The role of sensory and olfactory pathways in multiple chemical sensitivity.

Multiple chemical sensitivity (MCS) is characterised by non-specific and recurring symptoms affecting multiple organs and associated with exposure to chemicals, even at low concentrations, which are, under normal circumstances, harmless to the general population. Symptoms include general discomfort, cardiovascular instability, irritation of the sensory organs, breath disorders, hypersensitivity affecting the skin and epithelial lining of the gut, throat and lungs, anxiety, and learning and memory loss. Chemical intolerance is a key distinguishing feature of MCS, limiting considerably patients' lifestyle with serious social, occupational and economic implications. Since no specific diagnostic markers are currently available for chemical intolerance, the diagnosis relies on clinical symptoms. Despite the formulation of several hypotheses regarding the pathophysiology of MCS, its mechanisms remain undefined. A person-centred care approach, based on multidisciplinary and individualised medical plans, has shown promising results. However, more definite treatment strategies are required. We have reviewed the main experimental studies on MCS pathophysiology, focusing on the brain networks involved, the impact of environmental pollution on the olfactory system and the correlation with other pathologies such as neurodegenerative diseases. Finally, we discuss treatment strategies targeting the olfactory system.

Chemical intolerance: involvement of brain function and networks after exposure to extrinsic stimuli perceived as hazardous.

BACKGROUND: Chemical intolerance (CI) is a chronic condition characterized by recurring and severe symptoms triggered by exposure to low levels of odorous or pungent substances. The etiology of CI has been a controversial subject for a long time. The aim of this review is to summarize findings on the neurological processing of sensory information during and after exposure to low levels of odorous or pungent substances in individuals with CI, focusing on the brain function and networks. METHODS: Scientific studies on CI published between 2000 and 2019 in academic peer-reviewed journals were systematically searched using medical and scientific literature databases. Only peer-reviewed articles reporting original research from experimental human studies directly associated with CI, and involving related neurological responses or brain imaging after exposure to odorous or pungent substances (i.e., in chemical provocation tests), were considered. RESULTS: Forty-seven studies were found to be eligible for a full-text review. Twenty-three studies met the selection criteria and were included in this review. Evidence indicated that differences between subjects with CI and healthy controls were observed by brain imaging during and after exposure to odorous or pungent substances. Differences in brain imaging were also observed between initial exposure and after exposure to these substances. Neurological processing of sensory information after exposure to extrinsic stimuli in the limbic system and related cortices were altered in subjects with CI. A previous documentable exposure event was likely to be involved in this alteration. CONCLUSIONS: This review documents consistent evidence for the altered neurological processing of sensory information in individuals with CI. Further neurophysiological research exploring the processing of extrinsic stimuli and cognition of sensation through the limbic system and related cortices in CI, and the appearance of symptoms in individuals with CI, are required.

Becoming electro-hypersensitive: A replication study.

Idiopathic Environmental Intolerance attributed to Electromagnetic Fields (IEI-EMF) is an emerging environmental illness that is characterized by the attribution of various symptoms to electromagnetic fields (EMF). To date, research has not succeeded in objectifying the illness' semiology or etiology. IEI-EMF remains impossible to define other than in terms of the attributions of the persons affected. Yet, the genesis of these attributions is still not well understood. This study's objective is to replicate previous results relating to them, while correcting their limitations. Sixteen electro-hypersensitive (EHS) subjects lent themselves to both a sociological interview and a medical interview, and completed a set of standardized questionnaires. Three distinct types of biographical trajectories leading to persons becoming convinced of their hypersensitivity were identified, which were called the Reticent Attribution model, the Prior Attribution model, and the By Proxy Attribution model. These three models of EHS attribution process do not appear to lead to clinically distinct forms of IEI-EMF. What distinguishes them is the way in which the initial suspicion of the electromagnetic environment emerges. They demonstrate a diversification of the pathways to IEI-EMF. Nonetheless, in each model, the learning process that enables the EHS attribution to be materialized and operationalized is identical. The ability to establish causation between the electromagnetic environment and their condition is therefore the result of EHS subjects' trajectories, rather than their starting point. This observation is not congruent with models attributing IEI-EMF to nocebo reactions, which raises the question of these models' ecological validity. Bioelectromagnetics. 2019;9999:XX-XX. © 2019 Bioelectromagnetics Society.

