Elsevier

Neuropharmacology

Volume 62, Issue 2, February 2012, Pages 674-685
Neuropharmacology

Invited review
Hippocampal dysfunction effects on context memory: Possible etiology for posttraumatic stress disorder

https://doi.org/10.1016/j.neuropharm.2011.04.029Get rights and content

Abstract

Hippocampal volume reductions and functional impairments are reliable findings in posttraumatic stress disorder (PTSD) imaging studies. However, it is not clear if and how hippocampal dysfunction contributes to the etiology and maintenance of PTSD. Individuals with PTSD are often described as showing fear responses to trauma reminders outside of contexts in which these cues would reasonably predict danger. Animal studies suggest that the hippocampus is required to form and recall associations between contextual stimuli and aversive events. For example, the hippocampus is critical for encoding memories in which a complex configuration of multiple cues is associated with the aversive event. Conversely, the hippocampus is not required for associations with discrete cues. In animal studies, if configural memory is disrupted, learning strategies using discrete cue associations predominate. These data suggest poor hippocampal function could bias the organism toward forming multiple simple cue associations during trauma, thus increasing the chances of fear responses in multiple environments (or contexts) in which these cues may be present. Here we will examine clinical and preclinical literature to support a theory of hippocampal dysfunction as a primary contributory factor to the etiology of PTSD, and discuss future research required to test these hypotheses.

This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Highlights

► Hippocampal volume and function is reduced in PTSD. ► Individuals with PTSD show fear responses to trauma in a context-independent way. ► The hippocampus contributes to context memory but not associations with discrete cues. ► Hippocampal dysfunction biases learning toward simple cue associations. ► PTSD may evolve from loss of contextual fear learning due to hippocampal dysfunction.

Introduction

Some of the most robust and significant neural markers associated with posttraumatic stress disorder (PTSD) are altered hippocampal volume and activation differences. The hippocampal complex is critical for encoding emotional memory and modulating appropriate emotional responses to fear relevant stimuli. Here we will review the findings of neural circuit abnormalities in PTSD patients focusing on hippocampal alterations, discuss if hippocampal differences are markers of vulnerability traits or, rather, are linked to alterations posttrauma, and describe how these abnormalities might disrupt fear learning processes during trauma exposure and recall. We also propose future research avenues to test the hypothesis that hippocampal abnormalities contribute to the etiology of this disorder.

PTSD is unique among the mental health disorders in that symptoms are induced by exposure to a known environmental stimulus, i.e. a life-threatening or traumatic event. This external stimulus has been incorporated into the DSM diagnostic criteria as Criterion A, defined as having experienced both a traumatic stress (“experienced or witnessed actual or threatened death, injury or threat to the physical integrity of self or others”) and reacted to that experience with “intense fear, helplessness or horror”. Lifetime prevalence rates for experiencing Criterion A events vary widely depending on the country studied (∼80% in the U.S. vs. ∼20–30% in Germany and Switzerland; Breslau, 2009). However, of those that experience this type of trauma in their lifetime, only a subset will go on to develop chronic PTSD symptoms (∼10% in the US; Breslau, 2009, Kessler et al., 2005) suggesting individual vulnerability or risk factors play a role in development of PTSD (Vogt et al., 2007). Also, the conditional risk for developing PTSD varies depending upon factors such as gender and type of trauma, with females and individuals exposed to assaultive violence at highest risk (Breslau, 2009, Galea et al., 2005, Breslau et al., 1998).

The symptoms that result from exposure to a Criterion A event in vulnerable individuals are intrusive recollections of the traumatic event (Criterion B), avoidance of trauma reminders and emotional numbing (Criterion C), and hyperarousal, e.g. irritability, difficulty sleeping, and increased startle reactivity (Criterion D). If these symptoms persist for longer than 3 months, the condition is referred to as “chronic” (APA, 2000).

These symptoms invoke a significant toll on the individual suffering from the disorder, as well as their families and their place of employment (Schnurr et al., 2009). PTSD is associated with high levels of impairment across social and occupational domains (Alonso et al., 2004, Druss et al., 2008) with a work loss index and disability rivaling that of neurological disorders and exceeding that of diabetes (Alonso et al., 2004). Annual productivity loss from PTSD in the United States is estimated to be over 3 billion US dollars (Brunello et al., 2001). In contrast to other anxiety disorders, PTSD is independently and significantly associated with both suicidal ideation and suicide attempts (Sareen et al., 2005, Sareen et al., 2007). The lifetime prevalence rate for PTSD has been estimated at ∼7% (Kessler et al., 2005), and the current treatments are mainly psychotherapy based treatments (e.g. exposure therapy and cognitive therapy), with modest efficacy of pharmacological treatments (Committee on treatment of posttraumatic stress disorder IoMotNA, 2007). There is a clear need for development of novel therapeutic approaches, which undoubtedly will emerge with better understanding of the etiology of this disorder (Baker et al., 2009).

For a contemporary example of trauma and symptoms associated with PTSD, consider a soldier in Iraq or Afghanistan who experiences attack by an improvised explosive device (IED). Exposure to IED or mortar blasts are a common experience for soldiers deployed to these theatres. Approximately 15% of infantry soldiers experience a significant blast, with ∼33% of those going on to develop PTSD (Hoge et al., 2008). IEDs are often hidden in walls, garbage bags, or piles of rubbish along side the road. Following exposure to an IED attack, the soldier may develop a constellation of symptoms consistent with PTSD. For instance, the soldier may experience distressing dreams or recollections of the explosion, intense psychological and physiological reactions when exposed to cues that resemble important aspects of the event (e.g. driving on roads littered with trash), avoidance of such cues or conversations that may trigger memories of the event, a diminished interest in activities or neglect of relationships, hypervigilance for signs of danger, irritability/anger, insomnia, and increased startle reactivity. While we have provided a current, Western-centric example of combat-related PTSD, it is important to note that this example holds across various trauma types (i.e. a female raped by a bald man may experience intense physiological and psychological reactions when later confronted by a different bald man, etc.).

