Changes in Cerebral Blood Flow during Olfactory Stimulation in Patients with Multiple Chemical Sensitivity: A Multi-Channel Near-Infrared Spectroscopic Study
et al. (2013) Changes in Cerebral Blood Flow during Olfactory Stimulation in Patients with
Multiple Chemical Sensitivity: A Multi-Channel Near-Infrared Spectroscopic Study. PLoS ONE 8(11): e80567. doi:10.1371/journal.pone.0080567
Changes in Cerebral Blood Flow during Olfactory Stimulation in Patients with Multiple Chemical Sensitivity: A Multi-Channel Near-Infrared Spectroscopic Study
Kenichi Azuma 0
Iwao Uchiyama 0
Hirohisa Takano 0
Mari Tanigawa 0
Michiyo Azuma 0
Ikuko Bamba 0
Toshikazu Yoshikawa 0
Hiroaki Matsunami, Duke University, United States of America
0 We thank Dr. Yoshiyuki Mitsui, Department of Neurology, Kinki University Faculty of Medicine , Osakasayama, Japan for his helpful comments on the manuscript
Multiple chemical sensitivity (MCS) is characterized by somatic distress upon exposure to odors. Patients with MCS process odors differently from controls. This odor-processing may be associated with activation in the prefrontal area connecting to the anterior cingulate cortex, which has been suggested as an area of odorant-related activation in MCS patients. In this study, activation was defined as a significant increase in regional cerebral blood flow (rCBF) because of odorant stimulation. Using the well-designed card-type olfactory test kit, changes in rCBF in the prefrontal cortex (PFC) were investigated after olfactory stimulation with several different odorants. Near-infrared spectroscopic (NIRS) imaging was performed in 12 MCS patients and 11 controls. The olfactory stimulation test was continuously repeated 10 times. The study also included subjective assessment of physical and psychological status and the perception of irritating and hedonic odors. Significant changes in rCBF were observed in the PFC of MCS patients on both the right and left sides, as distinct from the center of the PFC, compared with controls. MCS patients adequately distinguished the non-odorant in 10 odor repetitions during the early stage of the olfactory stimulation test, but not in the late stage. In comparison to controls, autonomic perception and negative affectivity were poorer in MCS patients. These results suggest that prefrontal information processing associated with odor-processing neuronal circuits and memory and cognition processes from past experience of chemical exposure play significant roles in the pathology of this disorder.
Funding: This study was financially supported by a Grant-in-Aid for Scientific Research (ID: 22590568) provided by the Japan Ministry of Education, Culture,
Sports, Science and Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Multiple chemical sensitivity (MCS) is a chronic acquired
disorder characterized by non-specific and recurrent symptoms in
multiple organ systems associated with exposure to low levels of
odorous chemicals (e.g., organic solvents, pesticides, cleaning
products, perfumes, environmental tobacco smoke or combustion
products) . The symptoms of MCS are reactions to previous
chemical exposure that recur on subsequent exposure to the same
or structurally unrelated chemicals at levels below those
established as having harmful effects in the general population .
Patients with MCS report a variety of symptoms involving the
central nervous system (CNS); respiratory, skin and mucosal
irritation and gastrointestinal, musculoskeletal and cardiovascular
problems. Other reported symptoms include fatigue, headaches,
irritability, cognitive dysfunction, loss of concentration and
memory, dizziness, anxiety, dyspnea, cough, skin irritation,
dyspepsia, myalgia and many others [2,4]. CNS-related symptoms
such as headache, fatigue and cognitive deficits are especially
frequent among MCS patients [5,6].
Diagnosis of MCS can be difficult because of the inability to
assess the causal relation between exposure and symptoms [3,7].
No standardized objective measures for the identification of MCS
and no precise definition of this disorder have been established.
Therefore, most definitions of MCS are almost entirely qualitative,
relying on subjective reports from patients and clinicians of
distressing symptoms and environmental exposure. Some authors
prefer the term idiopathic environmental intolerance to avoid the
confusion of diagnosis and aetiology inherent in the term multiple
chemical sensitivity [8,9]. The symptoms of MCS may be related
to specific psychiatric disorders rather than a toxicogenic or
somatic source [2,10]. However, in some cases, symptoms cannot
be explained solely on a psychogenic basis.
Non-specific neural symptoms or dysautonomia may be evident
in some MCS patients who exhibit high sensitivity to odors after
exposure to small amounts of certain chemical substances .
One of the more plausible theories regarding the pathogenesis of
MCS is that a chemical factor triggers a multi-organic response
because of neurologic sensitization. This is plausible, given the
interconnections between the olfactory system, limbic system and
hypothalamus [12,13]. However, no studies have confirmed this
theory or any other neurologically-based mechanisms proposed
with regard to the origin of MCS [14,15].
