Differential Resting Quantitative Electroencephalographic Alpha Patterns in Women with Environmental Chemical Intolerance, Depressives, and Normals

Differential Resting Quantitative Electroencephalographic Alpha Patterns in Women with Environmental Chemical Intolerance, Depressives, and Normals Iris R. Bell, Gary E. Schwartz, Elizabeth E. Hardin, Carol M. Baldwin, and John P. Kline 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 5 14), depressives without such intolerances (D, n 5 10), and normal controls (N, n 5 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

From the Department of Psychiatry (IRB, GES, EEH), Department of Psychology (GES, IRB, CMB, JPK), Department of Neurology (GES), Family and Community Medicine (IRB), and the Division of Respiratory Sciences (CMB), University of Arizona Health Sciences Center, Tucson, Arizona; and the Department of Psychiatry, Tucson Veterans Affairs Medical Center, Tucson, Arizona (IRB). Address reprint requests to Dr. Iris Bell, Department of Psychiatry, Tucson Veterans Affairs Medical Center, Mail Stop 116A, 3601 S. 6th Avenue, Tucson, AZ 85723. Received August 22, 1996; revised March 18, 1997; accepted April 1, 1997.

Published 1998 Society of Biological Psychiatry

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. Biol Psychiatry 1998;43:376 –388 Published 1998 Society of Biological Psychiatry Key Words: Chemical odor intolerance, multiple chemical sensitivity, depression, EEG alpha, frontal asymmetry, attention, arousal

Introduction

S

elf-reported illness from the odors of low, presumably “nontoxic” levels of environmental chemicals (CI, chemical intolerance), including difficulty concentrating, dysphoric mood, and multiple somatic symptoms, is emerging as a significant public health problem, especially in women (Ashford and Miller in press). Prevalence studies in nonindustrial samples have demonstrated a rate of 15–30% for mild to moderate, and of 4% for severe CI (Bell et al 1993a, 1993b, 1993d, 1994, 1996a, 1996d in press a,b; Meggs et al 1996; Wallace et al 1991). Workers with occupational solvent exposure report CI at the high rate of 60% (Morrow et al 1990). The clinically severe cases, generally labeled multiple chemical sensitivity (MCS, Cullen 1987), usually a) involve numerous lifestyle changes to avoid chemicals (Bell et al 1995a; Simon et al 1990); b) overlap symptomatically with other controversial conditions such as chronic fatigue syndrome (CFS) and fibromyalgia (Buchwald and Garrity 1994; Fiedler et al 1996); and c) lead to increased rates of disability (Bell et al 1995a; Black et al 1990; Miller and Mitzel 1995; Simon et al 1990). Unlike CFS, MCS per se does not yet have a generally accepted case definition (Cullen 1987; Miller 1994). Societal implications of the problem include 0006-3223/98/$0.00 PII S0006-3223(97)00245-X

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increased worker absenteeism, disability claims, litigation (Simon et al 1990), and high utilization of health care services (Buchwald and Garrity 1994). Although the interpretation remains in dispute (Davidoff and Fogarty 1994; Terr 1993), and a substantial subset of MCS patients do not have any psychiatric diagnoses (Fiedler et al 1996; Simon et al 1993), the available data nonetheless indicate increased depression ratings in many persons with CI (Bell et al 1993a, 1993b, 1993c, 1994, 1996a, in submission) and MCS (Bell et al 1995a; Simon et al 1990, 1993). These findings include elevated depression subscale scores on the Symptom Checklist 90 (revised) and the Beck Depression Inventory (Bell et al 1996b; Doty et al 1988), as well as significantly increased lifetime prevalence of major depression diagnoses, e.g., from 30% (Black et al 1990) to 54% (Bell et al 1995a; Simon et al 1990), in CI and MCS compared with lower rates in various control groups. Recently, Fiedler et al (1996) reported that CI who cannot identify a clear date of onset for their condition associated with a specific chemical exposure and CFS have high rates of psychiatric disorders, notably depression (e.g., 54% in CI and 67% in CFS versus only 30% in MCS with a self-identified chemical initiation event and 11% in normals). Electroencephalography (EEG) may offer an objective tool to delineate the pathophysiology and subtypes of chemical intolerance (Bell 1994, 1996; Bell et al 1992; Benignus 1984; Muttray et al 1995; Schwartz et al 1994; cf., Prichep and John 1992) and to compare affectively disturbed CI and MCS with depressives. Staudenmayer and Selner (1990), for example, compared resting qEEG patterns at the right parietal site P4 of MCS clinic patients with those of a mixed group of psychologically disordered outpatients with unspecified levels of CI, and controls without psychopathology but with various medical conditions. They found similarities in pattern between the MCS and psychologic groups in elevated beta activity (15–25 Hz) and decreased alpha-2 (9.8 –12.2 Hz) relative to the medical controls; however, CI by itself does not necessarily lead to the EEG patterns of depression. Nondepressed elderly with CI exhibited decreased rapid-eye-movement (REM) sleep and a trend toward a longer REM onset latency on polysomnographic recording (Bell et al 1996c), a finding contrary to objective sleep EEG parameters usually reported in major depressives (Reynolds et al 1985). Many (Brenner et al 1986; Pollock and Schneider 1990; Schaffer et al 1983), though not all (Knott and Lapierre 1987; Visser et al 1985) waking quantitative EEG (qEEG) studies suggest that depressives exhibit a) increases in the overall amount of alpha activity; and b) relative right anterior hemisphere activation at rest (asymmetry—less alpha on right than left) (Allen et al 1993; Davidson et al

