Post Traumatic Stress Disorder, Etiology and the Validity of Generalization Across Species.
September, 2015 Gabrielle Davelaar, 618791 Supervisor:
A.B. Satpute, PhD, University of Panoma Co-assessor: ....
Word count: 10.137 No. of References: 126
Master Brain and Cognitive Sciences, University of Amsterdam Track: Cognitive Sciences
University of Amsterdam Gabrielle.davelaar@gmail.com
Abstract
Post traumatic stress disorder (PTSD) affects roughly 31.3 million people in the USA alone, which is thought to be a growing number in the coming years. PTSD is caused by experiencing one or more traumas. Trauma induces the intense feeling of helplessness and fear impacting ones integrity.
No proper definition nor description of PTSD has been established, even though it is a disorder that effects large number of individuals.
Animal research has been used to get a better understanding of the neurobiological background of PTSD and to find effective treatments, many of these treatments have proven to be
effective.However, individuals who suffer from PTSD do not always respond well to these treatments. This is thought to be due to prolonged and repeated exposure to traumatic experiences.
Various research groups have argued that this specific group has many similarities with the current description of PTSD however may not respond well to treatments due to additional symptoms and
signs.
This thesis argues that there is, besides a difference in symptoms and signs, also a neurobiological differences between the two groups meaning that the current description of PTSD is incomplete.
1. INTRODUCTION
“I have been raped thirty times and it’s not even lunchtime, I can’t go to the toilet. Please bomb us.”
This was just one statement by a nine-year-old Yazidi girl who was asking Iraqi fighters for them. However, there are a countless number of statements from Yazidi women trying to escape the horrors of the Islamic State. Human Right Watch has stated that this was only the beginning and that the majority of Yazidi women in the refugee camps suffer from continuous extreme stress and anxiety (1). According to the Sidran Institute (2) rape has as estimated risk for developing PTSD of 49 percent.
“When I finally started driving again, about 3 months after, I was scared. But now its worse. I find its all I think about when I'm driving. My accident, or how I could get in one that the very moment. I
find myself holding my breath in intersections and when other cars are driving by me. I hate being the passenger, I'm always bracing and holding my breath and just completely terrified.” A statement from an individual whom has survived a car accident and has subsequently suffered from PTSD. Each year around 20-50 million people are injured or disabled in road crashes globally, next to 1.3 million people who die due to road crashes. Approximately 16.8 percent (2) of people who have been in a serious accident or injury develop PTSD.
“I came home from Iraq in March 2004, yet I’m still fighting a war, a war here at home. It’s a war of shadows, one that no one seems to really understand. A war of anger and anxiety, fought in the
recesses of my mind.”
Around 22 percent of the soldiers who returned back from the Afghanistan and Iraq war suffer from PTSD and is most likely to rise to 35 percent by 2023 (3). The numbers are even higher for
female military personnel where 71 percent develops PTSD due to sexual assault within the ranks of the army (4).
The annual costs in the USA alone are estimated to be around $ 42.3 billion dollars per year to provide treatment. In which patients suffering from PTSD have among the highest rates of healthcare costs (2). Misdiagnosis and under treatment are the main cause of the high costs ( 2). These costs can be lowered profoundly when the right treatment is being used. Both human and animal research has been carried out to understand the neurobiological of PTSD in order to unravel why certain treatments work better for one patient than for another. In human research various meta-analyses have been performed to get a better overview of the main brain regions involved in PTSD. Some focusing on PTSD in general (5) PTSD in context to other anxiety disorders (6), specific to statistical analyses (7; 8; 9) and others to specific stimuli (8). However, no meta-analysis has looked into the effects of different traumas with in specific traumas which have a prolonged and repeated exposure while animal research has indicated that these effects can have significant effects on the neural results of PTSD. Which raises the question whether there are indeed different neural patterns activated when people suffer from PTSD due to a one-time trauma compared to prolonged and repeated exposure.
2. DISCUSSION OF THE LITERATURE
PTSD involves a family of symptoms and signs, ranging from, but not limited to, avoidance, intrusive memories, hyper-arousal and especially abnormalities in fear responses impairing functions in the social, interpersonal and occupational area (10). Current neurobiological, both human and animal, models try to understand how these symptoms and signs arise. A review of the methods and findings is discussed below.
2.1. Animal models of PTSD
Animal models provide a great value to understand the cellular, molecular and behavioral mechanisms of the psychopathology of PTSD ( 11). The models create an experimental environment that can influence a variety of factors, which are able to determine the vulnerability or resilience of an individual’s trauma such as early-life experience, genetic predisposition and social support. Most PTSD animal models use stressors such as escapable/inescapable electric shocks (12), predators such as snakes or cats (13), prolonged stress (12) or predator scent such as urine of cats (14). There are currently three main models in animal research on PTSD, all focusing on different traits of PTSD. One of them, the predator-exposure model, has three notable variations, which will also be included below. Each section will focus on one specific animal model, discussing the symptom or sign being studied, used method and the results.
2.1.1 Pavlovian fear conditioning models
The Pavlovian fear conditioning models specifically targets the recurrent and intense symptoms of fear. It is mainly used to measure the neurobiology of trauma severity and the understanding of genetic changes across generations.
In order to recreate an obvious traumatic event leading to symptoms of intense fear, rodents learn to associate shock delivery with a certain cue. Once they learned the association, e.g. a shock in combination with a tone, the rodents are re-exposed to the same tone again (often a week later than
the initial conditioning) but without the shock ( the traumatic stimulus). This is done to measure the rodents’ memorization of the association to the traumatic stimulus, in order to see to what level the same behavior (freezing) occurs. Moreover, different intensity levels of shock delivery are used to research the effects of trauma severity in relationship to persistence and strength of the recurrent memory together with repeating the experiment across different generations.
Results in rodents showed signs of freezing together with brain region changes in the
amygdala, hippocampus and the prefrontal cortex. Other research specified on genetical changes have found genetical modification in the second and third generation of rodents who were fear conditioned, showing changes in genes responsible for regulating the stress hormone CrF (15).
2.1.2 Predator-exposure models
Predator-exposure models focus on symptoms and signs that involve cognitive deficits in learning and memory and the long lasting nature of the psychopathology of PTSD.
The main method, which is being used is where rodents are exposed to a predator (often a cat), which varies in the degrees of contact and direct exposure (with and without physical contact) or indirect exposure (cat odor).
Various results have been found using this method on all levels from cellular level to behavioral. On cellular level inflammation has been found (16), hyper and hypo activation in the amygdala, prefrontal cortical and hippocampal circuits(17). On behavioral levels show signs and symptoms of persistent increased anxiety, changes in memory (deficits in short term memory) and various other general cognitive changes (18). The predator-exposure models has multiple variations, where the targeting symptoms differ. The first variation is the predator-based psychosocial stress
model which incorporates social instability in combination with fear response. It has been argued
that chronic social instability increases the chance of developing PTSD (19). Common chronic social instability factors are lack of support, control and a reminder of traumatic experience and great uncertainty about the future (20).
In order to create chronic social instability Sprague-Dawley rats are placed in a space with unstable housing conditions for one to two months. The rats are exposed two to four times in the time period to the odor of predators or are immobilized in the presence of a predator (19).
