Positron tomographic emission study of olfactory induced emotional recall in veterans with and without combat-related posttraumatic stress disorder.

Abstract

Memory for odors is often associated with highly emotional experiences, and odors have long been noted by clinicians to be precipitants of trauma symptoms in posttraumatic stress disorder (PTSD). Primitive brain systems involved in fear responsivity and survival also mediate smell, including the olfactory cortex and amygdala. The purpose of this study was to measure neural correlates of olfaction in PTSD.
We exposed male combat veterans with PTSD (N = 8) and without PTSD (N = 8) to a set of smells, including diesel (related to traumatic memories of combat), and three other types of smells: odorless air, vanilla/coconut, and hydrogen sulfide (H2S) (respectively, a neutral, positive, and negative hedonic nontraumatic smell) in conjunction with PET imaging of cerebral blood flow and assessment of psychophysiological and behavioral symptoms. All subjects also underwent a baseline of olfactory acuity.
PTSD patients rated diesel as unpleasant and distressing, resulting in increased PTSD symptoms and anxiety in PTSD versus combat controls. Exposure to diesel resulted in an increase in regional blood flow (rCBF) in amygdala, insula, medial prefrontal cortex, and anterior cingulate cortex, and decreased rCBF in lateral prefrontal cortex in PTSD in comparison to combat controls. Combat controls showed less rCBF changes on any smell, and did not show amygdala activation upon diesel exposure.
These data support the hypothesis that in PTSD trauma-related smells can serve as strong emotional reminders. The findings indicate the involvement of a neural circuitry that shares olfactory elements and memory processing regions when exposed to trauma-related stimuli.