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1979, 1985; Henriques and Davidson 1991; Nystrom et al 1986). Both alpha findings may be trait markers for affective disorder vulnerability; depressives exhibit them even after recovery from the depressed state (Henriques and Davidson 1988; Pollock and Schneider 1989). The frontal alpha finding also predicts individual differences in inhibited (cf., shy) temperament in that infants with resting frontal asymmetry show greater emotional reactivity to the novelty of separation from their mothers (Davidson and Fox 1989). Notably, shyness is a temperamental feature of nondisabled persons with CI (Bell et al 1993a, 1993b, 1995b, 1996a), but not necessarily of disabled MCS patients (Bell et al 1995a). Overall, decreased alpha implies greater mental activation or alertness in attentional function, whereas increased alpha indicates the reverse, e.g., relaxed wakefulness (Niedermeyer and Lopes da Silva 1993; Ray and Cole 1985). Bell et al (Bell 1994, 1996; Bell et al 1992, 1993c, 1996b in submission, 1996d, in press) have proposed that the neurobehavioral process of time-dependent sensitization (TDS) (Antelman 1988, 1994) could explain the progressive and persistent amplification in reactivity to chemicals reported in persons with CI. TDS is the increase in responsivity to a given stimulus (physical or psychological stressors, pharmacologic agents, chemicals) by the passage of time between successive exposures (Antelman 1988, 1994; Sorg et al 1996; Stewart and Badiani 1993). TDS is a proposed model for the long-term course of craving for addictive substances (Robinson and Berridge 1993; Sills and Vaccarino 1994) as well as of recurrent affective disorders (Post 1992). Animals given repeated intermittent exposures to sensitizing agents can exhibit increases over time in EEG alpha-1 and alpha-2 (Ferger et al 1996 — correlated with increased D2 dopamine receptor activation at higher initiating doses) and/or beta responses (Burchfiel and Duffy 1982; Kay 1996). Both functional neuroimaging data (Heuser et al 1994) and visuospatial divided attention and visual memory test abnormalities (Bell et al 1995b in submission, 1995c; Fiedler et al 1996) point to the possibility of right frontal lobe dysfunction in MCS. Notably, dopamine depletion in prefrontal cortex can enhance sensitizability in animals (Deutch et al 1990; Hamamura and Fibiger 1993; Kalivas and Barnes 1993; Mitchell and Gratton 1992). Solvents, which commonly initiate MCS (Miller and Mitzel 1995), can deplete central nervous system dopamine and initiate TDS (Von Euler et al 1994), as well as impair spatial learning in animals (Von Euler et al 1993). No previous research in human subjects with CI has examined frontal EEG alpha patterns over time in a sensitization protocol. Consequently, the purpose of the present study was to characterize the psychological profiles and resting qEEG absolute alpha patterns, especially

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in frontal sites, of moderately ill CI with affective distress, depressives without CI, and normals without CI or depression, all recruited from the community rather than from a clinical setting.

in all groups were run throughout the protocol without timing sessions to coincide with any particular point in the menstrual cycle. This study was approved by the University of Arizona Institutional Review Board; all subjects gave their informed consent prior to participation.

Methods and Materials

Procedure

Subjects The subjects were nonsmoking, nonalcoholic (screened by the CAGE questionnaire—Ewing 1984, and by psychiatric/medical interview), nonpregnant women, aged 30 –50 years (the gender and age range reportedly most susceptible to MCS—Ashford and Miller in press), in stable medical health. They were recruited by newspaper advertisement and flyers placed in local fitness clubs. The advertisements sought volunteers with and without chemical odor intolerance and with and without depression. Inclusion criteria were as follows: i) chemical intolerant group (CI) had to score a mean of $20/25 on the five-item Chemical Intolerance Index (CII—Bell et al 1994, 1995a; Szarek et al in press), averaged over telephone and follow-up written questionnaire screening, and consider themselves to be “especially sensitive to certain chemicals,” but without restrictions on the basis of depression status (i.e., CIs had to be high in CI, but were permitted to vary in depression from low to high levels); ii) depressed group (D) had to score a mean CII score ,13 (cf., mean population score 13.1 in Bell et al 1993a) and a mean score of $17 on the Symptom Checklist 90 (revised) (SCL-90-R— Clinical Psychometric Research, Inc., Towson, MD) 13-item depression subscale, averaged over telephone and follow-up written questionnaire screening (cf., mean score 17.1 for solventexposed workers in Morrow et al 1993), and a current DSM-III-R diagnosis of major depression on screening interview (i.e., D had to be low in CI and high in depression); and iii) normal group (N) had to have a mean CII score ,13, a mean SCL-90-R depression score #13 (cf., mean score 11.4 for nonexposed workers in Morrow et al 1993), not consider themselves to be “especially sensitive to certain chemicals,” and not have a current DSMIII-R diagnosis of major depression (i.e., N had to be low in both CI and depression). Exclusion criteria to minimize subject risk during laboratory chemical exposures were life-threatening medical conditions including heart, liver, or kidney disease; anaphylactic shock, asthma, and/or bronchitis requiring bronchodilators in the past 10 years; seizures; head trauma with history of loss of consciousness; fainting spells; insulin-dependent diabetes; electroconvulsive therapy in the 6 months prior to participation; psychosis; and active suicidality. Potential subjects with acute upper respiratory infections were asked to defer participation until the acute illness had resolved to limit variation in olfactory detection ability between subjects. To minimize motivation for secondary gain, potential subjects involved in pending workers compensation or chemical injury-related litigation cases were also excluded. No subject could be taking benzodiazepines for at least 2 weeks prior to and during participation in the study. Subjects could be taking other prescribed medications, but had to be on a stable dosage for at least 3 months prior to and during study participation. Subjects

