Brain responses to olfactory and trigeminal exposure in idiopathic environmental illness (IEI) attributed to smells — An fMRI study
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,
References (50)
- et al.
Self-reported chemical sensitivity in Germany: a population-based survey
Int J Hyg Environ Health
(2005) - et al.
Multiple chemical sensitivities: a systematic review of provocation studies
J Allergy Clin Immunol
(2006) - et al.
Overlap in prevalence between various types of environmental intolerance
Int J Hyg Environ Health
(2014) - et al.
Comparing non-specific physical symptoms in environmentally sensitive patients: prevalence, duration, functional status and illness behavior
J Psychosom Res
(2014) - et al.
On the scent of human olfactory orbitofrontal cortex: meta-analysis and comparison to non-human primates
Brain Res Rev
(2005) - et al.
The neuronal correlates of intranasal trigeminal function-an ALE meta-analysis of human functional brain imaging data
Brain Res Rev
(2010) - et al.
Chemosensory function and psychological profile in patients with multiple chemical sensitivity: comparison with odor-sensitive and asymptomatic controls
J Psychosom Res
(2006) - et al.
Attention bias and sensitization in chemical sensitivity
J Psychosom Res
(2009) - et al.
An olfactory-limbic model of multiple chemical sensitivity syndrome: possible relationships to kindling and affective spectrum disorders
Biol Psychiatry
(1992) Clinically relevant EEG studies and psychophysiological findings: possible neural mechanisms for multiple chemical sensitivity
Toxicology
(1996)
Improvement of fMRI data processing of olfactory responses with a perception-based template
Neuroimage
A review of systems and networks of the limbic forebrain/limbic midbrain
Prog Neurobiol
Large-scale brain networks and psychopathology: a unifying triple network model
Trends Cogn Sci
Expecting unpleasant stimuli—an fMRI study
Psychiatry Res
The pain matrix reloaded: a salience detection system for the body
Prog Neurobiol
Neural coding of stimulus concentration in the human olfactory and intranasal trigeminal systems
Neuroscience
Imaging of brain activation by odorants in humans
Curr Opin Neurobiol
Activation and habituation in olfaction — an fMRI study
Cognitive modulation of olfactory processing
Neuron
Neurocircuitry models of posttraumatic stress disorder and beyond: a meta-analysis of functional neuroimaging studies
Neurosci Biobehav Rev
Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness
Semin Arthritis Rheum
The chemical sensitivity scale: psychometric properties and comparison with the noise sensitivity scale
J Environ Psychol
A national population study of the prevalence of multiple chemical sensitivity
Arch Environ Health
Medically unexplained symptoms and neuropsychological assessment
J Clin Exp Neuropsychol
Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review
Psychosom Med
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