Multiple Chemical Sensitivity: Review of the State of the Art in Epidemiology, Diagnosis, and Future Perspectives.

OBJECTIVE: Systematic bibliography analysis of about the last 17 years on multiple chemical sensitivity (MCS) was carried out in order to detect new diagnostic and epidemiological evidence. The MCS is a complex syndrome that manifests as a result of exposure to a low level of various common contaminants. The etiology, diagnosis, and treatment are still debated among researchers. METHOD: Querying PubMed, Web of Science, Scopus, Cochrane library, both using some specific MESH terms combined with MESH subheadings and through free search, even by Google. RESULTS: The studies were analyzed by verifying 1) the typology of study design; 2) criteria for case definition; 3) presence of attendances in the emergency departments and hospital admissions, and 4) analysis of the risk factors. OUTLOOK: With this review, we give some general considerations and hypothesis for possible future research.

An assessment of the autonomic nervous system in the electrohypersensitive population: a heart rate variability and skin conductance study.

The aim of the study was twofold: first, to compare the activity of the autonomic nervous system (ANS) between the population self-declared as electrohypersensitive (EHS) and their matched control individuals without intended exposure to electromagnetic fields (EMF). The second objective was to determine whether acute exposure to different radiofrequency signals modifies ANS activity in EHS. For that purpose, two different experiments were undertaken, in which ANS activity was assessed through heart rate variability (HRV) and skin conductance (SC). In the first experiment, a comparison between the EHS group (n = 30) and the control group (n = 25) showed that the EHS has an increased number of responses to auditory stimuli as measured by skin conductance activity, and that none of the short-term heart rate variability parameters differ between the two matched study groups. The second experiment, performed in a shielded chamber, involved 10 EHS from the first experiment. The volunteers participated in two different sessions (sham and exposure). The participants were consecutively exposed to four EMF signals (GSM 900, GSM 1800, DECT, and Wi-Fi) at environmental level (1 V/m). The experiment was double blinded and counterbalanced. The HRV variables studied did not differ between the two sessions. Concerning electrodermal activity, the data issued from skin conductance and tonic activity did not differ between the sessions, but showed a time variability. In conclusion, the HRV and SC profiles did not significantly differ between the EHS and control populations under no exposure. Exposure did not have an effect on the ANS parameters we have explored.NEW & NOTEWORTHY This study provided analysis on the skin conductance parameters using a newly developed method (peak/min, extraction of skin conductance responses) that had not been performed previously. Additionally, the skin conductance signal was decomposed, considering tonic and phasic activities to be a distinct compound. Moreover, this is the first time a study has been designed into two steps to understand whether the autonomic nervous system is disturbed in the EHS population.

Multiple chemical sensitivity: Genotypic characterization, nutritional status and quality of life in 52 patients. / Sensibilidad química múltiple: caracterización genotípica, estado nutricional y calidad de vida de 52 pacientes.

BACKGROUND AND OBJECTIVES: Multiple chemical sensitivity (MCS) is a chronic, multisystem syndrome of unknown etiology. The aim of the present study was to describe the nutritional status and quality of life of patients suffering from MCS, as well as to identify potential polymorphisms associated with this illness. PATIENTS AND METHODS: A cross-sectional, descriptive study was performed on patients with a diagnosis of MCS. Data on anthropometric and body composition variables, hand muscle strength and quality of life were collected. The selection of single nucleotide polymorphisms (SNPs) was based on genes previously associated with MCS and genes involved in inflammatory and oxidative stress pathways. RESULTS: A total of 52 patients (93.2% female), with a mean age of 50.9 (10.3) years were included in the study. Among them, based on their BMI, 48% had an inadequate nutritional status (17% were underweight and 32% were overweight or obese). Thirty percent of patients had a low muscle mass for their age, 84% had muscle strength below the tenth percentile, and 51.8% had a high fat mass percentage. Regarding quality of life, all median scores were lower than those of other illnesses assessed for every subscale assessed. Statistically significant differences between patient cases and controls were found with respect to rs1801133 (MTHFR), rs174546 (FADS1) and rs1801282 (PPARγ) polymorphisms. CONCLUSION: A high percentage of patients had a poor nutritional status, low muscle strength and decreased muscle mass. These facts exacerbate the already-lower quality of life of these patients. Specific genetic polymorphisms associated with the syndrome or its pathogenesis were not identified.