The model found that the majority of psychosocially stressed rats had signs and symptoms of exaggerated startle, increased cardiovascular reactivity, heightened anxiety and exaggerated response to yohimbine, deregulation of the HPA axis, increased adrenal weight and growth impairment (21). Moreover, research has shown that social instability thus indeed heightens the chance that the traumatic event will create symptoms and signs linked to PTSD. The predator based psychosocial stress model has been especially valuable for the pharmacotherapy treatments
for patients with PTSD due to the understanding of the epigenetic changes in the brain (22; 23). A second variation on the predator exposure model is the single prolonged stress
paradigm, which looks into the effects of duration of trauma while dealing with one single event.
The method is almost the same as described in the predator exposure model except for the fact that the event only happens once and varies in duration (usually longer than the traditional exposure model where usually 80 trials were used on one day). The variation of rodent used in this model is usually New Zealand white rabbits, which is unlike other PTSD related studies in which it is common place to use Sprague-Dawley rats. This is most likely due to the susceptibility of causing the target symptom or sign. Main results which have been found are exaggerated acoustic startle and disruption in the retention of extinction memories (24; 25).
The predator scent stress paradigm, is the last variation which targets the variety of emotional
response of individuals to get a better understanding why some patients fail to recover and develop a chronic form of PTSD.
In order to achieve this, Sprague Dawley rats are in an enclosed environment for 10 minutes with well-soiled cat litter unable to escape. The control group is exposed to fresh and unused litter (12).
Each study differs, however they can range from a single exposure to a repetition for 31 days. Results of the rat studies showed that 25 percent of the rats displayed extreme behavioral response (which was classified as PTSD like behavior), 25% resilient and 50% intermediate response (12).
2.1.3 Age stress paradigm
The age stress paradigm looks into the effects of early life stress in both male and female rats/ mice. Normally only male rats are used in studies due to the effects of the hormonal cycle on female rats. However, for this model prenatal stress is part of the model and therefore female rates are used.
There are two methods to create early-life, prenatal and postnatal stress. Prenatal stress is induced using various methods, one of them is using bright lights in which the pregnant dams are restrained for 45 minutes in the last week of pregnancy. Postnatal stress is created by limiting the amount of nesting material, in which the mother with her just born pups cannot provide enough maternal care, resulting in an enduring stressor on her pups (26).
A second method separates the dam from her pups. Pending on the early life stressor (prenatal or postnatal) long last effects have been found. Prenatal stress resulted in male mice impaired behavioral stress response (decreased avoidance) and anhedonia (27). In female mice, long-term behavioral alterations have been found where the ability to cope with intense stress in adulthood seems to be the opposite of male impaired behavioral stress response in some situations ( 27).
Studies focusing on post-natal stress showed various changes on epigenetic, neural and behavioral level after one week. The effects of early life stress results in sustained changes in the CrH expression, an important pre-process for the development of the limbic-HPA-axis and DNA methylation across generations (28). Other changes are concerned with elevated hippocampal plasticity in adulthood (29), and trauma-induced psychopathology (30). An important note is the fact that sex plays an important role, in which female mice were more prone to epigenetic changes
than male mice ( 31).
2.1.4 Summary and Critique of Animal Models
Animal research has shown that age, single versus prolonged exposure and sexes play a significant role in bimolecular, pathophysiological and pharmacological levels of PTSD. Thus, that the etiology of PTSD is influenced by the factors mentioned above. Factors that are not always feasible to research in human studies.
What should be noted however, is the fact that stress studies in rodents have produced complex, often opposing, gender differences in stress and memory processing (32; 33). Animal models have been used to better understand avoidance symptoms and re-experiencing, which both are associated with PTSD (34). Unfortunately, these are only two of the full spectrum of PTSD symptoms and signs thus making the models incomplete and over simplistic (35). Especially when these methods are being used for pharmacological drug testing, resulting in only treating certain symptoms and signs of PTSD. Another issue is the trauma duration, which plays an important role in these models. Symptoms due to, for example rape are better suited the current fear models as an explanation than term trauma events such as combat exposure. Reason for this is that longer-term events involve more complex psychological symptoms such as loss, moral crises, dreams, meaning, thoughts and feelings of personal failure (35).
Another difficulty with animal studies is that it is still questionable whether memories observed in trauma patients are similar to the ones, which are created in animal fear models (35). It nevertheless, creates a valuable foundation for further human research, in particular what type of factors have to be taken into account when researching PTSD in human context.
2.2 Human studies
Human studies on PTSD range from genetic to behavioral research in order to get a better understanding of the phenomena. One part being focused on the influences of situational causes of PTSD and the other, the mechanisms during symptoms experience. As for the mechanisms, some
argue that it is a problem in the memory circuits, others argue that it is a problem in the affective circuits (specifically the fear circuit). The situational causes on the other hand range from gender to age onset.
2.2.1 the neural circuits during symptoms
Memory plays an important role in PTSD, which is currently being described as a severe anxiety disorder. The problem, however, is that anxiety disorders don’t entail the most important symptoms PTSD patients suffer from: flashbacks and re-experiencing the traumatic event.
Flashbacks and re-experience are a form of autobiographical memory caused by conditioning (repetition of the traumatic event) and certain triggers evoke specific autobiographical memories.
Even though brain regions concerned with autobiographical memory can differ per task, they are nevertheless several regions that seem to be activated across many of the autobiographical retrieval tasks. Next to the hippocampus the medial and lateral prefrontal cortex, the amygdala, the lateral parietal cortex and the sensory cortices within the occipital and temporal-lobes seem to play a role in autobiographical retrieval (36, 37, 38). Each of these areas contribute separately to an overall retrieval of an autobiographical memory. Whether these areas form a specific ‘autobiographical memory network’ or belong to more general abilities of self-referential processing (39), mind-wandering (40) or cognitive-affective simulation of possible outcomes is still debatable. What can be concluded is that each of these regions are often mentioned in PTSD (41; 42; 43).
As for symptoms linked to memory, it is often argued that flashbacks and re-experiencing are caused by a disruption in the memory network, in which PTSD doesn’t go through the three phases of memory correctly causing the effects of re experience and flashbacks.
Memory research has indicated that memories are built in three phases: acquisition, consolidation and retrieving a memory (44). Even though, the three phases always stay the same,
memories are solidified differently pending on the type of event. Emotional content of an experience has influence on how the event is remembered and can thus influence the recalled information during autobiographical retrieval(45).
This is due to its phenomenological characteristics; significant feelings of vividness, perceptual details (46; 47) and variety of specificity levels (48; 49). Once these levels are high, the memory often will be most vividly and durably remembered (50; 51) compared to events in which the levels of emotion and personal relevance were lower (52).
Another critical issue is the amount of recalls. Frequent recalls strengthen memories, memories are not necessarily fixed and can be changed over time, a process which is called re-consolidation (44). In a study conducted by by Soeter and Kindt (53) human subjects were asked to generate a fearful memory after a loud sound or a picture of spiders. Before the experiment, one group was given propranolol the other group a placebo.A week after the experiment, both groups were reminded of the fearful memory, the propranolol group showed significant less fear than the’placebo’ group. This group felt less emotion and therefore their ability to face fear was increased.
