A polysomnographic study of sleep disturbance in community elderly with self-reported environmental chemical odor intolerance

A Polysomnographic Study of Sleep Disturbance in Community Elderly with Self-Reported Environmental Chemical Odor Intolerance Iris R. Bell, Richard R. Bootzin, Cheryl Ritenbaugh, James K. Wyatt, Gia DeGiovanni, Tina Kulinovich, Jennifer L. Anthony, Tracy F. Kuo, Steven P. Rider, Julie M. Peterson, Gary E. Schwartz, and Kathleen A. Johnson Subjective sleep complaints and food intolerances, especially to milk products, are frequent symptoms of individuals who also report intolerance for low-level odors of various environmental chemicals. The purpose of the present study was to evaluate the objective nature of nocturnal sleep patterns during different diets, using polysomnography in community older adults with self-reported illness from chemical odors. Those high in chemical odor intolerance (n = 15) exhibited significantly lower sleep efficiency (p = .005) and lower rapid-eyemovement (REM) sleep percent (p = .04), with a trend toward longer latency to REM sleep (p = .07), than did those low in chemical intolerance (n = 15), especially on dairy-containing as compared with nondairy (soy) diets. The arousal pattern of the chemical odor intolerant group differed from the polysomnographic features of major depression, classical organophosphate toxicity, and subjective insomnia without objective findings. The findings suggest that community elderly with moderate chemical odor intolerance and minimal sleep complaints exhibit objectively poorer sleep than do their normal peers. Individual differences in underlying brain function may help generate these observations. The data support the need for similar studies in clinical populations with chemical odor intolerance, such as multiple chemical sensitivity patients and perhaps certain veterans with "Persian Gulf Syndrome." Key Words: Chemical odor intolerance, cacosmia, environment, sleep efficiency, REM sleep, geriatric, shyness, dairy BIOL PSYCHIATRY1996;40:123--133

Introduction Subjective complaints of sleep disturbance, including nocturnal insomnia, daytime sleepiness, and cognitive slowing are common symptoms both in individuals who From the Departments of Psychiatry ORB, RRB, GES, GD, TK, JMP), Psychology (RRB, GES, IRB, JKW, JLA, TFK, SPR), Neurology (GES), and Family and Community Medicine (CR, KAJ), University of Arizona Health Sciences Center, Tucson, Arizona, and the Department of Psychiatry, Tucson Veterans Affairs Medical Center, Tucson, Arizona (IRB).

© 1996 Society of Biological Psychiatry

have documentably elevated, chronic occupational exposures to various environmental toxicants (e.g., solvents) (Edling et al 1993; Lindelof et al 1992; Monstad et al 1992) and in those who report subjective illness from presumably nontoxic, low-level chemical exposures (e.g., Address reprint requests to Dr. Iris Bell, Department of Psychiatry, Tucson Veterans Affairs Medical Center, Mail Stop I16A, 3601 S. 6th Avenue, Tucson, AZ 85723. Received October 31, 1994; revised June 6, 1995.

0006-3223/961515.00 SSDI 0006-3223(95)00330-J

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solvents, pesticides, gasoline, perfumes, new carpet) (Ashford mad Miller 1991; Bell et al 1993a, b; 1994a, b; in press b; Miller 1994). In the former population, various investigators have observed increased amounts of rapideye-movement (REM) sleep in pesticide-exposed workers (Burchfiel and Duffy 1982) or increased rates of sleep apnea in solvent-exposed workers as a major factor in the sleep disorders (Edling et al 1993; Monstad et al 1992). In the latter population, however, which is heterogeneously composed of persons with controversial conditions such as multiple chemical sensitivity (MCS) (Ashford and Miller 1991; Cone and Suit 1992; Cullen 1987; Fiedler et al 1992; Meggs 1993), sick building syndrome (SBS) (Kreiss 1989; Middaugh et al 1992), chronic fatigue syndrome and fibrornyalgia (Buchwald and Garrity 1994), and recently, "Persian Gulf War syndrome" (PGS), little previous research has examined objective measures of sleep with polysomnography (May et al 1993). Polysomnography (Bliwise 1993; Carskadon et al 1976; Reynolds and Shipley 1985; Gillin et al 1985) can help to characterize the objective correlates of subjective nocturnal insomnia and daytime sleepiness and to differentiate actual from "pseudo" insomnia. Despite variability among the various populations in overall symptom patterns, the core symptom common to all persons who believe low-level chemicals can elicit their illness flares is the "cacosmia" itself. Ryan et al (1988) defined cacosmia in solvent-exposed workers as an altered sense of smell and subjective perception of illness, including but not limited to headache, nausea, or dizziness, from low-level exposures to substances such as perfume or gasoline; however, cacosmics from community and clinical samples report not only chemical sensitivities, but also markedly increased rates of concomitant food and drug intolerances (Bell et al 1993b, c, e, 1995a; Black et al 1990; Doty et al 1988; Miller 1994; Randolph 1978). Affected individuals indicate that these substances can cause the same central nervous system and systemic symptoms, including insomnia and difficulty concentrating, that they experience from low-level chemical exposures (Randolph 1978). Milk and dairy products are among the most, whereas legumes (e.g., soy) are among the least, frequent food intolerances claimed by some severely cacosmic patients who lack classical allergic (atopic, immunoglobulin E-mediated) involvement (Parker et al 1990); however, studies relying on patient self-reports of symptoms elicited by foods have produced both positive (Egger et al 1992; van de Laar and van der Korst 1992) and negative (Jewett et al 1990; Parker et al 1990; Rix et al 1984) results. No polysomnographic studies of the effects of specific foods such as milk on sleep in food- and/or chemicallysensitive adults have been done. Infants with chronic