Association of Odor Thresholds and Responses in Cerebral Blood Flow of the Prefrontal Area during Olfactory Stimulation in Patients with Multiple Chemical Sensitivity.

Multiple chemical sensitivity (MCS) is a disorder characterized by nonspecific and recurrent symptoms from various organ systems associated with exposure to low levels of chemicals. Patients with MCS process odors differently than controls do. Previously, we suggested that this odor processing was associated with increased regional cerebral blood flow (rCBF) in the prefrontal area during olfactory stimulation using near-infrared spectroscopic (NIRS) imaging. The aim of this study was to investigate the association of odor thresholds and changes in rCBF during olfactory stimulation at odor threshold levels in patients with MCS. We investigated changes in the prefrontal area using NIRS imaging and a T&T olfactometer during olfactory stimulation with two different odorants (sweet and fecal) at three concentrations (zero, odor recognition threshold, and normal perceived odor level) in 10 patients with MCS and six controls. The T&T olfactometer threshold test and subjective assessment of irritating and hedonic odors were also performed. The results indicated that the scores for both unpleasant and pungent odors were significantly higher for those for sweet odors at the normal perceived level in patients with MCS than in controls. The brain responses at the recognition threshold (fecal odor) and normal perceived levels (sweet and fecal odors) were stronger in patients with MCS than in controls. However, significant differences in the odor detection and recognition thresholds and odor intensity score between the two groups were not observed. These brain responses may involve cognitive and memory processing systems during past exposure to chemicals. Further research regarding the cognitive features of sensory perception and memory due to past exposure to chemicals and their associations with MCS symptoms is needed.

Lack of contralateral suppression in transient-evoked otoacoustic emissions in multiple chemical sensitivity: a clinical correlation study.

Multiple chemical sensitivity (MCS) is a chronic disorder characterized by a variety of symptoms associated with the exposure to chemicals at a concentration below the toxic level. Previous studies have demonstrated peculiar responses in brain activity in these patients with respect to sensory stimuli while the association between chemical sensitivity and other environmental intolerances such as noise sensitivity has been questioned by researchers. In this study, a cohort of 18 MCS patients underwent transient-evoked otoacoustic emission (TEOAE) testing with and without contralateral suppression to evaluate the functionality of the medial olivocochlear (MOC) reflex involved in speech-in-noise sensitivity. Results were compared with an age- and gender-matched control group (n = 20) and correlation analysis with disease onset and quick environmental exposure sensitivity inventory (qEESI) symptom severity scale was performed. Subjects affected by MCS showed statistically significant impairment of MOC reflex, and the onset of the disease and several symptom subscales showed to be correlated to such reduction in some of the frequencies tested. These data suggest that alterations of MOC reflex could be part of the complex features of this disease although more studies are needed to further explore auditory perception disorders in environmental intolerances.

Multidimensional assessment of self-reported chemical intolerance and its impact on chemosensory effects during ammonia exposure.

PURPOSE: Healthy individuals differ in self-reported chemical intolerance (CI). It is unclear whether this inter-individual variability impacts well-being and performance in environmental and occupational settings with chemical exposures. So far, operational definitions and questionnaires of CI have either emphasized physical symptoms or affective/behavioral disruption. In contrast, this study focused on healthy individuals who reported strong CI which generalized to awareness, physiology, affect, and behavior. We investigated whether generalized self-reported CI is associated with hyper-reactivity and reduced cognitive functioning due to chemosensory-mediated distraction during ammonia exposure. METHODS: An online sample (N = 321) answered established CI questionnaires. Based on the convergent self-reports in these questionnaires, healthy women with generalized CI and healthy female control participants were selected (total N = 26). Baseline characterization was performed using implicit association, lung and olfactory function tests, health-related self-reports, plasma inflammatory and metabolic markers. Performance in neurobehavioral tasks, perceptual ratings, nasal inflammatory, neuroendocrine, and autonomic nervous system reactivity were examined by means of a 75-min whole-body challenge to ammonia (stepwise increase: 0-10 ppm). RESULTS: Correlational analyses confirmed the multidimensionality of CI. Participants with generalized self-reported CI exhibited better olfactory function and reported stronger pungency during the challenge than controls. Cognitive performance and physiological response to the challenge were comparable between the two groups. CONCLUSIONS: Self-reports of CI are complex and not easily assessed by unidimensional questionnaires. While generalized self-reported CI is associated with altered chemosensory processing, it seems unlikely that it modulates health effects and cognitive functioning during chemical exposure.