Studies involving activation using positron emission tomography
(PET) with several different odorants have indicated that patients
with MCS process odors differently from controls. Regions of the
brain engaged in odor processing (the amygdala, piriform cortex
and insular cortex) are less activated in MCS patients than in
controls; furthermore, an odorant-related increase in activation of
the anterior cingulate cortex (ACC) and cuneus/pre-cuneus is
observed . Baseline regional cerebral blood flow (rCBF) in
MCS patients was otherwise normal; abnormal patterns were
observed only in response to odor signals. This pattern of
activation in MCS may be a top-down regulation of odor response
via the cingulate cortex. Furthermore, the results of challenge tests
by exposure to odorous chemicals indicated neuro-cognitive
impairment in MCS patients, and single photon-emission
computed tomography brain dysfunction was found particularly in
odor-processing areas, thereby suggesting a neurogenic origin of
MCS . In functional magnetic resonance imaging (fMRI)
studies involving exposure to odorants, a strong signal-intensity
reaction was seen in the limbic system of MCS patients . This
result suggests that fMRI analysis may be useful in the diagnosis of
MCS. These studies provide useful pathophysiological information
regarding the symptoms associated with MCS, enhancing our
general understanding of this disorder. However, the use of these
imaging modalities may put a physical or psychological burden on
patients because of the risk of reactions with contrast agents, long
testing periods and radiation exposure.
Near-infrared spectroscopy (NIRS) is an optical technique that
provides a non-invasive measure of changes in haemoglobin and
oxygenation in the human brain . NIRS works on the
principle that near-infrared light is absorbed by oxygenated
(oxyHb) and deoxygenated (deoxyHb) haemoglobin (Hb), but not
by other tissues. Although the spatial resolution of NIRS is inferior
to that of other functional neuroimaging methodologies such as
PET and fMRI, NIRS has the advantage of a high time resolution
of ,0.01 s and the feasibility of being performed under natural
conditions . Changes in blood flow and oxygenation in the
brain are closely linked to neural activity. Changes in oxyHb
concentration during tasks reflect neuronal activity because they
correlate with evoked changes in rCBF . When neurons
become active, local blood flow to the relevant brain regions
increases and oxygenated blood displaces deoxygenated blood.
Measurement of oxyHb concentrations is most useful because
changes in oxyHb are the most sensitive indicators of changes in
rCBF among the three NIRS parameters (oxyHb, deoxyHb and
Near-infrared rays sent out from the NIRS device can provide
visual access to the cerebral cortex within approximately 20 mm
from the scalp. An odorant-related increase in activation in the
ACC has been observed in MCS patients . The ACC is
involved in adequate control of top-down or bottom-up
modulation of stimuli and is connected to the prefrontal cortex (PFC) .
Therefore, evaluation of rCBF in the PFC using NIRS imaging
may provide valuable information on specific activation due to
odor stimulation in MCS patients. This may aid in defining and
clarifying the pathology of this disorder. In this study, a simple test
for diagnosing MCS was developed, and it involved the evaluation
of changes in rCBF in the PFC of MCS patients.
MCS patients were diagnosed in the outpatient department for
people with chemical sensitivities in the Hyakumanben Clinic
(Outpatient Department of Sick House Syndrome). There are
several case definitions for MCS, including those of Randolph in
1965 , Cullen in 1987 , Nethercott et al. in 1993  and
the MCS 1999 Consensus in the United States . The most
comprehensive and well-known case definition is the MCS 1999
Consensus . Hence, MCS was diagnosed according to the
1999 consensus criteria  at the Hyakumanben Clinic between
October 2009 and December 2011. Criteria were as follows: 1)
Symptoms in multiple organ systems that were reproducibly
triggered by exposure to low levels of multiple chemically
unrelated and odorous chemicals. 2) Chronic symptoms (more
than 1 year) that could be improved or resolved by removal of the
incidents. The symptoms associated with MCS have similarities to
those of chronic fatigue syndrome, fibromyalgia [32,33] and
psychological disorders . Therefore, patients diagnosed with
chronic fatigue syndrome or fibromyalgia syndrome were
excluded from the study. In addition, patients suspected of having
psychological disorders were examined by a qualified psychiatrist
or practitioner of psychosomatic medicine, and those diagnosed
with mental health disorders as per the Diagnostic and Statistical
Manual of Mental Disorders IV or the International Classification
of Diseases 10 were also excluded from the study. These criteria
have been used in previous Japanese studies [35,36]. Furthermore,
patients who had hyperpiesia, hyperlipidemia, diabetes and
allergic rhinitis were also excluded.
All MCS patients had been receiving treatment for MCS at this
clinic. Recruitment for this study was conducted in the 3 months
prior to the olfactory stimulation test using NIRS. The MCS
condition of all patients was reconfirmed by the clinic physician on
the occasion of the recruitment. Controls were recruited from the
public and were selected to match patients by age and sex at the
group level. The peripheral blood of all patients and controls was
tested for the usual parameters (Blood cells, Hb, Ht, PL, T-BiL,
TP, Alb, AST, ALT, c-GT, ALP, LDH, ChE, AMY, CPK, BUN,
Cre, GLU, HbA1c, LDL, HDL, TG, Na, Cl, K, Ca, CRP, RF,
ANA, HBs, HCV, NK activity). Results of all haematological
examinations were normal. Exclusion criteria for all patients and
controls included smoker; drug or alcohol abuse; current use of
antihypertensive medication, antihistamines or rheumatoid
arthritis agents; pregnancy and severe nasal stuffiness.