Research has indicated that memories are often remembered better when levels of emotion are heightened. Soeter and Kindt (53) highlight the effects of propanolol, a medication that reduces the experience of fear when one is confronted with a fearful memory. One of the symptoms of PTSD is the re-experiencing of the traumatic event causing fear and anxiety. Medications such as propanolol are nonselective beta blockers and are used for a variety of diseases and disorders, including PTSD. The propanolol targets the symptoms of nightmares and re- experiencing (54). What is defined as emotion is a contentious issue and therefore how one can reduce an emotion is debated. Classical theory would argue that emotions are caused by bodily responses rather than the interpretations given to them (55; 56). In case of fear, a fearful stimuli triggers bodily responses, such as increased heart rate, which then in turn are perceived as being fearful. Most contemporary neuroscientists hold this view where the stimulus is causing bodily experience
of fear travels via the classical sensory pathways, where it splits at the mid-brain and thalamic level into the cortical and sub-cortical circuits; from there sensory information travels through the thalamus (intralaminar and geniculate nuclei) to the amygdala (55; 57).
Due to the excessive amount of research on fear conditioning related to the amygdala, a hypothesis has been proposed in which the amygdala plays a crucial role in PTSD. What has been observed in patients who have been diagnosed with PTSD is that they suffer from a broad range of symptoms varying, but not limited to, avoidance, intrusive memories, hyper-arousal and especially abnormalities in fear responses impairing functions in the social, interpersonal and occupational area (APA, 2000; for an extensive overview of the symptoms, see appendices).
Fear is believed to be the dominant issue in PTSD resulting in a proposed neural circuit of PTSD assuming that the re-assessment of the traumatic incident is prevented due to hyper responsivity of the amygdala caused by coexisting anterior cingulate cortex (ACC) and medial prefrontal cortex hypo response and a deficient hippocampal function (58).
2.2.3 Situational causes
In order to develop PTSD, people have to go through trauma. However, not everyone who experiences trauma will develop PTSD. Individuals chances of developing the disorder vary. Several situational causes have been linked to the increased chance of developing PTSD. Such as, previous trauma (59), genetical markers (60) and age onset (61).
A variety of studies focused on one target group alone such as survivors of a mining accident (62), the Iran and Afghanistan war (63), car accidents (64), child abuse (65) and various other trauma events. In order to study these effects in the brain various stimuli have been used to measure the trauma response in PTSD patients compared to controls who did not develop PTSD. Stimuli used are script-driven imagery (66; 67; 68; 69), sounds (70; 71), pictures (62; 65; 72), IAPS (73), emotional stroop test (74) and odor (43). Of these results various meta-analyses have been performed to find the neural correlates of PTSD. Some only focusing on the type of stimuli, (9)
others on the statistical analysis being used and some on PTSD in general (8). However, to our knowledge, no meta-analyses have specifically focused on the situational causes. Meta-analyses have shown a variety of results. Thus far research has mapped out the neural differences and similarities between control groups and patients. However, one must treat previous meta-analyses with caution as they are prone due to the great variability within the patient group data, such as age, gender, type of trauma and various other influence factors.
Even though, between meta-analyses many inconsistencies are still apparent, some level of consistency can be found. Many of the brain areas mentioned in the literature are to a large extent the same. The most discussed brain region is the amygdala, both with hyper and hypo activity response (75; 70; 58; 76; 77; 42; 43) The main symptom the amygdala is linked to is severity of ones PTSD ( 42; 79). A second area which appears in neuroimaging studies is the hippocampal area, this area also shows inconsistencies in hyper and hypo active response (74; 79) much debate occurs as to which sumptom tis may be linked to. Neuroimaging studies on the hippocampal area report link itto emotional words processing (80), associative learning (81) and consolidation of experienced events from short-term memory to long- term memory (82). The medial prefrontal cortex (mPFC) is the third region mentioned in PTSD neuroimaging studies. The mPFC is assumed to be responsible for emotional processing and in case of PTSD the mPFC is mostly linked to decreased or even activation failure. This effect has been noted in a wide range of different stimuli, negative and neutral (76; 83), script-driven imagery (84; 85) and emotional Stroop task (86). The final areas, the anterior cingulate cortex and the thalamus, are responsible for regulating emotion and conflict, inhibition of response and function as a sensory relay station. Both have been described as being reduced in volume in patients with PTSD.
Several theories have mentioned inconsistent results, where some areas are in certain studies hyper responsive, while in others hypo responsive some cases showing no difference from the control group. One of those theories is comorbidity with other psychiatric disorders such as bipolar affective disorder and phobias. Other theories are found in previous results which have shown that
it is fairly difficult to diagnose PTSD due to a great variability within its patients group, both in length of time and the severity of the stressor (87). Therefore it could be assumed that PTSD does not show immediately after a trauma but could surface unexpectedly. Resulting in misdiagnosis in which co-morbid disorders are often first diagnosed such as bipolar affective disorder, substance abuse disorders and other anxiety disorders (88) and later PTSD. Another theory has proposed that different type of traumas may cause great variability between the different studies (87). Man- made traumas such as rape and torture have a different effect on the human mind than natural disasters such as tsunami’s and accidents. The difference being man-made traumas are purposeful whereas the natural traumas are not. It therefore appears important to limit the variability within a group. Different subgroups could ultimately give a better understanding whether situational causes of PTSD cause the inconsistencies and if so which situational causes play a major role in this.
2.2.4 Summary and critique of human research
Human research has provided some significant insights in regards to PTSD, some of which would not have been discover solely by animal-research. Due to communication, researchers can focus on certain triggers which involve higher cognitive functions.
However, human research is bound to natural sampling, thus resulting in a great variety due to groups of patients. None of the patients are the same and due to its limited accessibility to patients for research many researchers need to compromise in order to get enough patients for one study. Nevertheless, some form of restriction within studies can be applied such as sexes, age and type of trauma. Various articles have done this (64; 79; 89), however many studies still mix different types of trauma, such as car accidents with sexual abuse patients, Which could ultimately result in contradictory and biased results.
Moreover, previous methods have shown limitations. A number of different paradigms of stimuli have been used varying from provocation studies to functional connectivity analysis to get significant results. In which symptom provocation studies are the most common in the literature on
PTSD in combination with neuro imaging tools. Unfortunately, many of the early studies done with neuro imaging tools suffered from methodological limitations such as heterogeneity, small sample sizes and inadequate control groups. Various meta-analyses focusing on PTSD have been published, the variation of the meta-analyses ranges from using several different types of stimuli combined (90) to PTSD and other anxiety disorders (6). Regrettably, still too broad where combining patients with different backgrounds make it difficult to address which situational causes influence certain results.