HEALTH HISTORY AND PSYCHOLOGICAL MEASURES. Subjects underwent a two-stage screening process to ensure stability in their status on chemical intolerance and depression. They began with a telephone screening interview that included demographic information; the CII, a five-item self-rated scale on frequency of self-rated illness from pesticide, paint, perfume, car exhaust, and new carpet (1 5 almost never; 5 5 almost always, possible range 5–25, where MCS patients score a mean of 22—Bell et al 1995a); the Simon Lifestyle Change Survey for Chemical Sensitivity (Simon et al 1990 —MCS patients score $2–3); the SCL-90-R depression subscale; and medical/surgical and medication history. Next, they had an in-person evaluation by an advanced psychiatric resident, who performed a medical/ psychiatric history and physical examination, and by a trained research assistant, who administered the Cain Olfactory Identification Test (10-item) (Cain et al 1988), Hamilton Depression Rating Scale (Hamilton 1960), a series of baseline cognitive tests, and blood samples (reported elsewhere). Subjects completed a battery of questionnaires that included the full SCL90-R, Seasonal Pattern Assessment Questionnaire (Rosenthal et al 1987), overall rating of health (210 to 110), a perceived life stress rating scale for each 5-year period of their lives from birth until the present (1 5 least stressful; 5 5 most stressful), Barsky Amplification Scale (Barsky et al 1988), Noise Sensitivity Scale (Weinstein 1978), Anxiety Sensitivity Index (Reiss et al 1986), Cheek–Buss Shyness Scale (Cheek and Buss 1981), McLean Limbic Symptom Checklist (33-item Likert scale based on the ictal symptoms of temporal lobe epilepsy) (Teicher et al 1993), and the 13-item short form of the Marlowe–Crowne Social Desirability [Repressiveness] Scale (Reynolds 1982). EEG LABORATORY SESSIONS. Subjects then reported to the Chemical Psychophysiology Laboratory in an older, off-campus house on a side street near the University for two separate 3-hour sessions, scheduled 1 week apart at the same time of day for a given person. Subjects were told that they would receive chemical exposures at various points during each session. When chemical exposures were not intended within a session, stainless steel Allermed Space Saver 400 air filters (Wylie, TX) ran in both the subject and recording rooms. The subject room had hardwood floors and was unfurnished, with the exception of a metal armchair for the subjects and modified metal music stand to hold the test vials. The sessions involved the same procedures each time. Subjects completed the 65-item Profile of Mood States Scale (POMS—Educational and Industrial Testing Service, San Diego, CA 92107), gave a salivary cortisol sample, had vital signs taken, and took a divided attention test at the beginning and end of each session. During each session, subjects underwent hookup using phenol-

qEEG in Chemically-Intolerant Women

free conductive gel with a latex cap embedded with EEG electrodes positioned via the International 10/20 System (Electrocap International, Eaton, OH). Cap electrode impedances were kept below 5kV. Nineteen channels of baseline resting EEG referenced to linked ears were recorded with eyes open and eyes closed for 1 min while subjects sat quietly in a metal chair. Instructions were to relax and minimize movement. Computerized EEG recording occurred in the adjacent room; subjects were observed through a glass window in a wooden door separating the subject and recording rooms. Following the baseline recording, subjects underwent an extended series of cognitive tests, and blinded and randomized 1- and 2-min low-level chemical (ethanol, galaxolide, propylene glycol) and sham (empty, distilled water) exposures in foil-covered glass scintillation vials during the remainder of each session (reported elsewhere). Total time of chemical exposures per session was 9 min. DATA ANALYSIS. The qEEG raw signal was recorded on a Lexicor NeuroSearch 24 apparatus (Boulder, CO) with a 2-Hz high-pass filter and a 60-Hz notch filter enabled. Sampling rate was 256 Hz. The Lexicor also uses antialiasing low-pass filters with automatic settings for 1/4 the sampling rate. Digitized data were stored on magnetic tape. EEG data were subjected to visual inspection by a research assistant blind to the hypotheses of the study for rejection of epochs within each 1-min recording that contained eye movement or gross muscle artifact (e.g. deflections .50 mV), and then processed with fast Fourier transformation to determine the absolute magnitude of each frequency band in microvolts. The absolute alpha frequency range was set at 8 –12 Hz. Demographic data were evaluated using one-way analyses of variance for continuous measures and chi-square with Yates’ correction or Fisher Exact Tests for categorical measures. Primary data analysis of the qEEG alpha data focused on the Fz, Cz, and Pz midline sites as well as the F7, F3, Fz, F4, and F8 coronal array. Frontal asymmetry was calculated as a difference score of F4 2 F3 (right minus left), where more negative values indicate greater right frontal activation (i.e., less alpha). SPSS for Windows and Statistica for Windows were used to perform the multivariate repeated-measures analyses of covariance (MANCOVA, using age as covariate, on which the groups differed) on the qEEG data.

