The current study provides evidence supporting the presence of allocentric spatial processing deficits in chronic PTSD. Although previous studies have not consistently documented general visuospatial impairment in PTSD, prior investigations have largely employed “egocentric” (in reference to body-midline) rather than “allocentric” (related to configural relationships among distal stimuli) tasks. The specific nature of this spatial deficit was demonstrated in the current study by the fact that differences in allocentric performance were maintained even after controlling for multiple measures of general visuospatial ability.
Of additional interest is the fact that the difference observed in allocentric spatial processing between PTSD and non-PTSD combat veterans in this study seems to represent a pre-existing familial risk factor as evidenced by the presence of a comparable deficit in their identical co-twin brothers who had neither combat-exposure nor PTSD. These “high risk” co-twins demonstrated significantly impaired performance relative to the non-PTSD combat veterans and their “low risk” unexposed co-twins. Furthermore, the severity of PTSD symptomatology in combat-exposed participants was predicted not only by their own performance on the Cube and Paper Test but also by the performance of their unexposed identical co-twins. We have previously demonstrated in this sample (
Gilbertson et al. 2002,
2006) that the deficits observed in the familial vulnerability pattern cannot be explained by comorbidity confounds (e.g., alcohol/substance abuse, depression) or medication use. In the current study, we also extend this finding to history of head injury. The ExP+ twins and their UxP+ co-twins differ in these comorbid conditions (i.e., UxP+ co-twins do not show elevated comorbid conditions, history of head injury, or medication use), yet the ExP+ and UxP+ co-twins show similar performance in the dependent variable of interest, in this case allocentric spatial processing.
When placed in a prediction model alongside measures of IQ and verbal declarative memory, Cube and Paper Test performance was the best (and only) predictor of hippocampal volume in study participants. We found no significant relationship between hippocampal volume and the measures of verbal declarative memory and IQ that differentiated PTSD and non-PTSD veterans in this sample (
Gilbertson et al. 2006). This is the first study to provide evidence that the role of hippocampal morphology in PTSD might be related to allocentric spatial processing. It should be noted, however, that our findings do not clearly establish the overall specificity of the hippocampus in mediating this task, and non-hippocampal regions (e.g., posterior parietal, orbitofrontal) might be expected to impact performance as well. In animal studies,
Corwin et al. (1994) demonstrated the potential relevance of orbitofrontal cortex to allocentric processing, although human studies have been less compelling (
Galati et al. 2000;
Neggers et al. 2006). The fact that performance on the Cube and Paper Test continued to predict hippocampal volume even after adding amygdala volume or total grey matter volume to the regression model is suggestive of a prominent role for the hippocampus. However, it would be premature to rule out the impact of other brain regions, and more sophisticated allocentric tasks should be employed in future studies.
Configural cue processing deficits provide support, albeit of a preliminary nature, for what we believe to be an intuitively appealing, alternative model of hippocampal function in PTSD. This model, which has been broadly suggested by Davidson
et al. (
Davidson 2000;
Davidson et al. 2000), asserts that the role of the hippocampus in psychopathological disorders such as PTSD might involve deficits in the ability to encode context (e.g., patterns of environmental cues) to regulate emotional responses. Building on the general role attributed to the hippocampus in the spatial processing of environmental cues (e.g., “spatial map” theory of
O'Keefe and Nadel [1978]), numerous studies have begun to more specifically delineate the contribution of the hippocampus in shaping fear acquisition and extinction via contextual processing (
Anagnostaras et al. 1995;
Corcoran and Maren 2001;
Frankland et al. 1998;
Phillips and LeDoux 1994;
Winocur 1997). Background environmental cues might be important in “setting the scene” for interpreting the fear relevance of a given CS (
Schmajuk and Buhusi 1997; i.e., context-appropriate fear responding). Whereas the amygdala has been shown to play a critical role in the mediation of discrete CS–CR pairings, animal studies have demonstrated that lesions of the hippocampus (particularly the dorsal hippocampus) prevent or alter the acquisition and expression of many forms of contextual fear conditioning.
In the presence of compromised hippocampal capacity, animals might be less proficient in their ability to encode complex background environment to suppress context-inappropriate conditioned responses. As noted previously, the hippocampus has been shown to be especially relevant to the mediation of allocentric as opposed to egocentric spatial cues (
Burgess et al. 1999), a function that makes it ideal for complex, configural contextual processing. Other non-hippocampal brain regions can support the limited processing of context at a more elemental or individual cue level. However, an intact hippocampus seems to retain a relatively unique capacity for integrating multiple individual elements into a relational whole while at the same time suppressing more elemental cue processing by other brain regions (
Driscoll et al. 2005;
Maren 2001;
Sutherland et al. 1989). Reduced hippocampal capacity would therefore be expected to result in a relative over-reliance on contextual conditioning to simple, elemental cues mediated by non-hippocampal brain regions. A larger or more functional hippocampus, which monitors the presence and configural relationship of multiple cues within an environment and not merely the presence of individual or isolated cues, might better discriminate whether a particular contextual environment appropriately signals the relevance of a conditioned fear response.