Long-Term Follow-Up in Patients With Airway Chemical Intolerance.

OBJECTIVE: A 5-year follow-up study showed that a group of patients with airway symptoms from chemicals and scents had lasting symptoms, together with enduring increased capsaicin cough sensitivity. The aim was to follow up the same patients after another 5 years. METHODS: All previously participants were invited for an additional follow-up. They visited the clinic twice; at one opportunity, they undertook a capsaicin inhalation provocation, and at the other, a methacholine provocation, and answered various questionnaires. RESULTS: Sixteen patients attende the study after a median of 8 years. They reported unchanged symptoms from chemicals and scents; the capsaicin cough sensitivity was still increased, and the repeatability for the capsaicin inhalation was good. CONCLUSIONS: Airway symptoms induced by chemicals and scents constitute a chronic disease, with unchanged trigger factors, persistent symptoms, and unchanged, long-lasting sensory hyperreactivity.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.This study was supported by grants from the Herman Krefting Foundation Against Asthma/Allergy, the Swedish Heart and Lung Foundation, and the Swedish Cancer and Allergy Fund.

Involvement of Subcortical Brain Structures During Olfactory Stimulation in Multiple Chemical Sensitivity.

Multiple chemical sensitivity (MCS) patients usually react to odour compounds and the majority of neuroimaging studies assessed, especially at the cortical level, many olfactory-related correlates. The purpose of the present study was to depict sub-cortical metabolic changes during a neutral (NC) and pure (OC) olfactory stimulation by using a recently validated (18)F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computer tomography procedure in 26 MCS and 11 healthy (HC) resting subjects undergoing a battery of clinical tests. Twelve subcortical volumes of interest were identified by the automated anatomical labeling library and normalized to thalamus FDG uptake. In both groups, when comparing OC to NC, the within-subjects ANOVA demonstrated a relative decreased metabolism in bilateral putamen and hippocampus and a relative increased metabolism in bilateral amygdala, olfactory cortex (OLF), caudate and pallidum. The between-groups ANOVA demonstrated in MCS a significant higher metabolism in bilateral OLF during NC. As in HC subjects negative correlations were found in OC between FDG uptake in bilateral amygdala and hippocampus and odor pleasantness scale, the latter positively correlated with MCS subjects' bilateral putamen FDG uptake in OC. Besides FDG uptake resemblances in both groups were found, for the first time a relative higher metabolism increase in OLF in MCS subjects at rest with respect to HC was found. When merging this aspect to the different subcortical FDG uptake correlations patterns in the two groups, the present study demonstrated to describe a peculiar metabolic index of behavioral and neurological aspects of MCS complaints.

Chemosensory perception, symptoms and autonomic responses during chemical exposure in multiple chemical sensitivity.

PURPOSE: Multiple chemical sensitivity (MCS) is a prevalent medically unexplained symptom characterized by symptom reactions to everyday chemical exposure below hygienic thresholds. The aim of this study was to investigate the expressions of hyper-reactivity in MCS during whole-body exposure to low concentrations of the odorant n-butanol. METHODS: We exposed 18 participants with MCS and 18 non-ill controls to a low concentration of the odorant n-butanol using an exposure chamber. The first 10 min constituted blank exposure, after which the n-butanol concentration increased and reached a plateau at 11.5 mg/m(3). RESULTS: MCS participants, compared with controls, reported greater perceived odor intensities, more unpleasantness to the exposure and increasing symptoms over time. MCS participants also expressed higher pulse rate and lower pulse rate variability than controls did. No group differences were found for breathing rate or tonic electrodermal activity responses. CONCLUSIONS: We conclude that MCS sufferers differ from healthy controls in terms of autonomic responses, symptoms and chemosensory perception during chemical exposure.

Vestibular impairment in Multiple Chemical Sensitivity: Component analysis findings.