Results Demographics and Psychological Profiles Table 1 summarizes the descriptive features of each group. The CI were significantly older than the other two groups; consequently, all of the qEEG MANCOVA analyses included age as a covariate. The CI also rated their overall health as significantly poorer than did the N. Groups did not differ significantly for educational level, marital status, left-handedness, amount overweight, or Cain olfactory identification ability. Subjects worked in settings involving primarily indoor air environments, but not in manufacturing or service occupations in which the job responsibilities involved routine use of industrial chemicals;

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Table 1. Descriptive Characteristics of Chemically Intolerant, Depressed, and Normal Groups [Mean (SD)] Chemical intolerant (CI) Depressed (D) Normal (N) (n 5 14) (n 5 10) (n 5 11) Age (years)a 45.1 (4.8) 40.0 (5.6) 38.1 (6.5) Education (2 5 high 2.9 (0.9) 2.3 (0.7) 2.7 (0.9) school; 3 5 college) Marital status (% 50%/36%/14% 20%/40%/30% 9%/55%/36% divorced/% single/% married) Write with left hand (%) 7% 10% 0 Amount overweight (lb) 25.2 (61.6) 18.7 (55.1) 10.9 (32.0) Cain Olfactory 7.7 (1.1) 6.8 (1.2) 7.3 (2.2) Identification score (0 –10) Overall self-rated health 2.7 (5.9) 4.7 (4.0) 7.7 (2.6) (210 to 110)b Significant analyses of variance, with Student–Newman–Keuls post hoc tests p , .05: a CI . D, N. b CI , N.

however, some occupations might have involved increased exposures to certain substances, e.g., flight attendant (1 CI) and aircraft fuel/fumes, pesticides; nurse’s aide (1 D) and disinfectants, latex gloves. Only the CI (fluoxetine n 5 3; nortriptyline n 5 1; doxepin n 5 1) and D (fluoxetine n 5 1; sertraline n 5 3; imipramine n 5 1; trazodone n 5 2) groups reported ongoing use of psychotropic medications, which were selective serotonin reuptake blocking or cyclic antidepressant agents. Chisquare analysis indicated that 40% of the D group was taking selective serotonin reuptake inhibitor antidepressants, versus 21% of the CI and none of the N group [x2(2) 5 5.3, p 5 .07]. Groups did not differ significantly in use of other medications (categories were: nonsteroidal antiinflammatory drugs, acetaminophen, estrogen/progesterone, H2 blocker, thyroid preparations). The median age at which the CI reported first noticing that they were sensitive to environmental chemicals was 12 years old (range 2– 44 years). On a checklist review of systems, the CI attributed symptoms to chemical odor exposures at the following rates: headache 93%, lung problems 86%, sinus problems 86%, feeling confused or forgetful 71%, nasal problems 64%, dizziness or unsteadiness 64%, eye problems 64%, stomach problems 50%, skin problems 50%, burning or tingling in extremities 36%, muscle/joint problems 29%, and urinary/kidney problems 21%. Overall for possible classical atopy, the three groups did not differ significantly in proportion reporting physician-diagnosed hay fever, eczema, or hives; the CI had a trend toward more subjects with asthma in the past (asthmatics with a history of recent attacks in the past 10 years had been excluded) [CI: 21%,

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Table 2. Behavioral Health Histories of Chemical Intolerant, Depressed without Chemical Intolerance, and Normals [Mean (SD)] Chemical intolerant (CI) (n 5 14)

Depressed (D) (n 5 10)

Current smoker 0 0 Ever drink any alcohol 57% 30% Self-rated illness from drinking 3.0 (1.6) 2.5 (1.5) small amount of alcohol (1–5)a Chemical intolerance index 22.0 (1.8) 6.6 (1.6) (5–25)b Simon chemical sensitivity 2.3 (1.6) 0.2 (0.6) lifestyle changes (0 – 4)b Lifetime medical diagnosis of 36% 0 chemical sensitivityb SCL-90-R depressionc 18.6 (10.7) 28.8 (9.6) Hamilton Depression Rating 14.9 (13.7) 21.3 (10.2) Scale (21-item)a Rosenthal seasonality of 6.1 (3.6) 10.0 (5.3) depression scored Lifetime medical diagnosis of 71% 100% depressiona Lifetime medical diagnosis of 71% 40% late luteal phase dysphoric disorder1 Blood relative medical diagnosis 57% 30% of depression Blood relative medical diagnosis 50% 30% of anxietye Blood relative medical diagnosis 21% 0 of drug problem11 Blood relative medical diagnosis 64% 50% of alcohol problem Perceived life stressfulness 3.3 (0.9) 3.4 (0.8) (1–5)a

