Elsevier

Journal of Psychiatric Research

Volume 70, November 2015, Pages 58-66
Journal of Psychiatric Research

Burning odor-elicited anxiety in OEF/OIF combat veterans: Inverse relationship to gray matter volume in olfactory cortex

https://doi.org/10.1016/j.jpsychires.2015.08.015Get rights and content

Highlights

  • Combat veterans commonly report odors associated with their traumatic experiences.

  • Volumetric imaging revealed insult of the olfactory cortex in combat-related PTSD.

  • Olfactory cortical atrophy was inversely related to odor-elicited PTSD symptoms.

Abstract

Despite the anatomical overlap between the brain's fear/threat and olfactory systems, a very limited number of investigations have considered the role of odors and the central olfactory system in the pathophysiology of PTSD. The goal of the present study was to assess structural differences in primary and secondary olfactory cortex between combat veterans with and without PTSD (CV + PTSD, CV-PTSD, respectively). An additional goal was to determine the relationship between gray matter volume (GMV) in olfactory cortex and the distressing properties of burning-related odors. A region of interest voxel-based morphometric (VBM) approach was used to measure GMV in olfactory cortex in a well-characterized group of CV + PTSD (n = 20) and CV-PTSD (n = 25). Prior to the MRI exam, combat-related (i.e., burning rubber) and control odors were systematically sampled and rated according to their potential for eliciting PTSD symptoms. Results showed that CV + PTSD exhibited significantly reduced GMV in anterior piriform (primary olfactory) and orbitofrontal (secondary olfactory) cortices compared to CV-PTSD (both p < .01). For the entire group, GMV in bilateral anterior piriform cortex was inversely related to burning rubber odor-elicited memories of trauma (p < .05). GMV in orbitofrontal cortex was inversely related to both clinical and laboratory measures of PTSD symptoms (all p < .05). In addition to replicating an established inverse relationship between GMV in anxiety-associated brain structures and PTSD symptomatology, the present study extends those findings by being the first report of volumetric decreases in olfactory cortex that are inversely related to odor-elicited PTSD symptoms. Potential mechanisms underlying these findings are discussed.

Introduction

Over the past 20 years, a large literature of neuroimaging studies investigating the structural brain changes associated with PTSD has emerged. While important initial investigations revealed PTSD-related volumetric reductions in hippocampus (Bremner et al., 1995, Gurvits et al., 1996, Stein et al., 1997), subsequent studies have described gray matter volume (GMV) reductions extending throughout limbic and paralimbic structures, as well as prefrontal cortical regions (Aupperle et al., 2013, Chen et al., 2006, Geuze et al., 2008, Keding and Herringa, 2015, Kuhn and Gallinat, 2013, Nardo et al., 2010, Rauch et al., 2003, Yamasue et al., 2003). To date, an inverse relationship between limbic/paralimbic GMV and PTSD severity, as well as the severity of the individual symptom clusters of re-experiencing, avoidance/numbing, and hyperarousal, has predominated (Araki et al., 2005, Kroes et al., 2011, Lindauer et al., 2004, Shucard et al., 2012, Thomaes et al., 2010, Villarreal et al., 2002, Yamasue et al., 2003); yet, other reports of positive associations between PTSD and early life trauma severity, and hippocampal/amygdala volume have also been reported (Baldacara et al., 2014, Weber et al., 2013).

Although the full range of pathophysiological processes that underlie PTSD-related decreases in brain volume are not completely understood, one mechanism by which severe stress may contribute to brain atrophy (e.g., hippocampal) has a great deal of support in both animal and human research. Evidence for the “glucocorticoid hypothesis” suggests that chronic stress, accompanied by dysregulation of glucocorticoids (i.e., cortisol), leads to hippocampus vulnerability and potential structural insult that could negatively impact cognitive function including learning and memory (Lindauer et al., 2006, Lupien et al., 1998, McEwen, 2000). In addition to increased baseline levels of salivary cortisol (Young et al., 2004), trauma-exposed individuals also exhibit memory-triggered augmented cortisol responses (Dekel et al., 2013) that can modulate regional brain activity (Liberzon et al., 2007). These studies suggest that traumatic reminders and re-experiencing of cues that resemble or symbolize the original trauma [termed conditioned stimuli, which from a fear conditioning perspective is believed to underlie the fear-related symptoms of PTSD (Briscione et al., 2014)] may contribute to the chronicity of glucocorticoid dysregulation and subsequent changes in brain structure and function.

