The human brain and body are capable of adapting to life experiences,including severe and traumatic stress

Running head: Brain changes in posttraumatic stress disorder

Current Directions in Psychology (in press)

Structural and functional neuroplasticity in relation to traumatic stress

Iris-Tatjana Kolassa, Thomas Elbert

Clinical Psychology & Neuropsychology, University of Konstanz, Germany

Abstract

The body’s stress response is an essential adaptive and protective mechanism to cope with threatening situations. However, chronic or traumatic stress leads to neuroplastic changes involving structural and functional alterations in the traumatized brain. We argue for a building block effect: exposure to different traumatic event types increases the probability of developing posttraumatic stress disorder (PTSD), via incremental enlargement of a fear network. Evidence on neuroplastic changes in PTSD is summarized, including recent results from research on animal models of stress-related neuroplastic remodeling, with an emphasis on structural and functional changes in the hippocampus, the amygdala, and the medial prefrontal cortex.

Key words

Amygdala, hippocampus, neuroplasticity, Posttraumatic Stress Disorder, stress

The human brain and body are capable of dealing with stressors such as danger or violent experiences in a flexible and adaptive way. Chronic or repeated traumatic stress, however, can damage organs, including the brain, and may weaken regulatory functional systems such as the hypothalamic-pituitary-adrenal (HPA) axis. The hippocampus and the HPA axis are involved in the feedback regulation of the stress hormone cortisol and thus in the body’s reaction to danger. Regulatory dysfunctions in these systems in the aftermath of highly stressful life events may result in mental illness. Whereas stressful life events like bereavement or role changes can lead to depressive disorders, exposure to extreme (traumatic) stress may lead to posttraumatic stress disorder (PTSD).

PTSD is characterized by ongoing intrusive, i.e., uncontrollable memories, including nightmares, a constant state of alarm (hyperarousal) and avoidance symptoms, including emotional numbing. Sleep disturbances, substance abuse, depression, and enhanced risk for suicide are common consequences, as are poor self-reported well-being, poor physical health, and increased health care utilization.

Traumatic stress here refers to potentially very harmful events eliciting feelings of helplessness, intense fear or horror associated with an alarm response (cf. Elbert, Rockstroh, Kolassa, Schauer, & Neuner, 2006), i.e., acute release of stress hormones. Each such experience is appropriately referred to as a trauma (Greek for “wound”) as it renders the victim stepwise more vulnerable to develop PTSD.

Building blocks: different traumatic stressors add up to produce PTSD

Investigating more than 3000 war refugees with varying degrees of traumatic stress exposure, Neuner et al. (2004) found that an increasing number of different traumatic event types experienced (e.g., torture, fighting, shelling, abduction, abuse/rape, forcible female circumcision) is accompanied by an increasing PTSD prevalence and symptom load, with PTSD prevalence reaching 100% for individuals having experienced 28 or more different traumatic event types (Figure 1) – a “building block” effect. Neuner et al. interpret this to mean that nearly anyone will develop PTSD once one has been exposed to a sufficiently high number of different traumatic stressors.

This building block effect may be a direct result of the development of a fear network, which is strengthened and extended in response to each new traumatic event (cf. Elbert et al., 2006). During a traumatic event, perceptual and emotional features of the situation are stored in memory – autobiographical context information (dates, external circumstances) as “cold” memories and sensory-perceptual information (fear, helplessness, high pulse) as “hot” memories (Metcalve & Jacobs, 1996), forming the nucleus of a network associated with the traumatic event. Subsequent traumatic events are associated with similar hot memories, leading to the integration of additional hot and cold memories into the existing fear network. Network connections are strengthened through synchronous activation via long-term potentiation: neural assemblies firing repeatedly in synch will tend to become associated, so that activity in one facilitates activity in the other. When the fear network is fully formed, the activation of a single memory item (e.g., seeing a man in a uniform or feeling one’s heartbeat) will cause the whole network to be activated in a cascade. Thus, memories of specific traumatic events will merge into an indistinct whole, and a fragmentation of autobiographic context memory results: it becomes harder and harder to associate specific cold memories with each traumatic experience (e.g., specific times, dates, locations and situation-specific information; cf. Elbert & Schauer, 2002). Consequently, traumatized persons often have difficulties in reconstructing dates and sequences of events associated with traumatic experiences (Foa & Riggs, 1993; cf. also McNally, 2006).

Brain regions implicated in PTSD

Neuropsychological research suggests that exposure to traumatic events and the consequent alterations in stress hormones cause alterations in the structure and functioning of the brain, affecting brain systems involved in learning, memory, and affective regulation. The amygdala, the hippocampus, and the medial prefrontal cortex (mPFC), which includes the anterior cingulate cortex (ACC), appear to be particularly involved in trauma-related neurocircuitry (cf. Shin, Rauch, & Pitman, 2006; compare Figure 2).