3. PERSONAL CRITICAL OPINION
3.1 Origin, meta-analyses and PTSD
Etiology in medicine is being described as knowing the cause of a disease or pathology. Its importance lies in understanding a disorder or disease with the goal of finding a way to cure or relief the disease or disorder. For psychiatric disorders, etiology is more difficult than for other diseases where a bacteria or a virus is the main cause of illness. However, the origin and development of PTSD is known. First, PTSD is correlated to particular factors (symptoms and signs) which appear to occur at the same time. Flashbacks and re experiencing are two of the various symptoms that are correlated to patients who suffer from PTSD. Secondly, without trauma, no one would suffer from PTSD, which can be seen as proof of cause and effect between these two factors. However, not everyone who goes through a traumatic event will develop PTSD, in which certain contributions in presence of a cause can lead to the condition of PTSD. Probable contributions or situational causes in PTSD are gender (women are more likely to develop PTSD), age (the brain is more adjustable when people are young, causing smaller volumes in some areas) and genetics (certain genetical traits make it possible to be more susceptible to develop PTSD). One could argue that type of trauma experiences contributes significantly to different types of PTSD, for example individuals who suffer prolonged and repeated trauma experience PTSD differently to those who experience trauma once. Patients suffering from PTSD due to prolonged and repeated
trauma met 92 percent of the diagnostic criteria for PTSD but also have additional symptoms alongside regular PTSD symptoms. This implicates that the type of trauma, one time versus prolonged and repeated trauma exposure cause different results. Where only trauma would not suffice as the cause, or etiology. However, symptoms and signs are not the most compelling evidence to prove that there is a significant difference. Experimental evidence involving intervention are needed to provide more sufficient evidence. One way to do this is through the use of meta-analyses.
Meta-analyses give a broad and profound overview of the research results being obtained within the field and are often valuable to get a grip on the etiology of a disease or disorder. Moreover, it gives the opportunity to limit the variability within groups and still have enough results to provide for significant results.
Another issue is the type of stimuli being used in order to provoke the symptoms of PTSD. Several reviews and meta-analyses do not make a distinction in regards to the type of stimuli being used. The current research has specifically looked at the autobiographical memory as a provocation stimuli. Autobiographical memory has proven to be a reliable source to provoke certain emotions.
Previous research has been discussed above, claiming various results linked to the etiology of PTSD. To find the common denominator in the various research papers, a meta-analysis has been performed to see whether it is indeed the case of a problem of etiology.
3.2 Meta-analysis
The present meta-analysis examines whether etiology, one time trauma exposure versus prolonged and repeated trauma exposure, matters for the brain basis of PTSD. Three analyses were performed, comparing patients suffering from PTSD due to a one time trauma exposure and trauma- exposed controls, patients suffering from PTSD due to a prolonged trauma exposure and trauma-exposed controls and a third group in which both PTSD trauma groups were compared to trauma- exposed controls without PTSD.
The third analysis, where both groups were combined is done to see what effects fade once various trauma types were combined.
Studies to test this theory were selected by searching PubMed, ScienceDirect and Google Scholar and reference lists for neuroimaging studies of PTSD in combination with autobiographical memory or self-driven scripts available until January 2015. To be eligible, studies must have reported brain coordinates of activation during the presented stimuli. Studies were included that contrasted a negative emotional condition (often referred to as anxiety/fear) with control groups as a baseline. The stimuli also had specific criteria in order to fit the meta-analysis. Included were studies in which negative stimuli was presented either through autobiographical memory, autobiographical script, audio recording or read by the interviewer. Excluded articles were those with negative stimuli via emotional faces, emotional words, IAPS and emotional Stroop test also studies using data from previously published data were excluded. This was done to again limit variability and moreover because autobiographical memory has proven to be a reliable source to provoke certain emotions. Finally, 22 studies were eligible, consisting of 304 patients, in which 128 were patients suffering from PTSD due to a one time trauma exposure and 176 patients suffering from PTSD due to multiple trauma exposure. The list of included studies can be found in table 1.
Reference Patients Emotional Stimulation Included Contrasts Symptom Provocation Method
Bremner et al.
(1999) 10 Neutral and traumatic scripts Trauma-neutral Yes PET
Britton et al.
(2005) 16 Neutral and traumatic scripts Trauma-neutral Yes PET
Frewen et al.
(2010) 10 Neutral and traumatic scripts Trauma-neutral Yes fMRI
Hopper et al.
Reference Patients Emotional Stimulation Included Contrasts Symptom Provocation Method
Shin et al.
(1999) 8 Neutral and traumatic scripts Trauma-neutral Yes PET
Lanius et al.
(2001) 9 Traumatic script Trauma-baseline Yes fMRI
Nardo et al.
(2011) 13 Script-driven Trauma-baseline Yes SPECT
Shin et al.
(2004) 17 Neutral and traumatic scripts Trauma-neutral Yes PET
Lanius et al.
(2005) 10 Script-driven Trauma-baseline Yes fmri
Lanius et al.
(2001) 11 Script-driven Trauma-neutral Yes fmri
Osuch et al.
(2009) 22 Neutral and traumatic scripts Trauma-neutral Yes PET
Lanius et al.
(2007) 11 Script-driven Trauma-neutral Yes fMRI
Hou et al.
(2007) 10 Script-driven and picturesTrauma-neutral Yes fMRI
Yang et al.
(2004) 5 Pictures Trauma-neutral Yes fMRI
Vermetten et
al. (2007) 8 Odor Trauma-neutral Yes PET
Lanius et al.
(2002) 7 Script-driven Trauma-neutral Yes fMRI
Bremner et al.
(1999b) 10 Pictures/images Trauma-neutral Yes PET
Liberzon et
al., 1998) 14 Combat-sounds Trauma-neutral Yes SPECT
Whalley et al.
(2013) 10 combat-pictures Trauma-neutral Yes fMRI
Morey et al.
(2008) 40 combat-pictures Fear/anxiety -neutral Yes fMRI
Pissiota et al.
(2002) 7 Combat-sounds Trauma-neutral Yes PET
Hendler et al.
(2003) 10 Combat-pictures Trauma-neutral Yes fMRI
Morey et al.
(2013) 10 combat-pictures trauma-neutral Yes fMRI
3.2.1 Meta-analytic procedure
The meta- analyses were executed by using the ES-SDM software (available at http:// www.sdmproject.com). The data was pre-processed in which all peak coordinates and statistical parametric maps were converted to Montreal Neurlogic Instiute coordinates (MNI), followed by creating SDM maps for each study within a whole-brain mask. Number randomizations used were 30. The second step included recreating statistical maps and effect-sizes maps, including their variances derived from the t-statistics. T-values were converted using standard formulas to create unbiased effect size and variance maps. If the statistical parametric map was unavailable only the effect size of the voxels of the exact peaks are calculated through the use of full width at half maximum (FWHM). Using the setting of 20 mm for optimal sensitivity and specificity (99). When in the same study a voxel value can be assigned to more than one coordinate, values were averaged weighting by the square of the distance to each peak close to it. Lastly, several tests were performed to test for heterogeneity and sensitivity.
3.2.2 Results
Results of the meta-analysis are different in all three cases. As shown in table 2, patients suffering from PTSD due to a one-time event exhibited hyper-activation in the left insula, left superior frontal gyrus and right superior temporal gyrus. Other areas which also showed significant hyper activation were the right insula and the corpus callosum (figure 1). In contrast, patients suffering from PTSD due to several traumatic events showed both hypo and hyper-activation compared to controls (see table 3). Hyper activation was found in the left striatum and various gyri. Hypo-activation corpus callosum, right median network, left superior longitudinal fasciculus III, right cerebellum, right heschl gyrus and the inferior network (figure 2). When both groups are combined only hyper-activated areas are significant compared to the control group. The corpus callosum and left insula had the most evident activations (table 4, figure 3).
description (increased areas) X Y Z Z-value P< Voxels
Left insula, (BA 48) -36 10 4 2.691 0.001 4222
Left superior frontal gyrus (BA 10) -2 54 22 2.315 0.001 2669
Right superior temporal gyrus 58 -30 20 2.234 0.001 632
Right insula, (BA 48) 40 0 10 2.013 0.001 178
Corpus Callosum 16 8 44 1.863 0.002 95
Corpus Callosum -10 -44 8 1.681 0.003 58
Table 2: hyper activated brain areas in patients suffering from PTSD due to a one time trauma event (only peak voxel are reported, additional local peaks and cluster peaks can be found in the appendices).