The validated self-report Quick Environmental Exposure and
Sensitivity Inventory (QEESI)  was utilized to confirm patient
selection. For patients to be designated as chemically sensitive,
high scores on the Chemical Intolerance ($40), Other Intolerance
($25) and Symptom Severity ($40) scales are necessary . In
this study, MCS patients were included if they met or exceeded at
least two of the three cut-off scores. Control patients were included
if they met or exceeded one or none of the three cut-off scores.
This study was approved by the ethical committee for human
research at the Hyakumanben Clinic (99642-61) and the Louis
Pasteur Centre for Medical Research (LPC.11) and was performed
according to the guidelines of the Declaration of Helsinki (1975).
All patients provided written informed consent and received the
equivalent of 5000 JPY for their participation. This study was
conducted from November 2010 to March 2012.
The card-type olfactory identification test kit (Open Essence;
Wako Pure Chemical Industries, Ltd., Osaka, Japan) was used for
the olfactory stimulation test. The capsuled odorant on the card is
printed, folded and pressed flat. The cards are numbered and 12
kinds of odorants are included. These 12 odorants are the same as
those used in the OSIT-J (Odor Stick Identification Test for the
Japanese). Therefore, they are naturally compatible with the
OSIT-J for Japanese patients with olfactory disturbance .
Significant correlations were found among the score for Open
Essence, the average recognition threshold of the T&T
olfactometer (Japanese standard olfactory test kit) and OSIT-J scores .
The examination time for Open Essence is the shortest among
these three tests. Therefore, very little time is required for this
examination. This kit is single-use and does not require a rubbing
tool. This guarantees total cleanliness and no contamination of
odorants . In the olfactory stimulation test used in this study,
the use of odorants that were harmless to the test patients and
general population and were commonly perceived during ordinary
daily activities was required. Therefore, of the 12 odorants, four
(mandarin orange, Japanese cypress, menthol and perfume) were
used in this study. Perception of these odors was accomplished by
placing the test card at a distance of approximately 30 mm from
the noses of both MCS patients and controls.
Interviews were conducted just prior to the olfactory stimulation
test and the assessments of health and nasal symptoms. The test
room was maintained at a temperature of approximately 22uC.
Patients sat in a comfortable chair in the room. They remained in
the test room long enough to feel comfortable before being
exposed to the odorants. During the experiments, the patients
closed their eyes and slowly repeated the Japanese alphabet in an
undertone to establish a stable rCBF prior to the olfactory
stimulation. And they continued to close their eyes and stopped to
repeat Japanese alphabet during olfactory stimulation. The
questionnaire on irritating and hedonic scale was completed
immediately after the olfactory stimulation. After that, they again
closed their eyes and slowly repeated the Japanese alphabet in an
undertone to establish a stable rCBF prior to the next olfactory
stimulation. Irritation was evaluated on a visual analogue scale,
with responses ranging from not at all to strong. Hedonic
responses were rated on a 5-point Likert scale ranging from
comfort (1) to discomfort (5). Olfactory stimulation was performed
with 10 repetitions of 30 s each after a rest period to establish the
baseline level, followed by a 10-s period of olfactory stimulation
and a 30-s rest period for stabilization of the olfactory mechanism.
The 10 repetitions were performed continuously, and the time
between tasks was 60 s. Olfactory stimuli were offered in the
following order: mandarin orange (MO), perfume (Pf),
nonodorant (NO), Japanese cypress (JC), menthol (Mt), Pf, JC, NO,
Mt and MO. The orders of ten repetitions (1 to 10) were presented
as follows: MO (1), Pf (2), NO (3), JC (4), Mt (5), Pf (6), JC (7), NO
(8), Mt (9) and MO (10).
NIRS data acquisition
Changes in Hb concentration in the PFC were measured using
the functional NIRS topography system OMM-3000 Optical
Multi-channel Monitor (Shimadzu Corporation, Kyoto, Japan),
which uses near-infrared light with wavelengths of 780, 805 and
830 nm. Pairs of illuminators and detectors were set 3 cm apart in
a 369 lattice pattern to form 42 channels through a holder set in
the PFC (Figure 1). Changes in concentration of oxyHb, deoxyHb
and totalHb were recorded every 130 ms using the NIRS system.
However, only oxyHb was analysed because these changes are the
most sensitive indicators of changes in rCBF and provide the
strongest correlation with blood oxygenation level-dependent
signals among the three NIRS parameters [24,25]. Optical data
were analysed on the basis of the modified BeerLambert Law and
signals reflecting the oxyHb concentration changes in an arbitrary
unit were calculated (millimolarmillimetre) .
