Early life stress, negative paternal relationships, and chemical intolerance in middle-aged women: support for a neural sensitization model.

This study (ntotal = 35) compared early life stress ratings, parental relationships, and health status, notably orthostatic blood pressures, of middle-aged women with low-level chemical intolerance (CI group) and depression, depressives without CI (DEP group), and normals. Environmental chemical intolerance is a symptom of several controversial conditions in which women are overrepresented, that is, sick building syndrome, multiple chemical sensitivity, chronic fatigue syndrome, and fibromyalgia. Previous investigators have postulated that people with CI have variants of somatization disorder, depression, posttraumatic stress disorder (PTSD) initiated by childhood abuse or a toxic exposure event. One neurobehavioral model for CI, somatization disorder, recurrent depression, and PTSD is neural sensitization, that is, the progressive amplification of host responses (e.g., behavioral, neurochemical) to repeated intermittent stimuli (e.g., drugs, chemicals, endogenous mediators, stressors). Females are more vulnerable to sensitization than are males. Limbic and mesolimbic pathways mediate central nervous system sensitization. Although both CI and DEP groups had high levels of life stress and past abuse, the CI group had the most distant and weak paternal relationships and highest limbic somatic dysfunction subscale scores. Only the CI group showed sensitization of sitting blood pressures over sessions. Together with prior evidence, these data are consistent with a neural sensitization model for CI in certain women. The findings may have implications for poorer long-term medical as well as neuropsychiatric health outcomes of a subset of women with CI. Subsequent research should test this model in specific clinical diagnostic groups with CI.

Serum neopterin and somatization in women with chemical intolerance, depressives, and normals.

The symptom of intolerance to low levels of environmental chemicals (CI, chemical intolerance) is a feature of several controversial polysymptomatic conditions that overlap symptomatically with depression and somatization, i.e., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and Persian Gulf syndrome. These syndromes can involve many somatic symptoms consistent with possible inflammation. Immunological or neurogenic triggering might account for such inflammation. Serum neopterin, which has an inverse relationship with l-tryptophan availability, may offer a marker of inflammation and macrophage/monocyte activation. This study compared middle-aged women with CI (who had high levels of affective distress; n = 14), depressives without CI (n = 10), and normals (n = 11). Groups did not differ in 4 p.m. resting levels of serum neopterin. However, the CI alone had strong positive correlations between neopterin and all of the scales measuring somatization. These preliminary findings suggest the need for additional research on biological correlates of 'unexplained' multiple somatic symptoms in subtypes of apparent somatizing disorders.

Differential resting quantitative electroencephalographic alpha patterns in women with environmental chemical intolerance, depressives, and normals.

BACKGROUND: Previous research suggests that a subset of individuals with intolerance to low levels of environmental chemicals have increased levels of premorbid and/or comorbid psychiatric disorders such as depression, anxiety, and somatization. The purpose of this study was to evaluate the psychological profiles and quantitative electroencephalographic (qEEG) profiles at baseline of women with and without chemical intolerance (CI). METHODS: Participants were middle-aged women who reported illness from the odor of common chemicals (CI, n = 14), depressives without such intolerances (D, n = 10), and normal controls (N, n = 11). They completed a set of psychological scales and underwent two separate qEEG recording laboratory sessions spaced 1 week apart, at the same time of day for each subject. RESULTS: CI were similar to D with increased lifetime histories of physician-diagnosed depression (71% vs. 100%), Symptom Checklist 90 (revised) (SCL-90-R) somatization scores, Barsky Somatic Symptom Amplification, and perceived life stressfulness, although D had more distress than either CI or N on several other SCL-90-R subscales. CI scored significantly higher on the McLean Limbic Symptom Checklist somatic symptom subscale than did either D or N. On qEEG, CI exhibited significantly greater overall resting absolute alpha activity with eyes closed, especially at the parietal midline site (Pz), and increased (sensitized) frontal alpha from session 1 to 2, in contrast with the D and N groups. D showed right frontal asymmetry in both sessions, in comparison with CI. CONCLUSIONS: The data indicate that CI with affective distress diverge from both D without chemical intolerance and N in qEEG alpha patterns at resting baseline. Although CI descriptively resemble D with increased psychological distress, the CI's greater alpha suggests the possibility of a) central nervous system hypo-, not hyper-, activation; and/or b) an overlap with EEG alpha patterns of persons with positive family histories of alcoholism.

Individual differences in neural sensitization and the role of context in illness from low-level environmental chemical exposures.