Figure 1: hyper activated brain areas in patients suffering from PTSD due to a one time trauma event.
description (increased areas) X Y Z Z-value P< Voxels
Left striatum -22 2 0 2.84 0.001 555
Left interior parietal (excluding supramarginal
and angular) -46 -56 42 2.56 0.001 248
Left middle frontal gyrus -34 52 14 2.55 0.001 236
Right median cingulate/ paracingulate gyri 10 18 42 2.44 0.001 142
Left inferior frontal gyrus, opercular part -50 16 20 2.46 0.001 133
Right postcentral gyrus 42 -30 54 2.36 0.002 94
description (decreased areas) X Y Z Z-value P< Voxels
Corpus callosum 8 20 -6 -2.812 0.002 1102
Right median network, cingulum 28 -8 -26 -2.881 0.001 360
Left superior longitudinal fasciculus III -34 -24 22 -2.42 0.001 273
Right cerebellum hemispheric lobule IV/ V
(BA37) 28 -44 22 -2.344 0.001 275
Right heschl gyrus, (BA 48) 48 -18 8 -2.09 0.002 107
Right inferior network, inferior longitudinal
Table 3: hyper and hypo activated brain areas in patients suffering from PTSD due to prolonged and repeated exposure to trauma events (only peak voxel are reported, additional local peaks and cluster peaks can be found in the appendices).
Figure 2: hyper and hypo responsive brain areas in patients suffering from PTSD due to prolonged and repeated trauma exposure. Red indicates hyper responsive brain areas, blue indicates hypo responsive brain areas.
description (increased areas) X Y Z Z-value P< Voxels
Corpus callosum 12 14 54 2.537 0.001 2635
left insula (BA 48) -36 10 2 3.316 0.001 2262
Left inferior parietal (excluding supramarginal
and angular) gyri (BA 40) -52 -52 40 2.491 0.001 1196
Right postcentral gyrus (BA2) 50 -28 50 2.694 0.001 333
Left cerebellum, hemispheric lobule IV/V
(BA18) -8 -54 -6 2.34 0.001 249
Left caudate nucleus -10 8 16 2.274 0.001 116
Table 4: hyper and hypo activated brain areas in patients suffering from PTSD due to prolonged and repeated exposure to trauma events and a one time trauma event (only peak voxel are reported, additional local peaks and cluster peaks can be found in the appendices).
Figure 3: hyper activated brain areas in patients suffering from PTSD due to prolonged and repeated trauma exposure and one time trauma exposure.
3.2.2.1 Group combination
Many of the areas in the third group, namely where the types of traumas are combined, indicated areas previously mentioned in other meta-analyses focused on PTSD (9; 6; 8). Previous meta-analyses by Hayes et al. (8) Sartory et al. (9) have discussed these areas more extensively and will not be further discussed in this thesis.
3.2.2.2 One time exposure trauma
Patients who suffer from PTSD due to a one time trauma showed no decreased areas and only show increased activity in the insulae, superior frontal gyrus, superior temporal gyrus and the corpus callosum. Especially the last one, the corpus callosum, is intriguing due to the results in the first group where the corpus callosum is decreased. It remains unclear why patients suffering from PTSD due to one trauma event in our meta-analysis show increased activation in the corpus callosum while the chronic PTSD patients show reduced activity. One possible explanation may be that the type of trauma plays a role, nevertheless no results were yet found on this topic.
It is noteworthy that the areas mentioned in the one time exposure group were completely different from the prolonged and repeated exposure group. Patients who suffer from PTSD due to a one-time trauma show no decreased areas and only show increased activity in the insulae, superior frontal gyrus, superior temporal gyrus and the corpus callosum.
The left superior frontal gyrus is an area involved in self-awareness and higher cognitive functioning with in specific the working memory (100). As for the superior temporal gyrus, activation is often associated with dissociative states and gets its projections from the amygdala, a region associated with fear response (57). Studies in which the superior temporal gyrus was evoked indicated signs of higher cognitive processing of the experience of fear and modulating the activity of the amygdala (101). Together with the amygdala the superior temporal gyrus is responsible for processing social information (102).
Secondly, increased insulae activity was notable in the meta -analysis, which is consistent with previous literature concerning a network responsible for the generation of fear responses during symptom-provoking stimuli (103). The insulae also seem to integrate the different components of pain, lesions in this area result in the ability to perceive pain without a corresponding pain reaction (104). Results in patients with depression and a number of other psychiatric disorders mentioned the insulae were important for interoceptive awareness (105). Moreover, increased activation of the insulae was linked to flashback intensity (106), even though mixed results have been found were reduced, insulae activation was found in combat-veterans suffering from PTSD( 107; 108). Lastly, the insulae together with the amgydalae involved in basic emotion processing of emotions such as anger and fear (109; 110). A possible explanation for this could be that it is due to the type of stimuli, for this study symptom-provocation, plays a significant role in this. In which ,previous meta-analytical studies have not focused on specific types of stimuli being used. The present study also failed to support the activation of the anterior cingulate cortex (ACC), which is yet again an area often associated with emotional regulation in PTSD. It must be noted though, that there is still a debate concerning the hyper and hypo-activation of the ACC in PTSD patients. Some studies report decreased activation(62; 93) whereas others show increased activation (98; 95). Activation of the ACC is nevertheless linked to significant amount of processes such as consciousness (111), registering pain (107), attention and motivation (112), emotional processing (113) and various other processes. This means that the ACC may well not be linked to PTSD in specific but linked to various symptoms of PTSD, which could explain why some studies show increased activation while other show decreased or even no activation.
Only the multiple traumatic events showed both decreased and increased areas. The areas showing less activation are mainly found in the right side of the brain. However, only the left superior longitudinal fasciculus showed less activation in the left side of the brain. Interestingly, results between the two different types of exposure time was significantly different. Not only do multiple traumatic events result in less activation, areas of increase are not comparable to patients
who suffer PTSD due to a one-time trauma. Secondly, the brain areas showing hypo or hyper activation are often linked to symptoms and signs which can also be traced back in animal research specified on exposure time with in specific prolonged and repeated trauma.
As for the areas showing less activation, for example, the corpus callosum which is often mentioned being reduced in patients who suffered from repetitive childhood trauma's (65). It is still unclear in previous research why a reduction occurs though it is most likely due to atrophy resulting from experiencing trauma's at a young age (114). Decreases in the corpus callosum have also been found in other psychiatric disorders such as attention deficit hyperactivity disorder (ADHD) (115), schizophrenia (116), autism (117) and dysthymia (118). The cingulum lies between the corpus callosum and the longitudinal fasciculus, these areas together are important for memory information and integration and the communication line between the different components of the limbic system.
