Brain Imaging and Behavior DOI 10.1007/s11682-015-9387-3

REVIEW ARTICLE

Different neural modifications underpin PTSD after different traumatic events: an fMRI meta-analytic study Maddalena Boccia 1,2 & Simonetta D’Amico 3 & Filippo Bianchini 1,2 & Assunta Marano 3 & Anna Maria Giannini 2 & Laura Piccardi 1,3

# Springer Science+Business Media New York 2015

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

* Maddalena Boccia [email protected] 1

Neuropsychology Unit, IRCCS Fondazione Santa Lucia of Rome, Rome, Italy

2

Department of Psychology, BSapienza^ University of Rome, Via dei Marsi, 78, 00185 Rome, Italy

3

Department of Life, Health and Environmental Sciences, L’Aquila University, L’Aquila, Italy

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 20 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.

Brain Imaging and Behavior

Neuropsychological and neurobiological aspects of PTSD 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 et al. 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. Functional neuroimaging studies in PTSD 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 coworkers (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 traumarelated 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 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 noPTSD 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.

Brain Imaging and Behavior

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. 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.

Method 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, combatrelated trauma and natural disaster) were included in further analyses on the role of the 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). 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 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

Brain Imaging and Behavior Table 1

Studies included in the general ALE meta-analysis

Paper

Na

Studies b

PTSD event c

Single ALE d

fMRI Paradigm

Sakamoto et al. 2005 Falconer et al. 2008 Lanius et al. 2003 Lanius et al. 2004 Lanius et al. 2007 Shaw et al. 2002 Chen et al. 2009 Mazza et al. 2012 Hou et al. 2007 Lanius et al. 2002 Lanius et al. 2005 Shin et al. 1999 Britton et al. 2005 Geuze et al. 2007 Morey et al. 2008 Pissiota et al. 2002

32 23 10 11 11 10 24 20 7 7 10 8 16 12 39 7

1 1 3 1 9 2 1 1 7 3 5 5 6 2 6 2

– – – – – – Catastrophe Catastrophe Catastrophe Physical/Sexual Physical/Sexual Physical/Sexual Veterans Veterans Veterans Veterans

– – – – – – ND ND ND PS PS PS V V V V

TR pictures, under perceptual threshold Go/No-Go Task Script-driven symptom provocation Script-driven symptom provocation Script-driven symptom provocation n-back task Encoding and retrieval memory tasks Affective priming task Symptom provocation paradigm/TR-STM Script-driven symptom provocation Script-driven symptom provocation Script-driven imagery Script-driven imagery Pain processing Emotional TR scenes TR sounds

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

(brainmap.org) using Mricro (http://www.mccauslandcenter. sc.edu/mricro/index.html).

Results General ALE: evidence that PTSD has a common neural network 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 Fig. 1). 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 (Fig. 2a).

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 were found at the level of the left caudate nucleus (CN), claustrum, globus pallidus and right claustrum and putamen (Fig. 2b).

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 (Fig. 2c).

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 (Fig. 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.

Brain Imaging and Behavior Table 2 Region showing consistent activations across neuroimaging studies of PTSD from the general ALE analysis

Region

BAa

Hemb

Volumec

ALE valued

Anterior Cingulate Gyrus Cingulate Gyrus Cingulate Gyrus Medial Frontal Gyrus Posterior Cingulate Gyrus

24 24 24 9 23

R R R L R

9672

0.030 0.025 0.024 0.018 0.026

2 2 4 −4 2

28 −2 16 36 −44

20 34 30 30 28

Cingulate Gyrus Posterior Cingulate Gyrus Posterior Cingulate Gyrus Claustrum Insula Thalamus, Midline Nucleus Thalamus, Ventral Lateral Nucleus Thalamus, Medial Dorsal Nucleus Inferior Frontal Gyrus Middle Frontal Gyrus Thalamus Medial Frontal Gyrus Medial Frontal Gyrus Inferior Parietal Lobule Hippocampus Anterior Cingulate Gyrus Anterior Cingulate Gyrus Superior Temporal Gyrus

31 23 29

R R R L L L L L R R R R L R R R L R

624

0.025 0.023 0.021 0.020 0.020 0.017 0.016 0.016 0.020 0.020 0.021 0.017 0.016 0.021 0.021 0.017 0.012 0.016

4 4 2 −32 −42 −6 −12 −6 46 46 10 4 −6 46 28 6 −2 56

−48 −52 −46 18 12 −16 −14 −8 42 48 −14 60 54 −52 −12 38 36 0

32 26 8 0 −2 16 4 6 −2 −4 0 6 4 40 −20 −6 −2 0

Parahippocampal Gyrus Claustrum Middle Frontal Gyrus Superior Temporal Gyrus

35

416 312 240 232

0.016 0.014 0.013 0.017

26 38 −40 −48

−32 18 38 −60

−12 −2 22 26

13

46 46 10 10 40 24 24 22

9 39

R R L L

5600

2504 1784

1488 1376 1360 1096 760 704

xe

y

z

Notes. a Brodmann’s areas if applicable; b Hemisphere; c Cluster volume (mm3 ); d Peack ALE value; e MNI coordinates

Functional connectivity of the MCC

Discussion

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 (Fig. 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 pallidus and right putamen. At the level of the thalamus, we found activation in the right medial dorsal nucleus and left ventral lateral nucleus.

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

Brain Imaging and Behavior Fig. 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

prevalence of PTSD (Husarewycz et al. 2014; Perrin et al. 2013; Ditlevsen and Elklit 2012; Santiago et al. 2013). 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 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 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

Brain Imaging and Behavior

Fig. 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)

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. 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

Brain Imaging and Behavior

Fig. 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

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). The trauma-related neural networks 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 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

Brain Imaging and Behavior

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. 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.

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.

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 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 preexisting factors in the development of PTSD. The next question that needs to be answered is whether the neural alterations we found were an Beffect^ of PTSD or a Bpredictive^ factor? Further investigations are required to better clarify the role of the neural alterations associated with PTSD.

Acknowledgments 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. Human and Animal Rights and Informed Consent No animal or human studies were carried out by the authors for this article and data from previous studies were collected using Brainmap database. Conflict of interest 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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Different neural modifications underpin PTSD after different traumatic events: an fMRI meta-analytic study.

Post-traumatic stress disorder (PTSD) is an anxiety condition that can develop after exposure to trauma such as physical or sexual assault, injury, co...
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