Questionnaire on physical and psychological status
Patients completed a self-report questionnaire for the assessment
of physical and psychological parameters as follows. Affective
reactions to and behavioural disruptions in daily activities from
odorous/pungent environmental chemicals were assessed using
the Chemical Sensitivity Scale for Sensory Hyper-reactivity
(CSSSHR) . Somatosensory amplification was assessed using the
Somato-Sensory Amplification Scale (SSAS) . Somatosensory
amplification refers to a tendency to experience physical sensations
as intense, noxious and disturbing. The anxiety-related version of
the Autonomic Perception Questionnaire (APQ) was used to
evaluate attentiveness to physical responses in anxiety-provoking
situations . The Tellegen Absorption Scale (TAS) was used to
measure imaginative involvement and openness to experience
. Repressive coping was assessed by the MarloweCrowne
Social Desirability Scale  and the Taylor Manifest Anxiety
Scale (TMAS) . The Negative Affectivity Scale (NAS) was used
to evaluate the tendency to experience and report negative
emotions, including anxiety, guilt, hostility and depression, with a
MCS (n = 12)
Controls (n = 11) p value
low negative affect reflecting a state of calmness . Lastly,
alexithymia was assessed using the Toronto Alexithymia Scale
(TAS-20) . Alexithymia can be evaluated using both the total
score and the scores of the three subscales, which assess difficulties
in identifying feelings (DIF), difficulties in describing feelings
(DDF) and externally-oriented thinking (EOT). Information about
these questionnaires and the physical and psychological scales was
provided by the Danish Research Centre for Chemical
Changes in oxyHb concentration are the best indicators of
changes in rCBF and brain activity. Therefore, oxyHb levels
during the olfactory stimulation were compared with oxyHb levels
during the pre-rest period as a baseline level in each channel for
evaluating the effects on brain activity of olfactory stimulation.
Because raw data of NIRS provided only relative values and could
not be averaged directly across patients or compared among
channels, raw data from each channel were converted into
zscores . The z-score was calculated using the mean value
and standard deviation of oxyHb changes during the pre-rest
period. Consequently, mean values and standard deviations during
the pre-rest period were respectively changed into z-scores 0 (mean
value) and 1 (standard deviation) for every channel. The t-test was
used to compare brain activity from NIRS imaging for each
channel between cases and controls. The non-parametric Mann
Whitney U test was utilized for analysis of the results of the
questionnaire administered after the olfactory stimulation test to
determine differences between MCS patients and controls. The
ttest was applied for analysis of the results of the physical and
psychological scales to determine differences between MCS
patients and controls at baseline. All data analyses were performed
using the SPSS statistics software, version 21.
Participants were 16 MCS patients (age, 4465 years; mean,
53.567.0 years; 1 male, 15 females) and 17 controls (age, 3962
years; mean, 50.268.4 years; 1 male, 16 females). Twelve
nonsmoking MCS patients (age, 4765 years; mean, 55.166.8 years;
all females) and 11 non-smoking controls (age, 3961 years; mean,
48.068.0 years; 1 male, 10 females) passed all criteria and were
included in the analyses. All MCS patients tried to avoid exposure
to odorous chemicals as much as possible. Occupational histories
showed that three MCS patients were clerical employees (hospital,
office and retail store) and nine were homemakers or pensioners
whose previous occupations included clerical employee (museum
or office), teacher, endoscopic operator, fabric tinter and
supermarket baker. Eight controls also tried to avoid exposure to
odorous chemicals as much as possible. Of them, occupations of
six included teacher, office worker, tester of ceramic parts and
voluntary worker in an environmental laboratory, and of the
remaining two, one was a pensioner and other was a homemaker.
Three controls consciously did not try to avoid exposure to
odorous chemicals and their occupations were office worker, child
welfare volunteer and voluntary worker in an environmental
NIRS imaging and subjective evaluation to odors
Results of the t-test in terms of the average of all channels (1 to
42) comparing z scores for oxyHb concentrations between MCS
patients and controls are shown in Table 1. In the olfactory
stimulation involving MO (1), which was conducted first, increases
in rCBF levels in the PFC were observed in both MCS patients
and controls. The difference in rCBF level between these groups
was not significant. Because MO (1) was the first test, the patients
may not have had the chance to get used to the olfactory
stimulation test. Therefore, this response may have been caused by
affective tension. After the first test, no increases in rCBF level
were observed in controls, and rCBF levels remained stable until
the end of the test involving MO (10).
Increases in rCBF levels in MCS patients were suppressed
during the olfactory stimulation involving NO (3) on the third
repetition. Responses in the PFC were normal; the difference
between MCS patients and controls was not significant. However,
on the eighth repetition involving NO (8), PFC activation was
observed in MCS patients. This difference between MCS patients
and controls was significant (p,0.001). This result suggested that
the olfactory system in MCS patients adequately distinguished the
non-odorant among the 10 odorant repetitions during the early
stage of the olfactory stimulation test. However, this result also
suggested that the olfactory system in MCS patients could not
adequately process odors in the late stage of the olfactory
stimulation test. Table 2 shows the correlation coefficient between
rCBF after the first and second exposure of the same odor in terms
of z scores for all channels (1 to 42). Comparing the rCBF between
first and second exposures revealed significant correlations in both
MCS patients and controls. However, the correlation coefficients
of MCS patients were lower overall than those of controls. In the
subjective evaluation, both MCS patients and controls responded
not at all on the irritation scale and undecided on the hedonic
scale for NO (Figure 2). However, NIRS imaging revealed that the
CNS of MCS patients may have been confused in the late stage of
the olfactory stimulation test.