The potential significance of hippocampus-based, allocentric processing of contextual cues for the pathophysiology of PTSD is perhaps best made evident in animal studies of extinction (i.e., loss of conditioned fear response when a CS is repeatedly presented in the absence of the US). It is generally accepted that stimulus-response conditioning has relative permanency (i.e., extinction does not destroy or cause an “unlearning” of the original conditioned response) (
Bouton 2002;
Rescorla 2001). Rather, inhibitory processes can temporarily or situationally suppress expression of the CR, resulting in extinction. One such inhibitory process contributing to extinction is environmental context (
Bouton 1993,
2000). In an important demonstration of this process in relation to hippocampal morphology,
Frankland et al. (1998) found that animals that received hippocampal lesions before fear conditioning were unable to fully differentiate aversive versus non-aversive contextual environments and failed to effectively extinguish conditioned fear responses in a new chamber that had no history of aversive conditioning. The mere presence of isolated cues associated with the original aversive chamber seemed capable of signaling the relevance of a fear response in the “safe” chamber. Frankland
et al. replicated this result in mice with genetic mutations associated with compromised hippocampal function. We propose that, consistent with this formulation, smaller hippocampal volume before trauma exposure might lead to failures in context-appropriate extinction of conditioned emotional responses, resulting in unremitting PTSD symptomatology.
In the clinical literature, the term “contextualization” has been coined to describe a patient's capacity to discriminate between “then” (original traumatic environment) and “now” (current environment), contributing to the persistence of PTSD-related symptoms (
Ehlers and Clark 2000;
Foa and Rothbaum 1998). The hippocampus might represent a biological substrate for this process, and the inability to adequately engage allocentric processing of contextual information might provide a model for understanding the persistent nature of conditioned emotional responses in chronic PTSD patients after removal from the original traumatic environment. The well-described re-experiencing symptoms of PTSD as documented in the DSM-IV (
American Psychiatric Association 1994; e.g., “physiological reactivity on exposure to internal or external cues” [criterion B(5)]) would be predicted by impaired hippocampal capacity to decode configural arrays of cues that would normally suppress inappropriate fear responses to the mere presence of isolated individual cues. Thus, for example, a combat veteran with unremitting PTSD who is no longer in the combat field might experience significant conditioned physiological and emotional responses when exposed to a single cue (e.g., sound of a helicopter, smell of gun powder, sight of a person who shares physical features with the former enemy, etc.) even though this cue exists in an array of complex cues that otherwise defines the context as safe.
A number of limitations to the current study should be acknowledged. We employed a rather simple paper-and-pencil task in our assessment of “allocentric” spatial processing. More complex procedures for measuring allocentric spatial processing with three-dimensional space or virtual reality (
Astur et al. 2002;
Driscoll et al. 2003) should be employed in future studies. Future studies employing psychophysiological conditioning and extinction protocols with human participants diagnosed with PTSD will also be required to more fully validate the model proposed here. Future studies will also require the inclusion of both remitted and unremitted populations of PTSD patients to more clearly establish a relationship between the course or chronicity of PTSD and allocentric processing.
An additional caution should be raised regarding the potentially confounding factor of overall intelligence. Cube and Paper Test differences did not maintain statistical significance when the covariates of verbal and overall IQ were taken into account. As described by
Miller and Chapman (2001), the interpretation of covariance analyses must be cautious when the covariate (i.e., IQ) differs between experimental groups (i.e., PTSD vs. non-PTSD). “Controlling” for differences in IQ under these circumstances can statistically underestimate the true difference and significance level of the dependent measure. Nonetheless, our findings can not definitively rule out the possibility that Cube and Paper performance reflects overall poorer cognitive functioning. A number of factors potentially mitigate this concern. First, the viewpoint that Cube and Paper performance is not simply synonymous with IQ is supported by the observation that the Cube and Paper task was predictive of hippocampal volume whereas IQ was not (likewise, Cube and Paper performance was predictive of hippocampal volume even when IQ was accounted for). Furthermore, not all aspects of IQ significantly attenuated the effects of Cube and Paper test performance (i.e., it remained significant when “controlling” for non-verbal IQ). Finally, the finding that other cognitive tasks were highly correlated with IQ in our sample (e.g., VOSP, FRT) yet did not differentiate PTSD and non-PTSD subjects (
Gilbertson et al. 2006) again mitigates against the notion that IQ alone is the relevant factor.
In recent years, neuroimaging studies have yielded an impressive array of findings uncovering significant brain-based differences associated with PTSD. These exciting developments have usefulness to the degree that coherent links can be established to the specific clinical phenomenology of interest. Findings of the current study suggest specific mechanisms by which hippocampal morphology and function might mediate particular clinical features of chronic PTSD. These findings further point to the potential importance of examining pre-existing, brain-based cognitive differences that might impact how a traumatic event is processed and therefore affect the severity and/or longevity of associated symptoms. Ultimately, the elucidation of these brain-based cognitive processes might guide the development of new behavioral treatment strategies (e.g., remediation of contextual cue deficits) that might improve the treatment of intractable or treatment-resistant PTSD.
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