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8 • PS Y C H O P H A R M A C O L O G Y BU L L E T I N: Vol. 40 · No. 1
ORIGINAL RESEARCH
Key Words: PTSD, brain imaging techniques, olfaction, memory, amygdala
Positron Tomographic Emission
Study of Olfactory Induced
Emotional Recall in Veterans with and
without Combat-Related
Posttraumatic Stress Disorder
By Eric Vermetten, MD,PhD,Christian Schmahl, MD,
Steven M.Southwick, MD, and
J.Douglas Bremner, MD
Dr. Vermetten is Head of Research, Military Mental Health, Central Military Hospital and Associate
Professor Psychiatry, University Medical Center, Utrecht, The Netherlands. Dr. Schmahl is
Assistant Medical Director, Department of Psychosomatic Medicine and Psychotherapy, Central
I n s t i tute of Mental Health, Mannheim, Germany. Dr. Southwick is Pr o fessor Psych i a t ry,
Department of Psychiatry in the Yale University School of Medicine at New Haven, CT, and is affil-
iated with the National Center for PTSD in the West Haven VAMC at West Haven, CT. Dr. Bremner
is Professor Psychiatry, Departments of Psychiatry and Behavioral Sciences and Radiology, Emory
U n i ve r s i ty School of Medicine at A t l a n ta, GA, and is Medical Director, A t l a n ta VAMC at Decatu r, GA .
To whom correspondence should be addressed: Eric Vermetten, MD, PhD, Department of
Psychiatry, Rudolf Magnus Institute of Neurosciences, University Medical Center, Heidelberglaan
100, 3584 CX Utrecht, The Netherlands. E-mail: e.vermetten@umcutrecht.nl
ABSTRACT~Objective: Memory for odors is often associated with highly emotional expe-
ri e n c e s , and odors have long been noted by clinicians to be pre c i p i tants of trauma sy m p-
toms in posttraumatic stress disord er (PT S D ) . Pri m i t ive brain sy s tems invo l ved in fear
re s p o n s iv i ty and surv ival also mediate smel l , including the olfac t o ry cortex and amyg-
d a l a .The purpose of this study was to measure neural correl a tes of o l f action in PT S D.
M e t h o d s : We exposed male combat ve terans with PTSD (N 5 8) and without PT S D
( N 5 8) to a set of s m el l s , including diesel (rel a ted to traumatic memories of c o m ba t ) ,
and three other types of s m el l s : o d o rless air, va n i l l a / c o c o n u t , and hyd ro gen sulfide (H2S )
( re s p e c t iv el y,a neutra l , p o s i t ive, and nega t ive hedonic nontraumatic smell) in conjunc-
tion with PET imaging of c ereb ral blood flow and assessment of p sy ch o p h y s i o l o g i cal and
b e h av i o ral sy m p t o m s . All subjects also underwent a ba s eline of o l f ac t o ry ac u i ty. R e s u l t s :
PTSD patients ra ted diesel as unpleasant and distre s s i n g , resulting in increased PT S D
symptoms and anxiety in PTSD versus combat controls. Exposure to diesel resulted in an
i n c rease in regional blood flow (rCBF) in amygd a l a , i n s u l a , medial pref ro n tal cortex ,
and anterior cingulate cortex , and decreased rCBF in lateral pref ro n tal cortex in PT S D
in comparison to combat contro l s . C o m bat controls showed less rCBF ch a n ges on any
s m el l , and did not show amygdala ac t ivation upon diesel ex p o s u re. C o n c l u s i o n s : T h e s e
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PET STUDY OF OLFACTORY INDUCED TRAUMATIC RECALL IN PTSD
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INTRODUCTION
It has been known for a long time that odors have the ability to serve
as a reminder of a far and distant past. Odor perception can retrieve
memories of life events with personal meaning and elicit strong affec-
tive experiences.1,2Olfactory information is projected from the olfactory
bulb to the primary olfactory cortex, which is composed of the anterior
olfactory nucleus, the olfactory tubercle, the piriform cortex, and the
amygdala, and projects to secondary olfactory regions, including the
hippocampus, ventral striatum and pallidum, hypothalamus, thalamus,
orbitofrontal cortex, insular cortex, and cingulate gyrus.3The olfactory
cortex is unique in having direct projections to the amygdala, which
plays a critical role in the process of fear responding. Several studies
provide evidence that the human amygdala also participates in the emo-
tional processing of olfactory stimuli.4–12The fact that the amygdala is
closely connected to the hippocampus and enthorhinal cortex, leading
to an emotional enhancement of odor memories, may explain their
unique long-term retention.
Clinicians have long noted that specific trauma-associated smells,
such as napalm or diesel in combat veterans can serve as precipitants of
emotional memories and induce traumatic recall in patients with post-
traumatic stress disorder (PTSD).13–15Several preclinical studies found
that olfactory cues play a critical role in conditioned fear responses,16–19
which indicates that the neural circuitry of olfaction closely parallels the
circuitry of the fear response. In these studies smell has been used suc-
cessfully as a probe of the amygdala, and of the orbitofrontal and medi-
al prefrontal cortex (mPFC), all areas of interest in PTSD.
Neuroimaging studies have begun to map out a neural circuitry of
PTSD.20,21Specific for symptoms of traumatic recall in PTSD, these
studies found decreased orbito-/prefrontal,22,23parietal,hippocampal,24–27
and temporal cortical function,24,28–31and increased function in posterior
cingulate and motor cortex.25,31,32Cerebral blood flow studies have also
found evidence for alterations in middle/inferior frontal gyrus and cere-
bellum.25,27,32–42Rauch et al found an increase in amygdala activation with
exposure to masked fearful faces in PTSD.43However, to date, and in
spite of preclinical evidence of amygdala involvement in emotional pro-
cessing and fear conditioning, clinical studies in PTSD have not
d a ta support the hypothesis that in PTSD trau m a - rel a ted smells can serve
as strong emotional re m i n d er s .The findings indica te the invo l vement of a
neural circuitry that shares olfactory elements and memory processing regions
when exposed to trau m a - rel a ted stimuli. Ps ych o ph a rm a c o l o gy Bull e t i n .
2 0 0 7 ; 4 0 ( 1 ) : 8 - 3 0 .
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consistently implicated the amygdala in the neural circuitry of emo-
tional memories.44This may be due to different factors, including dif-
ferences in research designs. Exteroceptive or internally generated
emotional states (recall) as generated by traumatic scripts may or not
correspond to exteroceptive events, such as external threat, and these
differences may account for the variability in findings related to amyg-
dala activation in PTSD. Smell memory represents a strong exterocep-
tive memory which is connected to neural circuits involving the
amygdala and is therefore an excellent model for probing the neural cir-
cuitry of emotional processing in PTSD.
The purpose of this study was to use PET in the examination of neu-
ral correlates of olfactory induced emotional recall in combat-related
PTSD. We hypothesized that the disposition of a smell to induce emo-
tional memories would correlate with its emotional valence,45and that
specifically for patients with PTSD exposure of trauma-related smells
would result in an increase in PTSD symptoms and increased activation
of brain areas implicated in the disorder.
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