Normal (N) (n 5 11) 0 64% 1.0 (0)

7.0 (1.8) 0 0 5.2 (4.8) 3.4 (3.0) 5.8 (4.4) 9% 27%

18% 0 0 27%

Table 3. Group Differences in Psychological Scale Scores [Mean (SD)]

Barsky Amplification Scalea Noise Sensitivity Scalea Anxiety Sensitivity Indexb SCL-90-R General severity indexc Somatizationa Anxietyc Phobic anxietyd Interpersonal sensitivityc Obsessive– compulsivityc Hostilityd Paranoiac Psychoticismc Cheek–Buss Shyness1 McLean Limbic Symptom Checklist (total score)a Limbic somatice Limbic sensoryf Limbic mnemonic Limbic behavior Marlowe–Crowne short form (repressiveness) (0 –13)

Chemical intolerant (CI) (n 5 14)

Depressed (D) (n 5 10)

Normal (N) (n 5 11)

11.7 (3.8) 95.0 (15.6) 20.6 (9.7)

13.8 (4.4) 90.7 (15.2) 25.7 (11.2)

7.7 (3.5) 75.0 (17.5) 13.8 (9.9)

1.1 (0.6) 16.0 (10.6) 9.6 (7.1) 3.5 (2.6) 9.6 (7.2) 13.3 (8.5) 4.4 (3.7) 4.4 (3.5) 6.3 (4.8) 2.4 (0.8) 34.0 (14.3)

1.9 (0.8) 18.4 (8.2) 18.2 (10.3) 10.6 (7.9) 19.1 (8.9) 20.0 (8.6) 10.2 (5.4) 8.7 (5.5) 13.6 (8.6) 2.5 (0.8) 32.4 (17.2)

0.2 (0.2) 2.0 (1.5) 1.5 (2.4) 0.1 (0.3) 2.7 (3.4) 3.0 (3.4) 1.5 (1.9) 0.9 (1.6) 0.9 (1.6) 1.8 (0.5) 16.3 (12.1)

13.5 9.3 5.6 5.6 5.5

(3.9) (6.7) (3.1) (3.5) (3.1)

9.6 9.4 7.6 5.9 5.3

(4.7) (7.1) (3.7) (4.6) (2.1)

6.8 3.1 3.9 2.5 7.7

(4.1) (3.2) (3.1) (2.9) (3.4)

Significant analyses of variance, with Student–Newman–Keuls post hoc tests p , .05: a CI, D . N. b D . N. c CI, D . N; D . CI, N. d D . CI, N. e CI . D, N. f CI . N. 1 p 5 .07 over all groups; no two groups differ significantly.

2.4 (0.6)

Significant analyses of variance, with Student–Newman–Keuls post hoc tests p , .05: a CI, D . N. b CI . D, N. c CI, D . N; D . CI, N. d D . N. e CI . N. 1 p 5 .07. 11 p 5 .09.

D: 0%, N: 0%; x2(2) 5 4.9, p 5 .09]. On family histories, the CI had the largest percentage of relatives with eczema [CI: 43%, D: 30%, N: 0%; x2(2) 5 6.1, p 5 .048] and a trend toward more relatives with hay fever diagnoses [CI: 50%, D: 40%, N: 9%; x2(2) 5 4.8, p 5 .09]. Table 2 illustrates that the CI rated themselves much higher for chemical intolerance and for associated lifestyle changes than did the other two groups. Nevertheless, only approximately one third of the CI reported a physician diagnosis of chemical sensitivity. The D group had the highest self-rated depression on the SCL-90-R subscale and the highest score for seasonality of mood, but CI and

D were comparable statistically in level of observer-rated depression on the Hamilton Depression Rating Scale on entry into the study. Both CI and D had extremely high rates of lifetime physician diagnoses of depression and comparable levels of perceived stress averaged over the first seven 5-year periods of life. The CI showed a trend toward the highest rate of physician-diagnosed late luteal phase dysphoric disorder. The CI reported the most blood relatives with physician diagnoses of anxiety disorders, as well as a trend toward the most family histories of drug problems. Both the CI and D indicated greater frequencies of illness from drinking small amounts of alcohol than did the N. On the other psychological measures (Table 3), CI and D were higher than N for Barsky Amplification, Noise Sensitivity, SCL-90-R somatization, interpersonal sensitivity, obsessive– compulsiveness, paranoia, and psychoticism, as well as total McLean Limbic Symptom scores; however, the D were still higher than the CI and N for SCL-90-R phobic anxiety and hostility, as well as general

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Table 4. Group Differences in Baseline POMS Mood Scale Scores at the Beginning of Each Laboratory Session [Mean (SD)]

Session 1 baseline POMS Tension–anxietya Anger– hostility1 Depression1 Fatiguea Confusiona Vigor Session 2 baseline POMS Tension–anxietyb Anger– hostility Depression Fatiguea Confusion Vigor

Chemical intolerant (CI)

Depressed (D)

12.4 (6.6) 9.3 (7.0) 12.1 (10.3) 13.5 (7.9) 9.4 (5.7) 11.9 (7.5)

14.7 (8.6) 11.2 (9.1) 15.7 (15.2) 13.6 (9.1) 9.3 (5.1) 9.8 (5.4)