Figure 3 provides topographical maps of average z scores for
oxyHb in MCS patients and controls. Figure 4 shows average t
values for each channel comparing z scores for oxyHb between
MCS patients and controls. Significant activation in the PFC was
observed for MCS patients on both the right and left sides (as
distinct from the center of the PFC) compared with controls.
Activation was defined as a significant increase in rCBF due to
olfactory stimulation. These activations were stronger in the test
MCS (n = 12)
Controls (n = 11)
for JC (4) on the fourth repetition and that for Pf (6) on the sixth
repetition. In the tests for MO (1), Pf (6), JC (7), Mt (9) and MO
(10), strong increases in rCBF were observed in the bottom right of
PFC in MCS patients (Figure 3). However, no significant
differences were found in the results of tests other than those for
Pf (6) between MCS patients and controls (Figure 4).
The results of subjective evaluation using the hedonic scale
indicated that scores for MCS patients were significantly higher
than those for controls, except JC scores. Scores for MO were
lower than those for the other odorants in both MCS patients and
controls. The results of subjective evaluation using the irritation
scale indicated that Pf (6) and Mt (9) scores for MCS patients were
significantly higher than those for controls. However, no
differences were found for other odors. Large ranges of scores in
controls were thought to be causally related to the results.
Physical and psychological measurements
Table 3 shows the results of the t-test for the physical and
psychological scales. CSS-SHR scores were significantly higher for
MCS patients than for controls (p,0.001). Therefore, chemical
sensitivity in MCS patients was demonstrated not only by the
results of the QEESI but also by those of the CSS-SHR scale. In
the psychological evaluations, APQ (p,0.001), NAS (p = 0.005)
and TAS-20 DIF (p,0.001) scores were significantly higher for
MCS patients than for controls. However, no significant
differences were observed in the SSAS, TAS, MCSD, TMAS,
TAS-20 total, TAS-20 DDF and TAS-20 EOT scores.
Figure 4. Average t value of each channel comparing z scores for oxyHb between MCS patients (n = 12) and controls (n = 11).
Statistically significant differences between groups are indicated as underlined values. *p,0.05, **p,0.01. Significant tendencies are indicated:
MCS (n = 12)
Controls (n = 11)
Responses in the PFC in MCS patients were normal for NO (3),
that is, the third repetition providing the non-odorant condition.
The difference in response to this condition was not significant
between MCS patients and controls. Activation of the PFC in
MCS patients was evident for NO (8), that is, the eighth repetition
providing the non-odorant condition. PFC activation for MO (1)
in MCS patients was higher than that for MO (10). These results
suggest that the olfactory system in MCS patients could not
adequately process odors in the late stage of the olfactory
stimulation test. However, no PFC activation was observed for
these odors in controls. In addition, rCBF remained stable until
the final repetition involving MO (10) in controls.
Inherent connections of the frontal lobe form vital feed-forward
and feedback circuits from the center of prefrontal information
processing. The extensive connections in the PFC are linked with
distant and broadly dispersed parts of the association and limbic
cortices. Prefrontal interconnections with the amygdala,
hypothalamus, midbrain and pons represent important subcortical linkages
of the extended prefrontal neural system. These are likely to
integrate higher-order brain functions mediated by the PFC with
more developmentally fundamental brain activities such as
emotional, visceral or autonomic functions [26,52,53]. Therefore,
the center of the PFC depends significantly on emotional linkages
with deeper brain structures related to control of pleasure, pain,
anger, rage, panic and aggression. On the basis of this
information, we postulate that prefrontal information processing
in MCS patients was activated by an emotional response to
repeated olfactory stimulation in the late stage of the test and that
the processing system in the PFC could not properly respond
despite differences in subjective reports about the odors. These
results suggest that this response may be characteristic of MCS
patients. Activation of the PFC may therefore have occurred
during the olfactory stimulation test using odorants ordinarily
encountered in daily activities.