Changes or decreased activity are related to emotional function change due to the limbic systems' involvement in emotions. Moreover, the inferior longitudinal fasciculus is also involved in the release of cortisol (119). Intriguingly, lower levels of cortisol have been consistently reported in patients suffering from PTSD due to war (120) and sexual assault or domestic violence (121; 122). However, cortisol levels of PTSD patients due to a one time traumatic event show the opposite effect, in which their cortisol levels are increased compared to controls (123). Short-term emotional events are stored because of the combination of cortisol and epinephrine. It has been proposed that this storage mechanism makes it possible to have flash bulb memories as a reminder to what to avoid in the future. Furthermore, cortisol plays a significant role in the inhibition of memory retrieval of already stored information (122). This possibly explains why patients with PTSD due to one time trauma event remember the event vividly while patients with PTSD due to a prolonged trauma tend to be unable to remember significant parts of the traumatic events while being conscious (124).
Many of the human brain areas mentioned are in the literature link to similar symptoms found in animal research while being exposed to prolonged and repeated trauma. Besides memory dysfunction, other symptoms observed in animal research linked to prolonged and repeated exposure traumas are deregulations in behavior and basic emotions (fear).
Many of the symptoms mentioned above fit the description of complex PTSD (C-PTSD) or Disorder of Extreme Stress Not Otherwise Specified (DESNOS), a subgroup of PTSD, however, this is not yet accepted by the American Psychiatric Association nor included in the DSM-IV. C-PTSD is associated with a history of prolonged trauma such as sexual abuse, physical abuse, emotional abuse, domestic violence and torture. C-PTSD differs from regular PTSD in various aspects, one of the most important is the loss of a coherent sense of self, emotional deregulation, dissociation and interpersonal problems (124; 125).
The meta-analysis of human findings thus supports the theory of C-PTSD and with that, the etiology is has a more significant impact than previously assumed.
3.3 Limitations and future considerations
Various issues have been encountered reviewing previous research, some of these were preventable, however, others were not.
One issue with the presented results is that patients with PTSD often deal with high co- morbidity, which can alter the results. As mentioned before the hyper-activation of the striatum is often linked to other disorders that are highly linked to PTSD. As PTSD has a high comorbidity rate it could well be the case that patients who participated have some form of comorbidity. However, comorbidity is not always easy to measure, not all the signs are easily recognizable or notable as such.
Meta-analytical analysis also contains certain unpreventable flaws, which are common amongst meta-analysis methods including ES-DSM. A key problem with analysis is the use of summarized data, using raw data from the included studies would more likely to be accurate.
A second limitation is the amount of variability across previous studies. There is too much variability across previous studies, which are most likely caused by several limitations, which have been discussed. Future studies should therefore be more precise in their method used in order to avoid discrepancies.
Results from the group with repetitive exposure to trauma events have various activated or deactivated brain regions that match the different symptoms of C-PTSD as opposed to PTSD, in which loss of a coherent sense of self is most appalling. However, some limitations have been expressed including meta-analytical and methodological weaknesses. Even though these weaknesses are often hard to avoid the effects could be decreased when future research focused on PTSD are more careful about the demographics being used. Reporting results independent of each other, such as sex, type of stimuli, trauma and age could provide valuable data for meta-analyses to better understand PTSD as a disorder. Moreover, further research is necessary to determine voxel patterns. For example, does the period in a human life span play a significant role in the voxel patterns occurring. As it has been argued that symptoms caused by traumatization during childhood differ from those of regular PTSD (119). Is this because of the type of trauma or rather the period in the human lifespan?
Furthermore, additional research is required to examine whether comorbid disorders such as depression and substance abuse cause significant differences in the brain patterns found in meta-analyses. Various studies have used patients with PTSD suffering as well from various comorbid disorders (64; 66). If it is indeed the case that comorbidity significantly alters the results, a division should also be made within the group in order to provide the right treatment program.
3. CONCLUSION
Approximately six out of ten people have at least once in a life-time been exposed to an traumatic event ranging from a life-threatening incident to war. Between 3 % and 15% of these people will develop Post Traumatic Stress Disorder (PTSD). However, those percentages are even higher when any form of sexual abuse or combat exposure has been the cause of PTSD (126). In addition, 42.3 billion dollars per year are spent on PTSD with high rates of misdiagnosis.
A good understanding of the neurobiological mechanism of PTSD is essential for the development of effective treatments. In the last decade, animal models have provided many insights on how trauma affects the brain and have been the key to many of the neuro- pharmacological treatments for PTSD.
Unfortunately, not all treatments seem to work as effectively as once proposed in animal research. There are various possible causes linked to ineffective treatments ranging from only targeting a small range of symptoms to treatments not being tested well enough with the great diversity within the patient group.
In our understanding the problem of ineffective treatments is caused by trauma etiology, in which we have limited our understanding of PTSD due to neglected variables both from animal and human research.
Both human and animal research have limitations when it comes to full comprehension of PTSD. Animal research has difficulties in controlling for human characteristics involving higher cognitive traits such as complex emotions, moral crises and feelings of personal failure. On the other hand, human research only involves natural sampling which creates diversity within the patient group. Nevertheless, if both fields combine each others knowledge the voids in research could be lessened significantly. Various variables can be controlled within human research, which showed in animal research to be important. They have shown some variables such as exposure time,
sex and age play an important role in the understanding of diversity between PTSD patients. This knowledge has therefore been used to get a better understanding of the results of human research on PTSD. Provocation is the only symptom based on autobiographical memory, which PTSD patients show limited variability in.
Results of this thesis have indicated that the type of trauma plays a significant role in the outcome of the results. When a patient has developed PTSD due to prolonged and repetitive exposure to trauma events, different brain regions are hyper or hypo active compared to a one-time exposure to a trauma event. The hypo activation disappears when the two groups are combined thus indicating the brain regions both groups have elements in common. However, it does not show how they differ from each other. yet not how they differ from each other.
Moreover, the results do shed light on why certain patients are unable to recover from PTSD and do not always show the same symptoms or signs as other patients with one time exposure PTSD. Therefore, this implicates that C-PTSD is indeed different from PTSD even though 92 percent of its patients also meet the diagnostic criteria for PTSD. Secondly, successful medical treatment tested on animals, could be effective for humans as well depending on the type of trauma. For example, rats that are traumatized due to one single trauma exposure, show that medical treatment is most suitable for human groups that have experienced trauma once rather than rats who experience prolonged trauma. One woud recommend that future studies should test whether the amount of trauma rats face minimizes the effective nature of medical treatments for patients who have experienced various types of trauma.
REFERENCES
1. Human Right Watch. Iraq: ISIS Escapees Describe Systematic Rape, Yezidi Survivors in Need of Urgent Care, april 14, 2015. https://www.hrw.org/news/2015/04/14/iraq-isis-escapees-describe-systematic-rape
2. Sidran Institute. Post traumatic Stress Disorder Fact sheet (2015). http://www.sidran.org/ resources/for-survivors-and-loved-ones/post-traumatic-stress-disorder-fact-sheet-2/.
3. Atkinson, MP, Guetz, A., Wein, LM (2009): A Dynamic Model for Posttraumatic Stress Disorder Amonger U.S. Troops in Operation Iraqi Freedom. Journal Management Science: 55(9):
1454-1468.
