Brain responses to olfactory and trigeminal exposure in idiopathic environmental illness (IEI) attributed to smells — An fMRI study

https://doi.org/10.1016/j.jpsychores.2014.09.014Get rights and content

Highlights

  • IEI patients did not rate intranasal exposures to chemicals as more intense than a control group

  • High BOLD signal in thalamus and parietal regions during chemical exposure in IEI

  • Low BOLD signal in prefrontal region during chemical exposure in IEI

  • IEI is not characterized by heightened reactions in chemosensory brain regions.

  • Results can be interpreted as an inability to inhibit chemosensory stimuli in IEI.

Abstract

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.

Introduction

A substantial proportion of the general population experience debilitating symptoms after being exposed to everyday chemicals at low concentrations assumed to be harmless [1], [2]. Unlike known toxicological effects of chemicals, the etiology of such self-reported chemical intolerance (CI) is unknown. There seems to be no clear dose–response relationship between exposure and reaction [3], and no general association between the type of chemical and symptoms. For example, being exposed to Eau de Cologne may cause dizziness in one person and breathing difficulties in another.

CI overlaps considerably with other medically unexplained symptoms such as building-related illness [4], fibromyalgia and chronic fatigue syndrome [5]. Although the severity of symptoms in CI is not fully explained by psychiatric or somatic morbidity, CI is co-prevalent with conditions such as post-traumatic stress disorder (PTSD), generalized anxiety disorder and depression [6], [7], [8]. Whether these conditions precede CI or the other way around is a matter of debate [9]. In addition to psychiatric and medically unexplained illnesses, more than 30% of individuals with asthma also report CI [10].

Multiple chemical sensitivity (MCS) [11] is a widely used clinical label for severe CI. However, the term idiopathic environmental intolerance (IEI) has been suggested as a replacement [12]. IEI is defined as an acquired disorder with multiple recurrent symptoms, associated with diverse environmental factors tolerated by the majority of people, with reactions not explained by any known medical or psychiatric/psychologic disorder. IEI may be further specified according to symptom attribution, e.g. IEI attributed to smells [12].

Smells are mediated by two cranial nerves — the olfactory and the trigeminal. Olfactory projection areas include the piriform cortex, olfactory regions of the orbitofrontal cortex (OFC), insula, hypothalamus, thalamus and hippocampus [13]. Trigeminal regions include not only the primary and secondary somatosensory cortices (SI and SII), prefrontal cortex, insula, cingulate gyrus and limbic system, but also areas relevant for olfaction such as the piriform cortex and OFC [14], [15].

Surprisingly, individuals with IEI/CI have not been shown to differ from non-intolerant ones in terms of olfactory detection sensitivity [16], [17], [18] or rated intensities of olfactory stimuli [17], [19], [20]. There is some evidence of lower trigeminal detection thresholds [21], and higher rated intensities of trigeminal stimuli in CI groups [19], [20], whereas others found no such result [17]. Whether CI/IEI is characterized by a specific trigeminal sensitivity is therefore not clear. Time-dependent changes in reactivity may be an important factor, as the differences in rated intensities of CO2 between a CI and a non-ill control group have been reported to increase after extended exposure [19].

Several theoretical explanations of the diffuse symptoms and weak association to chemosensory acuity have been put forward, and include neurogenic inflammation [22], classical conditioning [23], [24] and biochemical disruptions [25] as suggested underlying mechanisms. According to the neural sensitization theory, CI is attributed to a pathological hyper-reactivity of neurons in olfactory and limbic areas of the brain [26]. Other CI theories have also suggested hyper-reactivity in the central nervous system (CNS) as an important aspect [22]. The altered CNS responses are hypothesized to be paralleled by increased anxiety, avoidance, anticipatory stress [26], [27] and attention bias [22] to chemical exposure. Electrophysiological [19], [28] and brain imaging [20] studies have corroborated the involvement of such factors.

The aim of this study was to investigate whether the functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) signal differs between individuals with IEI attributed to odors and controls when exposed to low levels of olfactory and trigeminal stimuli. Because of the scarcity of brain imaging data in IEI, we investigated group differences in the whole brain. Nevertheless, we hypothesized that the IEI group, compared with controls, would (1) have higher BOLD signal responses to olfactory and trigeminal exposure mainly in areas of the limbic system [26], (2) rate repeated low-level chemical exposures as increasing in strength, both during the course of a single exposure block, and over the course of the exposure session [19], and (3) would have higher BOLD-signal responses in the piriform cortex and olfactory regions of the OFC due to the hypothesized differences in perceived intensities. As IEI sufferers are mainly women, the current study only included women.

Section snippets

Participants

After advertising in a local newspaper, 91 non-pregnant, right-handed women between 18 and 70 years of age who considered themselves either sensitive or non-sensitive to smells reported their interest in participating in the study. They filled out a web-based questionnaire containing questions about demographic information, general health and self-reported CI. Twenty-six women were selected to be included in the IEI group, based on the following criteria: (1) an affirmative answer to the

Results

Regions with significant BOLD signal differences between the IEI and control group are given in Table 2. The IEI group had a significantly lower BOLD signal response in the left superior frontal gyrus during AA exposure compared with controls. The IEI group had higher BOLD signal responses than controls during CO2 exposure in the left thalamus and left cerebellum as well as in several areas in the parietal, temporal, and frontal lobes. Fig. 1 illustrates whether the group differences in each

Discussion

The aim of this study was to investigate whether the BOLD signal differs between persons with IEI and controls when exposed to low levels of olfactory and trigeminal stimuli. Based on theoretical accounts [26], the first hypothesis was that the IEI group, compared with controls, would have higher BOLD signal responses to olfactory and trigeminal exposure mainly in areas of the limbic system.

The IEI group had higher BOLD signal in the thalamus during exposure, and lower in the superior frontal

Competing interest statement

The authors have no competing interests to report.

Acknowledgments and financial support

This study was funded by grants from the Swedish Asthma and Allergy Association's Research Fund (2007064-K), the European territorial cooperation program Botnia-Atlantica (grant number 162621), the Region Västerbotten (Sweden), and the Regional Council of Ostrobothnia (Finland) (grant number 201126). The authors thank Ann Rosén and Olov Sundström for preliminary interpretations, Micael Andersson at the Department of Integrative Medical Biology (Physiology section) for help with data analysis,

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