This study specifically demonstrated activation in the PFC on
both the right and left sides, as distinct from the center of the PFC,
in MCS patients compared with that in controls during olfactory
stimulation tests. Activation was observed in the early stage of the
olfactory stimulation tests, when the odor processing systems of
MCS patients were stable. In a previous study, patients with MCS
processed odors differently from controls, and an odorant-related
increase in activation of the ACC and cuneuspre-cuneus was
observed . The dorsal part of the ACC is connected with the
PFC and parietal cortex as well as the motor system and frontal
eye fields. Therefore, it is essential for processing top-down and
bottom-up stimuli and assigning appropriate control to other areas
in the brain. In contrast, the ventral part of the ACC is connected
with the amygdala, nucleus accumbens, hypothalamus and
anterior insula and is involved in assessing the salience of emotion
and motivational information [26,5456]. MCS occurs when
individuals are first sensitized via an initial exposure to a certain
amount of chemicals or repeated exposure to small amounts of
chemicals. Upon re-exposure, individuals become increasingly
sensitized, and often the effect spreads and they become bothered
by many additional chemicals . In this study, nine MCS
patients had episodes of initial exposure to chemicals that triggered
the first symptoms. These included use of organic solvents,
pesticides or incense in the workplace, use of pesticides or diesel
machines in the neighborhood or use of pesticides indoors. Three
patients had episodes of repeated exposure to solvents emitted
from a neighboring industrial plant or paint store or fragrances or
tobacco smoke emitted around the neighborhood. MCS patients
complained about a chemical sensitive condition thereafter. We
suggest that these exposure events were stored as memories in the
PFC through olfactory nerve circuits, causing various physical or
psychological responses such as emotional, visceral or autonomic
reactions during processing of top-down stimuli in later life when
they exposure to odorants. The psychological evaluations in our
study indicated that scores in MCS patients were significantly
higher than those in controls on the APQ, NAS and TAS-20 DIF
scales. These results also support the theory of response regulation
by memory in the PFC described above. NIRS imaging in
combination with the olfactory stimulation test may therefore be
valuable for objective evaluation and identification of patients with
Several studies have reported characteristic changes in the
odorprocessing region of the brain due to olfactory stimulation in MCS
patients [1618,57]. However, this is the first casecontrol study to
evaluate changes in rCBF in the PFC using NIRS imaging during
olfactory stimulation by odorants in MCS patients. Significant
differences were found between MCS patients and controls.
Further research regarding odor processing, stimulus detection,
cognition, provoking memory and information communication
between the PFC, ACC and olfactory nervous center during
olfactory stimulation in MCS patients is required.
There are some possible limitations in the present study. First,
the small sample size makes the results vulnerable to selection bias.
This could be alleviated by including a larger study population.
This is the first casecontrol study evaluating changes in rCBF in
the PFC using NIRS imaging during olfactory stimulation in MCS
patients. Activation in the PFC of MCS patients may be supported
by a similar finding observed in the ACC in a previous study .
A follow-up study for MCS patients for comparison with symptom
improvement in practice would also provide valuable information.
A second limitation of this study is the selection of the study group.
No standardized objective measures to identify and define MCS
have been established. Therefore, most definitions of MCS are
almost entirely qualitative, relying on subjective reports of
distressing symptoms and environmental exposure from patients
and clinicians. Several individuals with self-reported MCS
symptoms were excluded, at the discretion of the clinic physician,
because of mental disorders or allergic symptoms.
In conclusions, despite the small sample size, this experimental
study identified activation in the PFC due to olfactory stimulation
in MCS patients. The results indicated that NIRS imaging is a
valuable method for the objective evaluation of MCS. In addition,
the results suggest that prefrontal information processing
associated with the odor-processing neuronal circuits and memory and
cognition processing from past experience of chemical exposure
may play significant roles in the pathology of this disorder.
Conceived and designed the experiments: KA IU HT MT MA IB TY.
Performed the experiments: KA IU MT MA IB. Analyzed the data: KA
MA IB. Contributed reagents/materials/analysis tools: KA IU MT MA
IB. Wrote the paper: KA IU HT MT MA IB TY.
1. Cullen MR ( 1987 ) The worker with multiple chemical sensitivities: an overview . Occup Med 2 : 655 - 661 .
2. Graveling RA , Pilkington A , George JP , Butler MP , Tannahill SN ( 1999 ) A review of multiple chemical sensitivity . Occup Environ Med 56 : 73 - 85 .
3. Winder C ( 2002 ) Mechanisms of multiple chemical sensitivity . Toxicol Lett 128 : 85 - 97 .
4. Sorg BA ( 1999 ) Multiple chemical sensitivity: potential role for neural sensitization . Crit Rev Neurobiol 13 : 283 - 316 .
5. Berg ND , Linneberg A , Dirksen A , Elberling J ( 2009 ) Phenotypes of individuals affected by airborne chemicals in the general population . Int Arch Occup Environ Health 82 : 509 - 517 .
6. Lacour M , Zunder T , Schmidtke K , Vaith P , Scheidt C ( 2005 ) Multiple chemical sensitivity syndrome (MCS) - suggestions for an extension of the U . S. MCS-case definition. Int J Hyg Environ Health 208 : 141 - 151 .
7. McKeown-Eyssen GE , Baines CJ , Marshall LM , Jazmaji V , Sokoloff ER ( 2001 ) Multiple chemical sensitivity: discriminant validity of case definitions . Arch Environ Health 56 : 406 - 412 .
8. Bornschein S , Hausteiner C , Zilker T , Forstl H ( 2002 ) Psychiatric and somatic disorders and multiple chemical sensitivity (MCS) in 264 'environmental patients' . Psychol Med 32 : 1387 - 1394 .
9. Hausteiner C , Bornschein S , Zilker T , Henningsen P , Forstl H ( 2007 ) Dysfunctional cognitions in idiopathic environmental intolerances (IEI)-an integrative psychiatric perspective . Toxicol Lett 171 : 1 - 9 .
10. Eis D , Helm D , Muhlinghaus T , Birkner N , Dietel A , et al. ( 2008 ) The German Multicentre Study on Multiple Chemical Sensitivity (MCS) . Int J Hyg Environ Health 211 : 658 - 681 .