4. U.S. Department of veterans affairs, PTSD, National Center for PTSD. (2015). Retrieved from: http://www.ptsd.va.gov/professional/PTSD-overview/epidemiological-facts-ptsd.asp.
5. Karl A, Schaefer M, Malta LS, Dorfel D, Rohleder N, Werner A (2006): A meta-analysis of structural brain abnormalities in PTSD. Neurosci & Biobehav Rev 30 (7): 1004-1031.
6. Etkin A, Wager TD (2007): Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 164: 1476– 1488.
7. Eickhoff SB, Laird AR, Gefkes C, Wang LE, Zilles K, et al. (2009): Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty. Hum Brain Mapp 30: 2907–26.
8. Hayes JP, Hayes SM, Mikedis AM (2012): Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biology of Mood & Anxiety Disorders 2: 1–13.
9. Sartory G, Cwik J, Knuppertz H., Schurholt B, Lebens M, Seitz RJ, et al. (2013): In search of the trauma memory: a meta-analysis of functional neuroimaging studies of symptom provocation in Post traumatic stress disorder PTSD. PloS One 8(3).
10. American Psychiatric Association (2003: Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Press.
11. Andero R, Ressler KJ (2012): Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes Brain Behav 11(5): 503-12.
12. Cohen H, Zohar J (2004): An animal model of posttraumatic stress disorder: the use of cut-off behavioral criteria. Ann N Y Acad Sci 1032: 167-78.
13. Siegmund A, Wotjak CT (2007): A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear. J Psychiatr Res 41(10): 848-60. 14. Hendriksen H, Prins J, Olivier B, Oosting RS (2010): Environmental enrichment induces
behavioral recovery and enhanced hippocampal cell proliferation in an antidepressant resistant animal model for ptsd. Plos One 5(8).
15. Dias, BG, Ressler, KJ (2010): Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 17: 89-96.
16. Wilson, CB, McLaughlin, LD, Ebenezer, PJ, Nair AE, Dange, R, Harre, et al. (2014):
Differential effects of sertaline in a predator exposure animal model of post- traumatic stress disorder. Front Behav Neurosci 8 (256).
17. Adamec RE, Blundell J, Burton P. (2005): Neural circuit changes mediating lasting brain and behavioral response to preodator stress. Neurosci and Biobehav Rev 29(8) : 1225–1241.
18. Belzung, C, Hage EI, Moindrote G, Griebel, G. (2001): Behavioral and neurochemical changes following predatory stress in mice. Neuropharm 41 (3): 400-408.
19. Zoladz, PR, Conrad CD, Fleshner M, Diamond DM (2008): Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of traumatic stress disorder. Stress 11(4): 259-81.
20. Piotrwoski CS, Brannen SJ (2002): Exposure, threat appraisal, and lost confidence as predictors of PTSD symptoms following September 11, 2001. Am J of Orthopsychiatr 72: 476-485.
21. Roth TL, Zoladz PR, Sweatt JD, Diamond DM (2011): Epigenetic modification of hippocampal bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. J psychiatr 45(7) : 919-926.
22. Yehuda R, Bierer LM (2009): The Relevance of Epigenetics to PTSD: Implications for the DSM-V. J Trauma Stress 22(5): 427-434.
23. Zoladz PR, Diamond DM (2013): Current status on behavioral and biological markers of PTSD: A search for clarity in a conflicting literature. Neurosci Biobehav Rev 37(5): 860-895.
24. Kohda K, Harada K, Kato K, Hoshino H, Motohashi J, Yamaji H, et al. (2007): Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: A putative post-traumatic stress disorder model. Neuroscience 148: 22–33.
25. Knox D, Perrine SA, George SA, Galloway MP, Liberzon I, (2010): Single prolonged stress decreases glutamate, glutamine, and creatine concentrations in the rat medial prefrontal cortex. Neurosci Lett 480: 16–20.
26. Horovitz O, Tsoory MM, Hall J, Jacobson-Pick S, Richter-Levin G, (2012). Post-Weaning to Pre-Pubertal (‘Juvenile’) Stress: A Model of Induced Predisposition to Stress-Related Disorders. Neuroendocrinology 95: 56–64.
27. Louvart, H, Maccari, S, Darnaudery, M (2004): Prenatal stress affects behavioral reactivity to an intense stress in audlt female rats. Brain Research 1031 (1); 67-73.
28. Franklin T, Russig H, Weiss IC, Gräff J, Linder N, Michalon A, (2010): Epigenetic transmission of the impact of early stress across generations. Biol. Psychiatry 68: 408–415.
29. Oomen CA, Soeter H, Audureau N, Vermunt L, van Hasselt FN, Manders EMM et al. (2010): Severe early life stress hampers spatial learning and neurogenesis but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J Neurosci 30(19): 6635-6645.
30. Cohen H, Yehuda R, (2011). Gender differences in animal models of posttraumatic stress disorder. Gender differences in animal models of posttraumatic stress disorder. Dis Markers 30 (2-3): 141-150.
31. Raabe FJ, Spengler D, (2013): Epigenetic risk factors in PTSD and depression. Front Psychiatry 4 (80): 33-43.
32. Merz CJ, Tabbert K, Schweckendiek J, Klucken T, Vaitl D, Stark R, et al. (2010): Investigating the impact of sex and cortisol on implicit fear conditioning with fMRI.
Psychoneuroendocrinology 35(1): 33-46.
33. Schoofs D, Wolf OT, Smeets T (2009): Cold pressor stress impairs performance on working memory tasks requiring executive functions in healthy young men. Behav Neurosci 123(5): 1066-1075.
34. Yehuda R, LeDoux J (2007): Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56(1): 19-32.
35. Daskalakis NP, Yehuda R (2014): Principles for developing animal models of military PTSD. Eur J Psychotraumatol 5.
36. Svoboda E, McKinnon MC, Levine B (2006): The functional neuroanatomy of autobiographical memory: a meta-analysis. Neuropsychologia 44(12): 2189-2208.
37. Maguire EA (2002): Neuroimaging studies of autobiographical event memory. Philosophical Transactions of the Royal Society of London Series B, Biological Sciences 356: 1441-1451. 38. Fink GR, Markowitsch HJ, Reinkemeier M (1996): Cerebral representation of one’s own past:
neural networks involved in autobiographical memory. J Neurosci 16 (13): 4275- 4282. 39. Buckner RL, Wheeler ME (2001): The cognitive neuroscience of remembering. Nat Rev
Neurosci 2: 624-634.
40. Mason MF, Norton MI, van Horn JD, Wegner DM, Grafton ST, Macrae CN (2007): Wandering minds: the default network and stimulus-independent thought. Science 315 (5810): 393-395.
41. Ray SL, Vanstone M (2009): The impact of ptsd on veterans’ family relationships: an interpretative phenomenological inquiry. Int Journal Nurs Stud 46 (6); 838-847.
42. Protopopescu X, Pan H, Tuescher O, Cloitre M, Goldstein M, Engelien W. et al. (2005): Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects. Biol Psychiatry 57: 464–473.
43. Vermetten E, Schmahl C, Southwick SM, Bremner JD (2007): Positron tomographic emission study of olfactory induced emotional recall in veterans with and without combat- related posttraumatic stress disorder. Psychopharmacol Bull 40.