As stated above, only ∼10% of individuals exposed to traumatic stress develop chronic PTSD (Breslau, 2009; Kessler et al., 2005). Thus, there is considerable variability in trauma stimuli and their perception, as well as differential individual vulnerability to trauma effects. Therapeutic interventions have been limited in part because the pathways that mediate vulnerability to trauma, and hence that contribute to the etiology of PTSD, are not understood.

Factors associated with increased risk for development of PTSD include psychosocial factors and past trauma exposures (Vogt et al., 2007), as well as genetic and epigenetic factors (Afifi et al., 2010, Yehuda and Bierer, 2009, Charney, 2004, Crow, 2004, Kent et al., 2002, Meaney et al., 2000, Merikangas and Pine, 2004, Nemeroff, 2004, Rasmusson et al., 2001, Saigh and Bremner, 1999). Epigenetic factors that contribute to increased stress responses in adulthood are particularly interesting as these can both be non heritable (e.g. methylation occurring due to early life stress; McGowan et al., 2009) and heritable depending upon the developmental period of epigenetic programming (e.g. in utero methylation occurring in primordial germ cells that is passed on to subsequent offspring; Dunn et al., in press). These factors are beyond the scope of this review but are reviewed in this extensively elsewhere (Kremen, 2011, Mehta, 2011, Skelton, 2011).

PTSD has also been associated with abnormal hypothalamic–pituitary–adrenal axis markers (e.g. Bauer et al., 2010, Yehuda, 2009) as well as neural circuit abnormalities (see below). In the case of biological markers associated with PTSD however, there is debate over which of these markers are related to a vulnerability traits vs. those that are related to biological adaptations specifically after trauma exposure (e.g. state).

Section snippets

Cortical and subcortical findings

Structural MRI and functional MRI studies in PTSD report differences in volume and activation of limbic circuitry mediating stress responding, fear memory, and emotional modulation (Garfinkel and Liberzon, 2009, Rauch et al., 2006). Given its central role in the acquisition of the conditioned fear response, the amygdala is a region of interest in imaging studies with hypotheses of increased function based on the increased anxiety/fear responding in these patients (Shin et al., 2006). Due to its

Abnormalities in hippocampus-dependent processes

A substantial body of research in both animals and humans has implicated the hippocampus and parahippocampus in declarative memory (Squire, 1992, Eichenbaum, 2000). Declarative memory refers to the ability to recall facts and events. It is commonly divided into semantic memory (memory for specific facts) and episodic memory (memory for specific events). The observation of hippocampal volumetric and neurochemical abnormalities in PTSD has led to the suggestion that declarative memory may be

Genetic risk factors related to hippocampal function in PTSD

To date, there are few research studies linking candidate genetic risk factors with hippocampal abnormalities in PTSD. Animal and human studies suggest that mutations in the BDNF (brain-derived neurotrophic factor, a member of the neurotrophin family of polypeptide growth factors) can influence acquisition of fear learning and extinction (for a recent review see Frielingsdorf et al., 2010). A methionine in place of a valine in position 66 of the prodomaine of BDNF (Val66Met) has been linked

Hippocampus abnormalities: state or trait?

In order to understand how hippocampal abnormalities contribute to development and/or maintenance of PTSD, an important question is whether this reduced volume is a trait in vulnerable individuals or, rather, a manifestation of the disease state after experiencing trauma. Recent research is beginning to support a conceptualization of these abnormalities as a pre-existing vulnerability factor for development of the disorder. Gilbertson et al., 2002, Gilbertson et al., 2007 examined hippocampal

Brewin’s model of intrusive memory/flashbacks

Brewin et al., 1996, Brewin et al., 2010, Brewin, 2001 have developed a dual representation model of intrusive memories in PTSD involving two complementary forms of memory, one of which is dependent upon the hippocampus. The hippocampal-dependent memory is termed “verbally-accessible memory” or “context representation” (C-Rep, Brewin et al., 2010). Under ordinary circumstances, C-reps are comprised of the spatial context for a given event, which is encoded as allocentric (view-independent)

Future research

The theory outlined above suggests a testable hypothesis. Namely, that hippocampus volume, identified through structural MRI, will be correlated with performance in a fear conditioning paradigm requiring conjunctive processing in order to predict presence or absence of an aversive event. In order to test this hypothesis, tasks need to be developed that allow the researcher to demonstrate the use of either a conjunctive or elemental encoding strategy by forcing the use of conjunctive memory

Conclusions

The presence of hippocampal abnormality is a robust finding in neurobiological investigations of PTSD, with some evidence that this may be a pre-existing vulnerability factor relevant to the etiology of the condition. Moreover, a large body of animal research documents the contribution of the hippocampal formation to the encoding and retrieval of memory for context. The present article proposes a mechanism through which hippocampal dysfunction may interact with traumatic experience to influence

Acknowledgments

Dr. Acheson is supported by a Veteran’s Affairs Mental Illness Research, Education, and Clinical Center (MIRECC) fellowship and the Department of Defense, Dr. Gresack is supported by a NARSAD Young Investigator award, and Dr. Risbrough is supported by NIMH MH074697, the Veteran’s Affairs Center of Excellence for Stress and Mental Health and a VA Merit Grant. We would also like to acknowledge the helpful comments of Dr. Robert Clark.

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