11. Doty RL , Deems DA , Frye RE , Pelberg R , Shapiro A ( 1988 ) Olfactory sensitivity, nasal resistance, and autonomic function in patients with multiple chemical sensitivities . Arch Otorhinolaryngol Head Neck Surg 144 : 1422 - 1427 .
12. Bell IR , Miller CS , Schwartz GE ( 1992 ) An olfactory-limbic model of multiple chemical sensitivity syndrome: Possible relationships to kindling and affective spectrum disorders . Biol Psychiatry 32 : 218 - 242 .
13. Bell IR , Schwartz GE , Baldwin CM , Hardin EE , Klimas NG , et al. ( 1997 ) Individual differences in neural sensitization and the role of context in illness from low-level environmental chemical exposures . Environ Health Perspect 105 Suppl 2 : 457 - 466 .
14. Meggs WJ ( 1995 ) Neurogenia switching: a hypothesis for a mechanism for shifting the site of inflammation in allergy and chemical sensitivity . Environ Health Perspect 103 : 54 - 56 .
15. Miller CS ( 1997 ) Toxicant-induced loss of tolerance an emerging theory of disease? Environ Health Perspect 105 : 445 - 453 .
16. Hillert L , Musabasic V , Berglund H , Ciumas C , Savic I ( 2007 ) Odor processing in multiple chemical sensitivity . Hum Brain Mapp 28 : 172 - 182 .
17. Orriols R , Costa R , Cuberas G , Jacas C , Castell J , et al. ( 2009 ) Brain dysfunction in multiple chemical sensitivity . J Neurol Sci 287 : 72 - 78 .
18. Miki T , lnoue Y , Miyajima E , Kudo Y , Tsunoda M ( 2010 ) Enhanced brain images in the limbic system by functional magnetic resonance imaging (fMRI) during chemical exposures to patients with multiple chemical sensitivities . Kitasato Medical Journal 40 : 27 - 34 .
19. Jobsis FF ( 1977 ) Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters . Science 198 : 1264 - 1267 .
20. Miyai I , Tanabe HC , Sase I , Eda H , Oda I , et al. ( 2001 ) Cortical mapping of gait in humans: a near-infrared spectroscopic topography study . Neuroimage 14 : 1186 - 1192 .
21. Hock C , Muller-Spahn F , Schuh-Hofer S , Hofmann M , Dirnagl U , et al. ( 1995 ) Age dependency of changes in cerebral hemoglobin oxygenation during brain activation: a near-infrared spectroscopy study . J Cereb Blood Flow Metab 15 : 1103 - 1108 .
22. Kameyama M , Fukuda M , Yanagishi Y , Sato T , Uehara T , et al. ( 2006 ) Frontal lobe function in bipolar disorder: a multichannel near-infrared spectroscopy study . Neuroimage 29 : 172 - 184 .
23. Tanida M , Sakatani K , Takano R , Tagai K ( 2004 ) Relation between asymmetry of prefrontal cortex activities and the autonomic nervous system during a mental arithmetic task: near infrared spectroscopy study . Neurosci Lett 369 : 69 - 74 .
24. Hoshi Y , Kobayashi N , Tamura M ( 2001 ) Interpretation of near-infrared spectroscopy signals: a study with a newly developed perfused rat brain model . J Appl Physiol 90 : 1657 - 1662 .
25. Strangman G , Culver JP , Thompson JH , Boas DA ( 2002 ) A quantitative comparison of simultaneous BOLD fMRI and NIRS recordings during functional brain activation . Neuroimage 17 : 719 - 731 .
26. Etkin A , Egner T , Kalisch R ( 2011 ) Emotional processing in anterior cingulate and medial prefrontal cortex . Trends Cogn Sci 15 : 85 - 93 .
27. Randolph TG ( 1965 ) Ecologic orientation in medicine: comprehensive environmental control in diagnosis and therapy . Ann Allergy 23 : 7 - 22 .
28. Cullen MR ( 1987 ) The worker with multiple chemical sensitivities: an overview . Occup Med 2 : 655 - 661 .
29. Nethercott JR , Davidoff LL , Curbow B , Abbey H ( 1993 ) Multiple chemical sensitivities syndrome: toward a working case definition . Arch Environ Health 48 : 19 - 26 .
30. Anonymous ( 1999 ) Multiple chemical sensitivity: a 1999 Consensus . Arch Environ Health 54 : 147 - 149 .
31. Lacour M , Zunder T , Schmidtke K , Vaith P , Scheidt C ( 2005 ) Multiple chemical sensitivity syndrome (MCS) - suggestions for an extension of the U . S. MCS-case definition. Int J Hyg Environ Health 208 : 141 - 151 .
32. Park J , Kudson S ( 2007 ) Medically unexplained physical symptoms . Health Rep 18 : 43 - 47 .
33. Lavergne MR , Cole DC , Kerr K , Marshall LM ( 2010 ) Functional impairment in chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity . Can Fam Physician 56 : e57 - 65 .
34. Bornschein S , Hausteiner C , Zilker T , Forstl H ( 2002 ) Psychiatric and somatic disorders and multiple chemical sensitivity (MCS) in 264 'environmental patients' . Psychol Med 32 : 1387 - 1394 .