The amygdala is involved in the assessment of threat-related stimuli (cf. Shin et al., 2006). It has been suggested to be at the centre of a defence system involved in the acquisition and expression of conditioned fear. It receives information from all sensory modalities and projects to various subcortical structures involved in mediating specific signs of fear and anxiety, e.g., facial expression of fear, stress hormone release, galvanic skin response, blood pressure elevation, hypoalgesia, and freezing. The amygdala thus plays a pivotal role in mediating stress-related effects on behaviour and modulating hippocampal function.

The hippocampus is vital to memory formation and emotional regulation by putting specific events into their proper context, binding together multiple events that co-occur during an experience and converting short-term into long-term memories. Thus, it plays a central role in the encoding of context during fear conditioning.

The mPFC inhibits activation of the amygdala and is involved in the extinction of conditioned fear. The mPFC includes the anterior cingulate cortex (ACC), which is implicated in evaluating the emotional significance of stimuli and in attentional function (Cardinal, Parkinson, Hall & Everitt, 2002).

Evidence for structural brain changes in PTSD

Studies on animals

Animal studies, in particular research on tree shrews (tupaia belangeri), have revealed changes in hippocampal plasticity in response to various stressors, including less long-term potentiation, decreased formation of new nerve cells in the dentate gyrus, a subregion of the hippocampus, decreased hippocampal cell survival and increased programmed cell death, i.e., a regulated process which leads to the suicide of a cell in an organism, conferring an advantage during an organism’s life-cycle, in contrast to necrosis, which is a form of cell-death that results from acute tissue injury (cf. Duman, 2005).

In the medial prefrontal cortex, chronic stress results in dendritic atrophy, whereas dendritic hypertrophy is found in the amygdala. Evidence exists that stress-induced atrophy is reversible in the hippocampus and mPFC once stress has ceased. However, amygdala hypertrophy appears less readily reversible. This might be one reason why PTSD symptoms often diminish very slowly and sometimes not at all (see Miller & McEwen, 2006).

Studies on humans

A series of cross-sectional studies examined structural abnormalities of the hippocampus and other brain regions in subjects with various traumata. A meta-analysis by Karl et al. (2006) found that individuals with traumatic experiences but without PTSD showed significantly smaller left hippocampal volume compared to non-exposed controls. A subcluster of studies even revealed bilaterally reduced hippocampal volume in this group. In addition, Karl et al. reported smaller hippocampal volumes in PTSD patients compared to trauma-exposed and non-exposed controls. Among PTSD patients, higher severity of PTSD was associated with medium to large bilateral hippocampal volume reduction, while moderate PTSD was associated with small effects, which may be a neurological correlate of the building block effect of traumatic events posited above.

Volumetric abnormalities in PTSD are not restricted to the hippocampus, although the effect sizes in other brain structures are smaller than in the hippocampus (Karl et al., 2006). Individuals with PTSD show smaller left amygdala volumes than trauma-exposed and non-exposed controls. In addition, PTSD patients show smaller ACC compared to trauma-exposed controls. It has been suggested that the ACC differentiates between similar conditioned stimuli depending on their association with reinforcement to prevent generalization between conditioned stimuli (Cardinal et al., 2002). In line with the fear network model introduced above, various sometimes only peripherally trauma-associated stimuli can trigger flashbacks and intrusions in persons with PTSD. Thus, the functioning of the ACC may be disturbed in PTSD patients.

Chicken or Egg?

It has been proposed that a smaller hippocampus may not only be a consequence of PTSD but also reflect a genetic or at least a constitutional vulnerability for developing PTSD in the aftermath of traumatic events (McNally, 2006), possibly also leading to selection effects in hippocampus studies. Gilbertson et al. (2002) studied monozygotic twins in which one member of each pair experienced combat in Vietnam, while the other stayed at home. Combat veterans who developed PTSD had smaller hippocampi than combat veterans without PTSD. Crucially, the stay-at-home siblings of PTSD combat veterans also had smaller hippocampi, and the hippocampal volume of the stay-at-home sibling was even negatively correlated with the severity of the combat sibling’s PTSD. Thus, a smaller hippocampus may well be a predisposing factor to develop PTSD after a traumatic event. However, one could argue that both siblings with small hippocampi had been exposed to childhood traumas which may have led to smaller hippocampus volume. Indeed, both combat-exposed and combat-unexposed twins in pairs where the combat twin developed PTSD reported higher lifetime stress than pairs without PTSD. However, the effect was insignificant, which may be due to the small number of participants.

Nevertheless, Gilbertson et al’s study supports the building block effect of repeated traumatic events as posited above: combat veterans with PTSD reported more lifetime traumatic events than either their stay-at-home siblings or combat veterans without PTSD. Thus, a smaller hippocampus may be a predisposing factor for developing a PTSD in the context of a dose-response relationship – the “critical dose” of different traumatic event types needed to develop a PTSD may decrease with decreasing hippocampus volume.