Multiple chemical sensitivity (MCS) is a common clinical diagnosis in western populations and its symptoms are thought to be mainly related to chemical compounds exposure. Although MCS subjects refer to complain from many central nervous system symptoms, including dizziness, no study to now deepened vestibular detriment nor to what extent such an impairment could worsen MCS. Thus, the purpose of present study was to objectively highlight those clinical/subclinical aspects of vestibular impairment that could be related to MCS symptoms cohorts. A principal component analysis within a wide battery of otoneurological test scores was employed in 18 right-handed MCS patients and 20 sex- and age-matched healthy individuals. A deranged dimensionality in near-optimal re-weighting within otoneurological variables was found in MCS as compared with healthy subjects. These data seem to support the idea that MCS physiopathological underpinnings could lead to a peripheral and higher vestibular decay that could be addressed as a further aspect to better follow MCS patients up along natural history of disease in clinical practice.

In-situ Real-Time Monitoring of Volatile Organic Compound Exposure and Heart Rate Variability for Patients with Multiple Chemical Sensitivity.

In-situ real-time monitoring of volatile organic compound (VOC) exposure and heart rate variability (HRV) were conducted for eight multiple chemical sensitivity (MCS) patients using a VOC monitor, a Holter monitor, and a time-activity questionnaire for 24 h to identify the relationship between VOC exposure, biological effects, and subjective symptoms in actual life. The results revealed no significantly different parameters for averaged values such as VOC concentration, HF (high frequency), and LF (low frequency) to HF ratio compared with previous data from healthy subjects (Int. J. Environ. Res. Public Health 2010, 7, 4127-4138). Significant negative correlations for four subjects were observed between HF and amounts of VOC change. These results suggest that some patients show inhibition of parasympathetic activities along with VOC exposure as observed in healthy subjects. Comparing the parameters during subjective symptoms and normal condition, VOC concentration and/or VOC change were high except for one subject. HF values were low for five subjects during subjective symptoms. Examining the time-series data for VOC exposure and HF of each subject showed that the subjective symptoms, VOC exposure, and HF seemed well related in some symptoms. Based on these characteristics, prevention measures of symptoms for each subject may be proposed.

The implications of non-linear biological oscillations on human electrophysiology for electrohypersensitivity (EHS) and multiple chemical sensitivity (MCS).

The 'informational content' of Earth's electromagnetic signaling is like a set of operating instructions for human life. These environmental cues are dynamic and involve exquisitely low inputs (intensities) of critical frequencies with which all life on Earth evolved. Circadian and other temporal biological rhythms depend on these fluctuating electromagnetic inputs to direct gene expression, cell communication and metabolism, neural development, brainwave activity, neural synchrony, a diversity of immune functions, sleep and wake cycles, behavior and cognition. Oscillation is also a universal phenomenon, and biological systems of the heart, brain and gut are dependent on the cooperative actions of cells that function according to principles of non-linear, coupled biological oscillations for their synchrony. They are dependent on exquisitely timed cues from the environment at vanishingly small levels. Altered 'informational content' of environmental cues can swamp natural electromagnetic cues and result in dysregulation of normal biological rhythms that direct growth, development, metabolism and repair mechanisms. Pulsed electromagnetic fields (PEMF) and radiofrequency radiation (RFR) can have the devastating biological effects of disrupting homeostasis and desynchronizing normal biological rhythms that maintain health. Non-linear, weak field biological oscillations govern body electrophysiology, organize cell and tissue functions and maintain organ systems. Artificial bioelectrical interference can give false information (disruptive signaling) sufficient to affect critical pacemaker cells (of the heart, gut and brain) and desynchronize functions of these important cells that orchestrate function and maintain health. Chronic physiological stress undermines homeostasis whether it is chemically induced or electromagnetically induced (or both exposures are simultaneous contributors). This can eventually break down adaptive biological responses critical to health maintenance; and resilience can be compromised. Electrohypersensitivity can be caused by successive assaults on human bioelectrochemical dynamics from exogenous electromagnetic fields (EMF) and RFR or a single acute exposure. Once sensitized, further exposures are widely reported to cause reactivity to lower and lower intensities of EMF/RFR, at which point thousand-fold lower levels can cause adverse health impacts to the electrosensitive person. Electrohypersensitivity (EHS) can be a precursor to, or linked with, multiple chemical sensitivity (MCS) based on reports of individuals who first develop one condition, then rapidly develop the other. Similarity of chemical biomarkers is seen in both conditions [histamines, markers of oxidative stress, auto-antibodies, heat shock protein (HSP), melatonin markers and leakage of the blood-brain barrier]. Low intensity pulsed microwave activation of voltage-gated calcium channels (VGCCs) is postulated as a mechanism of action for non-thermal health effects.