5.7 4.3 5.2 4.2 4.3 15.6

12.1 (7.7) 9.4 (10.6) 10.9 (8.5) 11.7 (7.9) 9.5 (5.8) 12.9 (8.0)

12.3 9.2 12.0 13.9 9.3 10.4

5.9 (7.7) 6.2 (9.5) 7.7 (10.3) 4.4 (4.2) 5.9 (5.7) 15.4 (5.8)

(6.6) (8.1) (9.7) (6.6) (3.5) (5.6)

Normal (N) (4.6) (4.8) (4.7) (2.9) (2.5) (6.4)

No group by session interactions were significant. Significant analyses of variance with Student–Newman–Keuls post hoc tests p , .05: a CI, D . N. b CI . N. 1 p 5 .08 over all groups; no two groups differ significantly.

severity index, interpersonal sensitivity, obsessive– compulsiveness, paranoia, and psychoticism. The only variable on which the CI exceeded the D was on the McLean limbic somatic symptom subscale. For POMS mood ratings at the start of each laboratory session (Table 4), CI and D were comparable to each other but higher than N on tension–anxiety, fatigue, and confusion in session 1 but only for fatigue in session 2. CI exceeded N but not D for session 2 tension–anxiety. MANCOVAs (with age as covariate) performed over each of the six dimensions of the POMS for presession and postsession values of the two sessions revealed significant main effects for group on tension–anxiety, depression, fatigue, vigor, and confusion, but not anger– hostility. The only significant group by pre/post-interaction was for confusion, i.e., the D group rated themselves lower with less confusion, whereas the CI rated themselves slightly higher at the end of sessions with more confusion. The N stayed lowest and approximately the same in confusion from beginning to end of sessions [see presession POMS—Table 4; average postsession POMS confusion: mean (SD): CI: 9.6 (5.1); D 5.3 (3.9); N 4.8 (2.1); group by prepost: F(1,31) 5 3.3, p 5 .049]. There were no significant interactions for POMS subscales involving session as a factor.

qEEG Alpha Patterns Figure 1 demonstrates that the CI had significantly more baseline resting absolute alpha averaged over the midline

Figure 1. Increased baseline resting absolute (Abs) alpha activity averaged over Fz, Cz, and Pz (frontal, central, and parietal midline sites) with eyes closed in the chemical intolerant group. Main effect for group: F(2,28) 5 3.42, p , .047. Student– Newman–Keuls post hoc tests p 5 .02: CI . N; CI . D, where CI 5 chemical intolerant (n 5 13), D 5 depressed (without chemical intolerance) (DEP) (n 5 9), and N 5 normal (without CI or D) (NORM) (n 5 10).

electrode sites (Fz, Cz, Pz) than did either the depressed or normals. The three-way interaction shown in Figure 2 indicates that these group differences became especially accentuated going from frontal to posterior (parietal) midline when subjects closed their eyes. The only significant mood correlation for the CI group was between mean baseline resting alpha at Fz, Cz, and Pz, and POMS postsession fatigue ratings for session 2 (r 5 2.59, p 5 .03, i.e., more alpha at the beginning was associated with lower fatigue at the end of session 2). The D and N groups had nonsignificant correlations for the same item (respectively, r 5 .50, p 5 .2; r 5 2.15, p 5 .7). These correlation coefficients for the CI and D were significantly different from one another (t 5 22.26, p , .05). One prediction from the sensitization model for CI (Bell 1994; Bell et al 1992, 1996b, 1996d, 1997b in press) is that the novelty of the first session would obscure group differences that should emerge upon intermittent or spaced repetition (i.e., second session) of the testing. It can be seen in Figure 3 that the groups overlapped a great deal across the coronal array of F7–F8 in session 1, but diverged substantially in session 2. That is, the CI increased whereas the other two groups decreased in frontal alpha, especially at F3, Fz, and F4, from session 1 to 2. In terms of frontal alpha asymmetry (Figure 4), the D exhibited the most right-sided activation (less alpha) in session 1 compared with the other two groups. The greater right-sided activation of the D was still significant for session 2 in comparison with the CI, but not the N. Only the N group exhibited a significant correlation between the

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Figure 2. Increasing absolute (Abs) alpha activity from frontal to posterior (parietal) regions in the chemical intolerant group with eyes closed versus with eyes open at baseline rest averaged over the two sessions. Student–Newman– Keuls post hoc tests: CI . D at Pz and CI . N at Fz, Cz, and Pz with eyes open (p , .01); CI . D, N at Fz, Cz, and Pz with eyes closed (p , .001). Three-way interaction (covaried for age): F(4,54) 5 2.79; p , .0353.

[F4 2 F3] presession mean alpha difference and the postsession POMS Confusion subscale for session 1 (r 5 .63, p 5 .038). For this item, the CI (r 5 2.11, p 5 .7) and D (r 5 .18, p 5 .6) findings were not significant.