Situated at the junction of the temporal and frontal cortices, the primary olfactory (piriform) cortex, along with the extended olfactory circuit, shares common neuroanatomy with the brain's fear/threat circuit (LeDoux, 2012, Price, 1990), including many of the same limbic/paralimbic structures identified in the pathophysiology of PTSD (e.g., amygdala, hippocampus and surrounding cortex, anterior insula, and orbitofrontal cortex). Emerging evidence suggests that the olfactory system is particularly susceptible to insult and thus may serve as a sensitive indicator of structural integrity in these limbic/paralimbic and frontal neural networks. For example, olfactory dysfunction is reported in laboratory animals following exposure to environmental toxins (Blechinger et al., 2007), chronic stress (Mo et al., 2014), as well as mechanical percussion-induced closed head injury (Siopi et al., 2012); this type of dysfunction is also considered a prodromal marker of human neurodegeneration (Devanand et al., 2000, Lerche et al., 2014). Given that glucocorticoid receptors are widely distributed from the olfactory bulb throughout the olfactory cortex (Morimoto et al., 1996), and that hypercortisolemia can negatively affect olfactory structure (Kratskin et al., 1999) and function (Ezeh et al., 1992), the olfactory system and/or olfactory function is likely impaired by chronic stress and subsequent psychiatric conditions including PTSD.

Despite the anatomical overlap between the olfactory and fear/threat systems, as well as its vulnerability to insult, a limited number of investigations (Hinton et al., 2004, Vermetten and Bremner, 2003, Vermetten et al., 2007) have considered the role of the central olfactory system in their study of PTSD. To our knowledge, only one study assessed olfactory-related brain volume and reported reduced olfactory bulb volume in women with a history of childhood maltreatment (Croy et al., 2013). Other studies designed to assess clinical olfactory function in PTSD have been inconsistent (Croy et al., 2010, Dileo et al., 2008, Vasterling et al., 2000, Vasterling et al., 2003). However, recent preliminary data from our laboratory suggest that trauma-exposed combat veterans with and without PTSD may have a decreased ability to detect odors (Cortese et al., 2014), in addition to a self-reported reduction in general odor sensitivity (Cortese et al., 2015). It remains to be seen the degree to which this reduced sensitivity to odor is the result of generalized hyposmia, damage to the olfactory mucosa/receptors, perceptual difficulties mediated by cortical damage, or some combination of these factors.

Given our promising preliminary olfactory findings and the notion that re-experiencing trauma-related triggers may be associated with decreased GMV, as well as the fact that trauma-related differences in GMV along the olfactory pathway have not been adequately studied, we sought to assess GMV in combat veterans utilizing a region of interest (ROI) approach focused along the central olfactory pathway. We hypothesized that PTSD-related reductions in GMV in primary and secondary olfactory structures would be inversely related not only to general PTSD symptomology, but also to specific subjective ratings of odor hedonics and, most importantly, to increased odor-elicited re-experiencing of combat trauma.

Section snippets

Participants

Combat veterans with PTSD (CV + PTSD: n = 23) and without PTSD (CV-PTSD: n = 25) were recruited from the Ralph H. Johnson Veterans Affairs (VA) Medical Center, as well as the greater Charleston, South Carolina community via advertisement to participate in a larger study investigating odor-elicited anxiety. To meet eligibility for this study, participants were required to 1) have served in a combat zone in Iraq or Afghanistan [Operation Enduring Freedom (OEF), Iraqi Freedom (OIF), or New Dawn

Participant characteristics

The 20 combat veterans with PTSD (CV + PTSD) comprised 16 veterans that met DSM-IV criteria (APA, 1994) for current combat-related PTSD and 4 veterans that met current sub-clinical PTSD (i.e., met criterion A and 2/3 symptom clusters) and met diagnostic criteria for lifetime PTSD related to their combat experiences. Of the 20 CV + PTSD, 6 met diagnostic criteria for secondary depression, 3 had comorbid panic disorder and 1 had comorbid generalized anxiety disorder, but no other Axis I

Discussion

Our recent survey findings revealed a PTSD-related sensitivity to specific odors, with a significantly greater percentage of combat veterans with PTSD, compared to healthy combat veterans and civilians, reporting “burning” odors to be distressing (Cortese et al., 2015). The present laboratory results are consistent with those and reveal that burning odors (burning rubber and smoke), but not lavender, were rated as more intense and unpleasant, as well as significantly more effective at eliciting

Financial disclosures

All authors declare that they have no biomedical financial interests or potential conflicts of interest.

Contributors

BMC and TWU conceived and developed the study. BMC and KL collected the data. All authors contributed to the data analysis, manuscript composition, and illustrations. BMC wrote the first draft of the manuscript. All authors have approved the final manuscript.

Role of funding source

Funding for this study was provided by NIMH Grant K01 MH090548 (BMC).

NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Acknowledgments

Funding for this study was provided by NIMH Grant K01 MH090548 (BMC). The authors thank Drs. Anouk Grubaugh and Ron Acierno for their help with study recruitment.

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