Chemical intolerance.

Chemical intolerance (CI) is a term used to describe a condition in which the sufferer experiences a complex array of recurrent unspecific symptoms attributed to low-level chemical exposure that most people regard as unproblematic. Severe CI constitutes the distinguishing feature of multiple chemical sensitivity (MCS). The symptoms reported by CI subjects are manifold, involving symptoms from multiple organs systems. In severe cases of CI, the condition can cause considerable life-style limitations with severe social, occupational and economic consequences. As no diagnostic tools for CI are available, the presence of the condition can only be established in accordance to criteria definitions. Numerous modes of action have been suggested to explain CI, with the most commonly discussed theories involving the immune system, central nervous system, olfactory and respiratory systems as well as altered metabolic capacity, behavioral conditioning and emotional regulation. However, in spite of more than 50 years of research, there is still a great deal of uncertainties regarding the event(s) and underlying mechanism( s) behind symptom elicitation. As a result, patients are often misdiagnosed or offered health care solutions with limited or no effect, and they experience being met with mistrust and doubt by health care professionals, the social care system and by friends and relatives. Evidence-based treatment options are currently unavailable, however, a person-centered care model based on a multidisciplinary treatment approach and individualized care plans have shown promising results. With this in mind, further research studies and health care solutions should be based on a multifactorial and interdisciplinary approach.

Assessment of cerebral blood flow in patients with multiple chemical sensitivity using near-infrared spectroscopy--recovery after olfactory stimulation: a case-control study.

OBJECTIVES: Multiple chemical sensitivity (MCS) is a chronic acquired disorder characterized by non-specific symptoms in multiple organ systems associated with exposure to odorous chemicals. We previously observed significant activations in the prefrontal cortex (PFC) during olfactory stimulation using several different odorants in patients with MCS by near-infrared spectroscopy (NIRS) imaging. We also observed that the patients with MCS did not adequately distinguish non-odorant in the late stage of the repeated olfactory stimulation test. The sensory recovery of the olfactory system in the patients with MCS may process odors differently from healthy subjects after olfactory stimulation. METHODS: We examined the recovery process of regional cerebral blood flow (rCBF) after olfactory stimulation in patients with MCS. NIRS imaging was performed in 6 patients with MCS and in 6 controls. The olfactory stimulation test was continuously repeated 10 times. The study also included a subjective assessment of the physical and psychological status and of the perception of irritating and hedonic odors. RESULTS: After olfactory stimulation, significant activations were observed in the PFC of patients with MCS on both the right and left sides compared with controls. The activations were specifically strong in the orbitofrontal cortex (OFC). Compared with controls, autonomic perception and feelings identification were poorer in patients with MCS. OFC is associated with stimuli response and the representation of preferences. CONCLUSIONS: These results suggest that a past strong exposure to hazardous chemicals activates the PFC during olfactory stimuli in patients with MCS, and a strong activation in the OFC remains after the stimuli.

Brain responses to olfactory and trigeminal exposure in idiopathic environmental illness (IEI) attributed to smells -- an fMRI study.

OBJECTIVE: Idiopathic environmental intolerance (IEI) to smells is a prevalent medically unexplained illness. Sufferers attribute severe symptoms to low doses of non-toxic chemicals. Despite the label, IEI is not characterized by acute chemical senses. Theoretical models suggest that sensitized responses in the limbic system of the brain constitute an important mechanism behind the symptoms. The aim was to investigate whether and how brain reactions to low-levels of olfactory and trigeminal stimuli differ in individuals with and without IEI. METHODS: Brain responses to intranasally delivered isoamyl acetate and carbon dioxide were assessed in 25 women with IEI and 26 non-ill controls using functional magnetic resonance imaging. RESULTS: The IEI group had higher blood-oxygenated-level-dependent (BOLD) signal than controls in the thalamus and a number of, mainly, parietal areas, and lower BOLD signal in the superior frontal gyrus. The IEI group did not rate the exposures as more intense than the control group did, and there were no BOLD signal differences between groups in the piriform cortex or olfactory regions of the orbitofrontal cortex. CONCLUSIONS: The IEI reactions were not characterized by hyper-responsiveness in sensory areas. The results can be interpreted as a limbic hyperreactivity and speculatively as an inability to inhibit salient external stimuli.