This paper summarizes the clinical phenomenology of multiple chemical sensitivity (MCS), outlines the concepts and evidence for the olfactory-limbic, neural sensitization model for MCS, and discusses experimental design implications of the model for exposure-related research. Neural sensitization is the progressive amplification of responsivity by the passage of time between repeated, intermittent exposures. Initiation of sensitization may require single toxic or multiple subtoxic exposures, but subsequent elicitation of sensitized responses can involve low or nontoxic levels. Thus, neural sensitization could account for the ability of low levels of environmental chemicals to elicit clinically severe, adverse reactions in MCS. Different forms of sensitization include limbic kindling of seizures (compare temporal lobe epilepsy and simple partial seizures) and time-dependent sensitization of behavioral, neurochemical, immunological, and endocrinological variables. Sensitized dysfunction of the limbic and mesolimbic systems could account in part for many of the cognitive, affective, and somatic symptoms in MCS. Derealization (an alteration in perception making familiar objects or people seem unfamiliar or unreal) is a common MCS symptom and has been linked with limbic dysfunction in clinical neuroscience research. Sensitization is distinct from, but interactive with, other neurobiological learning and memory processes such as conditioning and habituation (compare adaptation or tolerance). In previous studies, hypotheses for MCS involving sensitization, conditioning, and habituation (adaptation) have often been considered in isolation from one another. To design more appropriate chemical exposure studies, it may be important to integrate the various theoretical models and empirical approaches to MCS with the larger scientific literature on individual differences in these potentially interactive phenomena.

Neural sensitization and physiological markers in multiple chemical sensitivity.

This paper summarizes the key features of the olfactory-limbic, neural sensitization model for multiple chemical sensitivity (MCS) and presents relevant data on chemically intolerant human subjects from laboratory studies using quantitative electroencephalography, polysomnography, neuropsychological tests, cardiovascular measurements, and blood markers. MCS is a poorly understood chronic, polysymptomatic condition in which some prior controlled research studies have failed to find evidence to differentiate active from placebo tests. Closer examination of past MCS research, however, reveals that studies have failed to incorporate the design and methodological approaches necessary to test for nonimmunological sensitization. Time-dependent sensitization (TDS) is a well-documented phenomenon in the pharmacology literature involving the progressive increase in a given response by the passage of time between the initial and subsequent exposures to a substance or a stressor. As in MCS, multiple, chemically unrelated agents can trigger TDS. Females time-sensitize more readily than do males. Pharmacological and nonpharmacological (stress) stimuli can cross-sensitize. Dopaminergic pathways in the brain and the hypothalamic-pituitary-adrenal axis are likely involved in TDS. Data on the symptomatology of MCS point to central nervous system involvement, including limbic regions that receive input from both olfactory (odor) and trigeminal (irritant) pathways. Limbic and mesolimbic brain regions are among the most sensitizable to repeated, intermittent environmental stimuli. Sensitizable individuals can show no difference or lesser responses to a test substance on initial exposure, but later exhibit much greater increases in responsivity on the next exposure after a period of days. For future research, it is essential to distinguish chemical intolerance symptoms such as derealization, sudden mood changes, musculoskeletal pain, menstrual dysfunction, and uncontrollable sleepiness from chemical phobia and avoidance behaviors. This model permits hypothesis-driven research on MCS and has major implications for interpretation of apparently positive and negative tests for "true" as opposed to "perceived" sensitivity to low levels of environmental chemicals.

Increased limbic system symptomatology and sensitizability of young adults with chemical and noise sensitivities.

We previously hypothesized that individual differences in (a) limbic system reactivity and (b) central nervous system sensitizability underlie vulnerability to environmental stimuli, not only in the controversial clinical condition multiple chemical sensitivity (MCS), but also in the general population. Earlier research has shown overlaps in the characteristics of persons who report noise and air pollutant sensitivities. This study assessed questionnaire responses of 897 young adult college students who reported high versus low frequency of illness from several environmental chemical odors and concomitantly high versus low sensitivity to environmental noise. Subjects who reported increased rates of illness from chemical odors with or without noise sensitivity scored significantly higher (P < 0.0001) on a measure of limbic system symptomatology derived from ictal sensory, somatic, mnemonic, and behavioral manifestations of temporal lobe epilepsy. The group rating high both for illness from chemicals and for noise sensitivity had characteristics predictive of heightened sensitizability from the animal research on time-dependent sensitization (progressive response amplification to repeated, intermittent stimuli over time): i.e., higher female to male ratio (gender risk factor), increased rates of drug abuse problems in blood relatives (genetic risk factor), trait shyness (hyperreactivity to novelty), and increased carbohydrate craving. Despite the increased family histories of drug abuse and levels of personal anxiety and depression, the chemical- and noise-sensitive group reported the lowest rates of current smoking or personal drug abuse problems and the highest frequency of illness from drinking a small amount of alcohol. Taken together, the findings suggest that limbic system dysfunction associates more with chemical than with noise sensitivity; that individuals with both chemical and noise sensitivity may be the most sensitizable subset of the population for prospective studies, and that, in their substance use patterns, young adults with both chemical and noise sensitivity are more similar to MCS patients than are their peers with chemical or noise sensitivity alone.