44. Debiec J, Diaz-Mataix L, Bush DE, Doyere V, LeDoux JE (2013). The selectivity of aversive memory reconsolidation and extinction processes depends on the initial encoding of the pavlovian association. Learn Mem 19(20): 695-9.
45. Holland AC, Kensinger EA (2010): Emotion and Autobiographical memory. Phys Life Rev. 7 (1):88-131.
46. Brewer WF (2001): Remembering our past: Studies in autobiographical memory. Cambridge University Press: New York.
47. Rubin DC, Kozin M (1984): Vivid memories. Cognition 16 (1): 81-95.
48. Barsalou LW, Nelsser U, Winograd E (1988): Remembering reconsidered: Ecological and traditional approaches to the study of memory. Cambridge Univ. Press. New York.
49. Conway MA, Rubin DC, Collins AF, Gathercole SE, Conway MA, Morris PE (2003): Theories of memory. Erlbaum: Hillsdale, New York, 2003; 103-139.
50. Buchanan TW (2003): Retrieval of emotional memories. Psychonomic bulletin 133: 761- 779. 51. Rogers TB, Kuiper NA, Kirker WS (1997): Self-reference and the encoding of personal
information. J Pers Soc Psychol 35 (9): 677-688.
52. Symons CS, Johnson BT (1997): The self-reference effect in memory: a meta-analysis. Psychol Bull 121 (3): 371-394.
53. Soeter M, Kindt M (2012): Erasing fear fonr an imagined threat event. Psychoneuroendocrinology 37 (11): 1769-1779.
54. Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK (2008): Effect of post- retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J Psychiatr Res 42 (6): 503–6. 55. LeDoux J.E. (1996): The Emotional Brain. New York: Simon & Schuster. New York:
Cambridge University Press.
56. Damasio A (1994): Descartes’ error: emotion, reason and the human brain. Putnam, 57. LeDoux JE (2000): Emotion Circuits in the Brain. Ann Rev Neurosci 23: 155–184.
58. Rauch SL, Shin LM, Phelps EA (2006): Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research—past, present, and future. Biol Psychiatry 60: 376–382.
59. Breslau N, Chilcoat HD, Kessler RC, Davis GC (1999): Previous exposure to trauma and PTSD effects of subsequent trauma:results from the detroit area survey of trauma. AM J Psychiatr 156 (6) : 902-907.
60. Broekman BFP, Olff M, Boer F (2007): The genetic background to PTSD. Neurosci Biobehav Rev 31(3) 348-362.
61. Bokszczanin A (2007): PTSD symptoms in children and adolescents 28 months after a flood: age and gender differences. J Trauma Stress 20(3), 347-351.
62. Hou C, Liu J, Wang K, Li L, Liang M, et al. (2007): Brain responses to symptom provocation and trauma-related short-term memory recall in coal mining accident survivors with acute severe PTSD. Brain Res 1144: 165–174.
63. Farnoosh H, Koshnood K, Desai MM, Falahati F, Kasl S, Southwick S (2006): Anxiety, depression, and posttraumatic stress in iranian survivors of chemical warfare. JAMA 296(5). 64. Lanius RA, Williamson PC, Densmore M, Boksman K, Gupta MA, Neufeld RW et al. (2001):
Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation. Am J Psychiatry 158:1920–1922.
65. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T, Charney DS (1999): Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am J Psychiatry 156: 1787–1795.
66. Nardo D, Hogberg G, Flumeri F, Jacobsson H, Larsson SA, Hallstrom T, et al. (2011). Self-rating scales assessing subjective well-being and distress correlate with rCBF in PTSD-sensitive regions. Psychol Med 41(12): 2549-2561.
67. Lanius RA, Blihm R, Lanius U, Pain C (2006): A review of neuroimaging studies in PTSD: heterogeneity of response to symptom provocation. J Psychiatr Res 40: 709-729.
68. Lanius RA, Frewen PA, Girotti M, Neufeld WJ, Stevens TK, et al. (2007): Neural correlates of trauma script-imagery in posttraumatic stress disorder with and without comorbid major depression: A functional MRI investigation. Psychiatry Res Neuroimaging 155: 45–56.
69. Lanius RA, Williamson PC, Densmore M, Boksman K, Neufeld RW, et al. (2004): The nature of traumatic memories: A 4-T fMRI functional connectivity analysis. Am J Psychiatry 161: 36– 44.
70. Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, et al. (1999): Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry 45: 817–826.
71. Pissiota A, Frans Ö, Fernandez M, von Knorring L, Fischer H, et al. (2002): Neurofunctional correlates of posttraumatic stress disorder: A PET symptom provocation study. Eur Arch Psychiatry Clin Neurosci 252: 68–75.
72. Yang P, Wu MT, Hsu CC, Ker JH (2004): Evidence of early neurobiological alternations in adolescents with posttraumatic stress disorder: a functional MRI study. Neurosci Letters 370: 13–18.
73. Liberzon I, Martis B (2006): Neuroimaging studies of emotional responses in PTSD. Ann Acad Sci 1071: 87-109.
74. Bremner JD, Vermetten E, Vythilingam M, Afzal N, Schmahl C, Elzinga B, et al. (2004): Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder. Biol Psychiatry 55(6): 612-620.
75. Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, et al. (2004): Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch Gen Psychiatry 61:168–176.
76. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B, et al. (2005): A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 62: 273–281.
77. Morey RA, Dolcos F, Petty CM, Cooper DA, Hayes JP, Labar KS et al. (2009): The role of trauma- related distractors on neural systems for working memory and emotion processing in posttraumatic stress disorder. J Psychiatr Res 43.
78. Dickie EW, Brunet A, Akerib V, Armony JL (2008): An fMRI investigation of memory encoding in PTSD: influence of symptom severity. Neuropsychologia 46: 1522–1531. 79. Osuch EA, Willis MW, Bluhm R, Ursano RJ, Drevets WC (2008): Neurophysiological
responses to traumatic reminders in the acute aftermath of serious motor vehicle collisions using [150]-H2O PET. Biol Psychiatry 64: 327–335.
80. Thomaes K, Dorrepaal E, Draijer NP, de Ruiter MB, Elzinga BM, van Balkom AJ et al. (2009): Increased activation of the left hippocampus region in Complex PTSD during encoding and recognition of emotional words: a pilot study. Psychiatry Res 171: 44 – 53.
81. Werner NS, Meindl T, Engel RR, Rosner R, Riedel M, Reiser M, et al. (2009): Hippocampal function during associative learning in patients with posttraumatic stress disorder. J Psychiatr Res 43: 309–318.
82. Squire LR, Schacter DL (2002). The Neuropsychology of Memory. Guilford Press.
83. Phan KL, Britton JC, Taylor SF, Fig LM, Liberzon I (2010): Corticolimbic blood flow during nontraumatic emotional processing in posttraumatic stress disorder. Arch Gen Psychiatry 63: 184–192.
84. Lindauer RJ, Booij J, Habraken JB, van Meijel EP, Uylings HB, Olff M, et al. (2008): Effects of psychotherapy on regional cerebral blood flow during trauma imagery in patients with post- traumatic stress disorder: a randomized clinical trial. Psychol Med 38: 543–554.
85. Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I (2005): Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol Psychiatry 57 :832– 840.