Discussion The current data suggest that middle-aged, well-educated women with CI and affective distress exhibit a divergent pattern of resting qEEG alpha activity from that of non-CI depressives and normals. That is, the CI group in this study exhibited greater absolute frontal F7–F8 alpha at rest over a 1-week period from session 1 to 2, than did the comparison groups; however, it was only the depressives without CI who showed the asymmetric right frontal activation (less alpha on right than left) previously reported in depression. These findings require replication and extension to larger samples of clinically ill depressives screened for chemical intolerance with evaluation over

more data points per session. Taken together, the data raise the possibility of identifying biological subtypes of depression with a self-report variable related to environmental reactivity and/or sensitizability, i.e., chemical odor intolerance. The presence or absence of CI to varying degrees in different samples of depressives may account in part for past difficulties in replicating qEEG alpha and/or asymmetry findings in the literature. The increased alpha in the current CI group is also notable in that the antidepressant drugs taken by both the CI and depressives usually produce slight decreases in alpha activity (Niedermeyer and Lopes da Silva 1993). Still, this study will require replication in medication-free participants. It is essential to emphasize that this investigation of resting qEEG patterns does not directly address the separate question of the “psychogenic” versus “toxogenic” nature of chemical odor intolerance. The design of the study included both active chemical and placebo exposures during both sessions for all subjects. The resting

Figure 3. Increase in chemical intolerant and decrease in depressed and normal groups of absolute (Abs) alpha activity from session 1 to session 2 over frontal array at baseline rest. Absolute alpha at F7–F8 at baseline with eyes closed over the two sessions, three-way interaction (covaried for age): F(8,116) 5 2.81; p , .0070.

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Figure 4. Differential patterns of frontal alpha asymmetry from session 1 to session 2. Student–Newman–Keuls post hoc tests: session 1 D , CI, N (both p , .001) for respective values; session 2 D , CI (p 5 .05), with no significant differences between D and N or between CI and N in session 2. More negative value for frontal asymmetry (difference score 5 F4 2 F3) indicates greater right frontal activation (less alpha); more positive frontal asymmetry value indicates lesser right frontal activation (more alpha). Group differences in frontal alpha asymmetry from session 1 to session 2, two-way interaction (covaried for age): F(2,28) 5 6.43; p , .0050.

alpha findings occurred at the beginning of the two sessions. As a result, the present findings are consistent at most with the hypothesis that persons with CI have an enhanced sensitizability, perhaps related to stress-elicited D2 dopamine receptor activation (Cornish and vanden Buuse 1995; Ferger et al 1996). The environmental factor(s) to which they may have been sensitized in this study could have included the stress of the procedures (Antelman 1988), the actual chemical exposures (Sorg et al 1996), or both. In view of our data on cardiovascular sensitization not only in the present subjects (Bell et al in submission b), but also in elderly CI without chemical exposures (Bell et al 1997a), it is feasible that the procedure alone, if perceived as sufficiently stressful, could have initiated sensitization in vulnerable individuals (Antelman 1988, 1994; Bell 1994, 1996; Yoshida et al 1993). At the same time, the POMS ratings of the CI did not increase or decrease systematically over sessions, making it less likely that the emotional response to the procedures per se explains the current EEG findings. Ray and Cole (1985) emphasized that in EEG, attentional demands may relate more to alpha, whereas affective responses may relate more to beta activity. Thus, the increased frontal alpha in the CI, taken together with functional neuroimaging evidence of right dorsofrontal hypoperfusion in MCS (Heuser et al 1994), might indicate a risk for impaired capacity in sustaining attention during complex tasks (Bell et al 1995c, in press b, in submission b), especially in the visuospatial realm (Retzlaff and Morris 1996; Valentino and Dufresne 1991; Woods and Knight 1986). Fiedler et al (1992, 1994, 1996) have previously proposed that MCS patients may have difficulty discriminating relevant from irrelevant signals and/or acquiring new information in the cognitive–atten-

tion realm. Such a possibility is accessible to additional empiric testing. The data point out the potential usefulness of the subjective report of chemical intolerance, whatever its etiology, in predicting qEEG alpha patterns in persons with negative affect. The increased alpha in women with CI may overlap similar observations in women with late luteal phase dysphoric disorder and positive family histories of alcoholism (Ehlers et al 1996). By the same token, it is difficult to reconcile the current frontal findings with the decreased alpha-2 at P4 seen in MCS patients by Staudenmayer and Selner (1990); however, they did not screen their comparison groups of psychologic patients and medical patients for the variable of chemical odor intolerance, nor did they specify medication usage such as benzodiazepines or intervening experimental procedures (cf., Antelman et al 1991, 1995) in their groups that might have accounted for their observations. They also did not systematically quantify the affective distress in any of their groups; and they examined only P4, not frontal electrode sites. The current data offer indirect evidence that chemical intolerance is not merely a misattributed psychological state. The hypothesis that CI is a psychiatric disorder characterized by denial of the psychological distress is the primary explanation for MCS offered by leading skeptics (Gots 1995; Sparks et al 1994; Staudenmayer and Selner 1990; Terr 1993). In addition to the lack of right frontal asymmetry in the current CI and the reduced REM sleep in the prior study of elderly CI (Bell et al 1996c), our laboratory has found that another elderly group with CI, who were depressed, had even lower postdexamethasone morning serum cortisols than did non-CI controls (Bell 1994; Bell and Amend 1994; cf., Demitrack et al 1991;