35. Hojo S , Kumano H , Ishikawa S , Miyata M , Sakabe K ( 2008 ) Clinical characteristics of physician- diagnosed patients with multiple chemical sensitivity in Japan . Int J Hyg Environ Health 211 : 682 - 689 .
36. Hojo S , Sakabe K , Ishikawa S , Miyata M , Kumano H ( 2009 ) Evaluation of subjective symptoms of Japanese patients with multiple chemical sensitivity using QEESI . Environ Health Prev Med 14 : 267 - 275 .
37. Miller CS , Prihoda TJ ( 1999 ) The Environmental Exposure and Sensitivity Inventory (EESI): a standardized approach for measuring chemical intolerances for research and clinical applications . Toxicol Ind Health 15 : 370 - 385 .
38. Kobayakawa T , Toda H , Gotow N ( 2008 ) Development of Card Type Olfactory Identification Test . Chem Senses 33 : S108 .
39. Miwa T , Shiga H , Tatsutomi S , Hirota K , Tsuchiya A , et al. ( 2008 ) Clinical Usefulness of the Card Type Olfactory Identification Test for Japanese Patients With Olfactory Disturbance . Chem Senses 33 : S108 .
40. Okamoto M , Matsunami M , Dan H , Kohata T , Kohyama K , et al. ( 2006 ) Prefrontal activity during taste encoding: an fNIRS study . Neuroimage 31 : 796 - 806 .
41. Nordin S , Millqvist E , Lowhagen O , Bende M ( 2004 ) A short Chemical Sensitivity Scale for assessment of airway sensory hyperreactivity . Int Arch Occup Environ Health 77 : 249 - 254 .
42. Barsky AJ , Goodson JD , Lane RS , Cleary PD ( 1988 ) The amplification of somatic symptoms . Psychosom Med 50 : 510 - 519 .
43. Mandler G , Mandler JM , Uviller ET ( 1958 ) Autonomic feedback: the perception of autonomic activity . J Abnorm Psychol 56 : 367 - 373 .
44. Tellegen A , Atkinson G ( 1974 ) Openness to absorbing and self-altering experiences (''absorption''), a trait related to hypnotic susceptibility . J Abnorm Psychol 83 : 268 - 277 .
45. Crowne DP , Marlowe D ( 1960 ) A new scale of social desirability independent of psychopathology . J Consult Psychol 24 : 349 - 354 .
46. Bendig AW ( 1956 ) The development of a short form of the manifest anxiety scale . J Consult Psychol 20 : 384 .
47. Watson D , Clark LA , Tellegen A ( 1988 ) Development and validation of brief measures of positive and negative affect: the PANAS scales . J Pers Soc Psychol 54 : 1063 - 1070 .
48. Taylor GJ , Bagby RM , Parker JD ( 2003 ) The 20-Item Toronto Alexithymia Scale . IV. Reliability and factorial validity in different languages and cultures . J Psychosom Res 55 : 277 - 283 .
49. Schroeter ML , Zysset S , Kruggel F , von Cramon DY ( 2003 ) Age dependency of the hemodynamic response as measured by functional near-infrared spectroscopy . NeuroImage 19 : 555 - 564 .
50. Matsuda G , Hiraki K ( 2006 ) Sustained decrease in oxygenated hemoglobin during video games in the dorsal prefrontal cortex: a NIRS study of children . Neuroimage 29 : 706 - 711 .
51. Horaguchi T , Ogata Y , Watanabe N , Yamamoto M ( 2008 ) Behavioral and near-infrared spectroscopy study of the effects of distance and choice in a number comparison task . Neurosci Res 61 : 294 - 301 .
52. Lewls MD ( 2005 ) Bridging emotion theory and neurobiology through dynamic systems modeling . Behav Brain Sci 28 : 169 - 245 .
53. Siddiqui SV , Chatterjee U , Kumar D , Siddiqui A , Goyal N ( 2008 ) Neuropsychology of prefrontal cortex . Indian J Psychiatry 50 : 202 - 208 .
54. Cardinal RN , Parkinson JA , Hall J , Everitt BJ ( 2002 ) Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex . Neurosci Biobehav Rev 26 : 321 - 352 .
55. Cardinala RN , Parkinsonb JA , Halla J , Everitt BJ ( 2003 ) The contribution of the amygdala, nucleus accumbens, and prefrontal cortex to emotion and motivated behavior . International Congress Series 1250 : 347 - 70 . http://dx.doi.org/10. 1016/S0531-5131(03)01013- 6 .
56. Zhang W , Lu J ( 2009 ) The Practice of Affective Teaching: A View from Brain Science . International Journal of Psychological Studies 1 : 35 - 41 .
57. Hillert L , Jovanovic H , A hs F , Savic I ( 2013 ) Women with Multiple Chemical Sensitivity Have Increased Harm Avoidance and Reduced 5-HT1A Receptor Binding Potential in the Anterior Cingulate and Amygdala . PLoS One 8 ( 1 ) : e54781 . doi:10.1371/journal.pone.0054781.