Burning odor-elicited anxiety in OEF/OIF combat veterans: Inverse relationship to gray matter volume in olfactory cortex
Graphical abstract
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.
References (89)
- et al.
Association between lower P300 amplitude and smaller anterior cingulate cortex volume in patients with posttraumatic stress disorder: a study of victims of Tokyo subway sarin attack
Neuroimage
(2005) A fast diffeomorphic image registration algorithm
Neuroimage
(2007)- et al.
Why voxel-based morphometry should be used
Neuroimage
(2001) - et al.
Reduction of anterior cingulate in adults with urban violence- related PTSD
J. Affect. Disord.
(2014) - et al.
Gray and white matter reduction in hyposmic subjects–A voxel-based morphometry study
Brain Res.
(2010) - et al.
Brief embryonic cadmium exposure induces a stress response and cell death in the developing olfactory system followed by long-term olfactory deficits in juvenile zebrafish
Toxicol. Appl. Pharmacol.
(2007) - et al.
Gray matter density reduction in the insula in fire survivors with posttraumatic stress disorder: a voxel-based morphometric study
Psychiatry Res.
(2006) - et al.
Differential odor sensitivity in PTSD: implications for treatment and future research
J. Affect. Disord.
(2015) - et al.
PTSD, but not childhood maltreatment, modifies responses to unpleasant odors
Int. J. Psychophysiol. off. J. Int. Organ. Psychophysiol.
(2010) - et al.
Effects of steroids on the olfactory function of the dog
Physiol. Behav.
(1992)
Exaggerated and disconnected insular-amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder
Biol. Psychiatry
Thinner prefrontal cortex in veterans with posttraumatic stress disorder
Neuroimage
Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder
Biol. Psychiatry
Post-traumatic stress symptoms correlate with smaller subgenual cingulate, caudate, and insula volumes in unmedicated combat veterans
Psychiatry Res.
Olfactory-triggered panic attacks among Cambodian refugees attending a psychiatric clinic
General Hosp. psychiatry
Chronic dexamethasone treatment potentiates insult to olfactory receptor cells produced by 3-methylindole
Brain Res.
Association between flashbacks and structural brain abnormalities in posttraumatic stress disorder
Eur. Psychiatry
Coping with emotions past: the neural bases of regulating affect associated with negative autobiographical memories
Biol. Psychiatry
Gray matter correlates of posttraumatic stress disorder: a quantitative meta-analysis
Biol. Psychiatry
J. rethinking the emotional brain
Neuron
Learning to smell the roses: experience-dependent neural plasticity in human piriform and orbitofrontal cortices
Neuron
Cortisol, learning, memory, and attention in relation to smaller hippocampal volume in police officers with posttraumatic stress disorder
Biol. Psychiatry
Smaller hippocampal volume in Dutch police officers with posttraumatic stress disorder
Biol. Psychiatry
Effects of adverse experiences for brain structure and function
Biol. Psychiatry
Effects of chronic stress on the onset and progression of Huntington's disease in transgenic mice
Neurobiol. Dis.
Distribution of glucocorticoid receptor immunoreactivity and mRNA in the rat brain: an immunohistochemical and in situ hybridization study
Neurosci. Res.
Gray matter density in limbic and paralimbic cortices is associated with trauma load and EMDR outcome in PTSD patients
J. Psychiatr. Res.
Olfactory system
Validity of modulation and optimal settings for advanced voxel-based morphometry
Neuroimage
The functions of the orbitofrontal cortex
Brain Cognit.
False positive rates in voxel-based morphometry studies of the human brain: should we be worried?
Neurosci. Biobehav Rev.
Statistical localization of human olfactory cortex
Neuroimage
An fMRI study of anterior cingulate function in posttraumatic stress disorder
Biol. Psychiatry
Symptoms of posttraumatic stress disorder and exposure to traumatic stressors are related to brain structural volumes and behavioral measures of affective stimulus processing in police officers
Psychiatry Res.
Fast and robust parameter estimation for statistical partial volume models in brain MRI
Neuroimage
Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder
Biol. Psychiatry
Voxel-based morphometric gray matter correlates of posttraumatic stress disorder
J. anxiety Disord.
Odors as effective retrieval cues for stressful episodes
Neurobiol. Learn. Mem.
Salivary cortisol and posttraumatic stress disorder in a low-income community sample of women
Biol. Psychiatry
Dissociated neural representations of intensity and valence in human olfaction
Nat. Neurosci.
Deployment and post-deployment experiences in OEF/OIF veterans: relationship to gray matter volume
PLoS One
The development of a clinician-administered PTSD scale
J. Trauma. stress
MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder
Am. J. Psychiatry
Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors
Front. psychiatry
Cited by (13)
High trait anxiety blocks olfactory plasticity induced by aversive learning
2022, Biological PsychologyPreliminary evidence for differential olfactory and trigeminal processing in combat veterans with and without PTSD
2018, NeuroImage: ClinicalCitation Excerpt :To our knowledge, we are the only research group to report structural deficits of the central olfactory system in PTSD, namely less gray matter volume (GMV) in piriform and olfactory orbitofrontal cortices in combat veterans with PTSD compared to trauma-exposed, but healthy, combat veterans (Cortese et al., 2015a). Interestingly, olfactory GMV in the combined group of veterans was inversely related to their ratings of burning odor-elicited PTSD symptoms (Cortese et al., 2015a). Although we and others have identified specific odors as being primary precipitants of re-experiencing and hyperarousal in both military and civilian trauma-exposed individuals (Cortese et al., 2015b; Hinton et al., 2004; Kline and Rausch, 1985; Vermetten and Bremner, 2003), very little is known regarding the sensory perception of and behavioral responses to trauma-related odors, especially when it comes to the neurobiology underlying changes in trauma-related odor processing.
Odor-induced recall of emotional memories in PTSD–Review and new paradigm for research
2016, Experimental NeurologyCitation Excerpt :Exposure to predator odor has long been used as an animal model for traumatic stress as it elicits unconditioned fear responses mediated by the extended amygdala, more specifically distinct neuronal populations of the amygdala proper as well as in the bed nucleus of the stria terminalis (Butler et al., 2012, 2016, Masini et al., 2009, 2010, Rosen et al., 2015). Whether hard-wired, unconditioned olfactory threat-cues also exist in humans is yet to be determined (for a discussion see Cortese et al., 2015a, 2015b). While responses to such unconditioned odors are highly informative regarding the neural pathways of odor processing in the context of fear, their explanatory power regarding the close link exposure to odors and the recall of emotional memories is limited.
Olfactory Dysfunction in Mental Illness
2023, Current Allergy and Asthma ReportsCase report: “Proust phenomenon” after right posterior cerebral artery occlusion
2023, Frontiers in Neurology