One problem in the field is that most studies investigating hippocampal atrophy in the aftermath of trauma have been cross-sectional. A longitudinal study by Bonne et al. (2001) investigated recent trauma survivors one week and six months after trauma and compared those who developed PTSD to those who did not develop PTSD. There was no significant difference in hippocampal volumes between individuals with PTSD and individuals without PTSD at either time point, nor a reduction of hippocampal volume within participants. However, we do not know how long neuroplastic and degenerative changes take to influence hippocampal volume. Effects may appear after a longer interval after the traumatic event, as a consequence of more chronic and complicated PTSD or after experiencing a higher traumatic load – Bonne et al. did not analyze the number of different traumatic event types experienced by each individual.

In line with an effect of trauma on hippocampal volume, Carrion, Weems & Reiss (2007) found that PTSD symptoms and prebedtime cortisol predicted hippocampal reduction in traumatized children over an ensuing 12- to 18-month interval. Thus, there is evidence for trauma-related reduction in hippocampal volume if one investigates a longer time frame.

Evidence for functional changes in PTSD

In functional neuroimaging research, individuals with PTSD are typically presented with reminders of their trauma to compare brain activations in response to trauma-related vs. neutral stimuli or compared to a matched non-PTSD control group. The major brain structures under investigation have been the hippocampus, the amygdala, the mPFC, and Broca’s area.

A few studies have investigated hippocampal function in PTSD. Findings are mixed, ranging from no or lower activation of the hippocampus during cognitive tasks to increased hippocampal activation at rest or across tasks (cf. Shin et al., 2006).

Amygdala sensitivity is enhanced in PTSD patients, even in response to non-trauma-related arousing stimuli. In addition, positive correlations between PTSD symptom severity and blood flow in the amygdala during exposure to trauma-related stimuli have been found (cf. Shin et al., 2006). Consequently, emotional or sensory triggers may more easily elicit vivid memories of traumatic events or even induce flashbacks.

Patients with PTSD demonstrate decreased activity in the mPFC (Bremner et al., 1999) and ACC (Shin et al., 2006). The decreased activation of the ACC may be associated with the inability of people with PTSD to extinguish fear (Hull, 2002). Intrusive memories of the trauma, accompanied by hyperarousal, both common in PTSD, are consistent with either a more responsive amygdala, a less active mPFC, or both (Shin et al., 2006).

Various studies reported a deactivation of Broca’s area during symptom provocation paradigms (cf. Hull, 2002). Broca’s area is the anterior language area located in the left frontal cortex of right-handed people. It is a common experience in clinical practice that PTSD patients have extreme difficulties in verbalizing their traumatic experiences, because the quality of emotional memories while re-experiencing is more emotional and sensory in nature.

However, while functional changes have been found in PTSD patients, it is unclear how these results are to be interpreted. Are neurons damaged, leading to less firing? Or has the number of neurons decreased? Or is functional connectivity between neurons changed in PTSD?

Genetic predispositions

Recently, genetic polymorphisms that influence stress sensitivity and the building of emotional memories have come under scrutiny. For example, de Quervain et al. (in press) showed in a Swiss population that persons with a deletion variant of the gene encoding the alpha(2B)-adrenoceptor, a synaptic membrane receptors targeted by stress hormones, show enhanced memory for emotionally arousing material. Correspondingly, in survivors of the Rwandan genocide suffering from PTSD the deletion variant was related to increased traumatic memory as measured by the intrusion symptom score.

This suggests that the price to pay for the deletion-related enhancement in emotional memory is increased traumatic memory and possibly a higher predisposition to PTSD. Thus, genetics may influence stress sensitivity and vulnerability to adverse consequences after traumatic events, while any connection to neurological changes is so far unknown.

Conclusions and Future Directions

Animal research suggests a coherent picture of stress-induced atrophy in the hippocampus and the mPFC and of hypertrophy in the amygdala. Studies in PTSD patients indicate volumetric as well as functional changes in the hippocampus, amygdala, and mPFC, while the cause-effect relationship is unclear. In addition, functional alterations in Broca’s area have been reported.

One key problem is that most existing studies on the neurological underpinnings of PTSD are cross-sectional. Changes in brain structure and function in response to traumatic events, PTSD development or even PTSD therapy could better be understood from longitudinal studies. Unfortunately, ethical studies are hard to design in this field.

Future studies on PTSD need to take into account that hippocampal atrophy may be both a consequence of traumatic stress and a marker for increased vulnerability for PTSD, via a building block effect. Thus, future research on the effects of traumatic stress on humans should focus on individuals who experienced traumatic events but did not develop PTSD in addition to analyzing the number of different lifetime traumatic events, in order to better understand the building block effect and the development of the fear network.

One implication of the neurological correlates of traumatic stress is that it may become possible to validate treatment approaches to PTSD on a biological level. Indeed, first functional effects of exposure treatment have been found – e.g., exposure therapy has been found to lead to reduced amygdala and increased ACC activation during fear processing (Felmingham et al., 2007) – which implies that structural and functional neuronal changes in PTSD may be reversible.

Author Note

¹Correspondence concerning this article should be addressed to Iris-Tatjana Kolassa, Department of Psychology, Clinical Psychology & Neuropsychology, University of Konstanz, 78457 Konstanz, Germany. E-mail: Iris.Kolassa@uni-konstanz.de

Research was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG).

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