030
2
28
20
Cingulate Gyrus
24
R
0.025
2
-2
34
Cingulate Gyrus
24
R
0.024
4
16
30
Medial Frontal Gyrus
9
L
0.018
-4
36
30
Posterior Cingulate Gyrus
23
R
5600
0.026
2
-44
28
Cingulate Gyrus
31
R
0.025
4
-48
32
Posterior Cingulate Gyrus
23
R
0.023
4
-52
26
Posterior Cingulate Gyrus
29
R
0.021
2
-46
8
Claustrum
L
2504
0.020
-32
18
0
Insula
13
L
0.020
-42
12
-2
Thalamus, Midline Nucleus
L
1784
0.017
-6
-16
16
Thalamus, Ventral Lateral Nucleus
L
0.016
-12
-14
4
Thalamus, Medial Dorsal Nucleus
L
0.016
-6
-8
6
Inferior Frontal Gyrus
46
R
1488
0.020
46
42
-2
Middle Frontal Gyrus
46
R
0.020
46
48
-4
Thalamus
R
1376
0.021
10
-14
0
Medial Frontal Gyrus
10
R
1360
0.017
4
60
6
Medial Frontal Gyrus
10
L
0.016
-6
54
4
Inferior Parietal Lobule
40
R
1096
0.021
46
-52
40
Hippocampus
R
760
0.021
28
-12
-20
Anterior Cingulate Gyrus
24
R
704
0.017
6
38
-6
Anterior Cingulate Gyrus
24
L
0.012
-2
36
-2
Superior Temporal Gyrus
22
R
624
0.016
56
0
0
Parahippocampal Gyrus
35
R
416
0.016
26
-32
-12
Claustrum
R
312
0.014
38
18
-2
Middle Frontal Gyrus
9
L
240
0.013
-40
38
22
Superior Temporal Gyrus
39
L
232
0.017
-48
-60
26
Table 2 – Region showing consistent activations across neuroimaging studies of PTSD, as result from
the general ALE analysis. Notes. a Brodmann’s areas if applicable; b Hemisphere; c Cluster volume
(mm3); d Peack ALE value; e MNI coordinates