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Yehuda et al 1993). If CI were merely misattributed depression, such neurobiological findings in CI should overlap, not diverge from, those of non-CI depression. Previous research has shown that the biological patterns of repressors, i.e., persons who deny negative psychological and behavioral characteristics about themselves, are more similar to those of persons who admit increased psychological distress than to those who truly lack the dysphoria (Lane et al 1990). In contrast, as in our earlier studies (Bell et al 1993c, 1996a, in submission b), the present CI admitted psychological distress, did not differ in Marlowe–Crowne scores from the comparison groups (Marlowe–Crowne is one measure of defensive repression), and did exhibit biological differences from non-CI depressives and normals. The Marlowe–Crowne findings differ from the observation of Fiedler et al (1996) of elevated Minnesota Multiphasic Personality Inventory (MMPI) Lie scale scores in chemically sensitive patients; however, differences in recruitment methods may account for the discrepancy on this point. That is, the latter study recruited from a clinical rather than a community population. Furthermore, neither somatization on the SCL-90-R nor fatigue on the POMS, but rather the McLean Checklist subscale scores for the somatic symptoms of temporal lobe dysfunction, distinguished the CI from depressives in the current study. This finding is consistent with the Bell et al (1992) hypothesis of specific limbic nervous system involvement in the symptoms of chemical intolerance and sensitivity. Limbic-related complaints such as feelings of unreality and spaciness (cf., Locatelli et al 1993; Mesulam 1985) are among the most commonly reported symptoms of MCS (Miller and Mitzel 1995). Limbic structures such as amygdala and hippocampus modulate mesolimbic initiation of TDS in animals (Kalivas and Alesdatter 1993; Yoshikawa et al 1993). Initial studies support the hypothesis that CI may be an indicator of heightened vulnerability to sensitization. Bell et al have demonstrated short-term sensitization of certain physiological variables such as diastolic blood pressure (Bell et al 1997, in submission c), heart rate (Bell et al 1997a, in submission c), and plasma beta-endorphin (Bell et al 1996b) in CI elderly. The trend toward drug problem histories in the relatives of the present CI may offer further evidence for increased sensitizability (see also Bell et al 1995b, in submission b, c). In animals, genetic factors are one of the leading individual difference variables that differentiate those more likely from those less likely to sensitize and to self-administer drugs (Kalivas et al 1993). In humans, Newlin and Thomson (1991) showed that nonalcoholic sons of alcoholics can sensitize their autonomic responses to alcohol in the laboratory compared with sons of nonalcoholics. Similar to the blood pressure

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and heart rate sensitization (Bell et al 1997a, in submission b, c) and attention deficits in the CI population (Bell et al 1995c, in press a, in submission b), offspring of alcoholics also exhibit heightened cardiovascular reactivity and impaired attentional abilities related to dorsofrontal dysfunction (Harden and Pihl 1995) in addition to the increased EEG alpha activity (Ehlers and Schuckit 1991; Ehlers et al 1996). Despite these overlaps, CI consistently report low rates of use and high rates of adverse reactions to alcohol and drugs (Bell et al 1993b, 1993c, 1995a, 1996a, in press a, in submission a; Miller and Mitzel 1995); however, as do sober alcoholics (Kampov-Polevoy et al 1997), CI crave and/or eat more foods with positive hedonic properties, e.g., sweets (Bell et al 1995b; Miller 1994; Parker et al 1990) and fats (Bell et al 1997a). Small sample size and short qEEG sampling periods are major limitations of the present study. These findings require replication and extension in larger samples, preferably including four groups, i.e., depressives with and without CI, CI without depression, and normals (cf., Bell et al in submission a). To ascertain generalizability and stability of findings, the possibility of individual differences in sensitizability also raises a need for more than two sessions spaced in time for both short-term and longitudinal comparisons, using more extended qEEG sampling intervals. The differences in alpha patterns despite similarities in psychotropic use for CI and D groups make it less likely that medications could account for the current findings. Still, subsequent studies should assess completely drug-free populations. Studies of workers with occupational solvent exposures, who report high rates of chemical odor intolerance (Morrow et al 1990; Ryan et al 1988) and exhibit cognitive (Ryan et al 1988; Morrow et al 1991, 1992a, 1992b) and affective (Morrow et al 1993) dysfunctions, have also noted a) increases in resting absolute alpha (Matikainen et al 1993); b) increases in total power of multiple EEG frequencies (Orbaek et al 1988); and c) failure to habituate autonomic responses to a challenging cognitive task over periods of months to years (Morrow and Steinhauer 1995). Occupational exposures in painters and other workers, however, are generally much higher than those in MCS patients without chemically related industrial jobs. In conclusion, these data provide preliminary evidence that the subjective variable of chemical intolerance may distinguish a biologically unique subtype of depression. The CI-related affective disorders may include impaired alertness and/or variable attentional capability (Bell et al 1995c, in press a, in submission b). Vulnerability to these problems may begin in childhood, based on our low age-of-onset in this now middle-aged CI sample. This study raises the need for additional research on CI and its possible relationship not only to depression, but also to

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sensitizability (Bell 1994, 1996; Bell et al 1993a, 1993b, 1995b, in press b), specific types of cognitive dysfunction (Bell et al 1993d, 1995c, in press a, in submission b), and associated disorders such as familial substance abuse.

This research was supported by a grant from the Environmental Health Foundation.

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