unexplained insomnia show normalized objective sleep patterns only after dietary elimination of milk, with increased total sleep time as well as sleep stages 2 and 3 (Kahn et al 1988). Milk reexposure under controlled conditions after weeks of elimination reactivates insomnia in such children (Kahn et al 1989). An advantage of studying foods rather than ambient chemicals in adult cacosmics is the potentially greater ability, limited mainly by compliance, to include or to exclude all possible exposures to a given substance for weeks at a time at home between laboratory sessions (Ashford and Miller 1991). The effects of whole foods on sleep, especially milk, in normal and pathologic populations have received much attention in the lay media but little systematic examination in the scientific literature. In normal animals, milk placed in the small intestine induces somnolence and shortens the interval between REM sleep periods (Fara et al 1969). Although the amino acid tryptophan has often been the focus of possible mechanisms for food-induced sleepiness, Fara et al (1969) implicated the ability of fat in milk to release the peptide hormone cholecystokinin and thereby cause the sleep effects. Moreover, milk can mobilize release of endogenous central nervous system (CNS) opioids (Blass and Fitzgerald 1988) as well as add multiple exogenous psychoactive hormones, including prolactin, somatostatin, thyroid hormones, estrogen, prostaglandins, and its own opioid derivatives, beta-casomorphins (Koldovsky and Thomburg 1987; Svedberg et al 1985). Beta-casomorphin-7 in neonatal animals can increase quiet sleep and decrease active (cf., REM) sleep (Taira et al 1990). In research on human subjects, Bell et al (1976) demonstrated greater postprandial self-rated sleepiness at midday in normal young adults after ingestion of warm milk or ice cream, among various foods, than after chewing sugar-free gum and drinking an equivalent volume of water. In contrast with the insomniac infants discussed above, Brezinova and Oswald (1972) observed increased total sleep time and decreased awakenings of normal elderly adults after sleep onset following bedtime ingestion of a cereal and milk beverage. As a result, the present study compared polysomnographic sleep patterns of a nonindustrial sample, i.e., healthy retired elderly from the community, with relatively lower and higher self-ratings of cacosmia, who were originally recruited for a study of the effects of dairy and nondairy dietary constituents on sleep of shy and nonshy older adults.

Methods

Subjects Subjects were older adult, nonalcoholic (screened with the CAGE scale--Ewing 1984) volunteers of both sexes in

Sleep Disturbance in Cacosmic Elderly

good health (N = 32). They were recruited by mail and telephone a) from a mailing list of previous participants in a university-sponsored health screening in an active retirement community near Tucson (Bell et al 1993d) who had scored at least 1 standard deviation above or below the sample mean on the Social Reticence Scale (Consulting Psychologists Press, Palo Alto, CA 94306; possible range 20-100); and b) from respondents to newspaper advertisements and senior center flyers asking for shy and outgoing persons to participate in a study of dietary effects on sleep. To minimize confounds and risks from medications, known milk or soy allergies/intolerances, and metabolic disturbances, subjects taking sedative-hypnotic drugs and those with histories of lactose intolerance, anaphylactic shock, asthma in the past year, cancer, serious heart/lung/ liver/kidney disease, epilepsy, and suicidality were excluded from the study. The recruitment process did not involve mention at any time of environmental chemical sensitivity, cheminal odor intolerance (cacosmia), or related topics. A questionnaire on chemical intolerances was one of a number completed by the subjects as part of a packet during the first part of the subject screening process; acceptance or rejection as a subject was not contingent upon answers to any cacosmia-related questions. Upon completion of data collection, subjects were paid for their participation. This sample had several advantages. Shyness and cacosmia overlap in terms of self-reported increases in insomnia, gastrointestinal symptoms, rhinitis, and food, especially milk, intolerances (Kagan et al 1987; Bell et al 1993a, c, d, 1994a, b, 1995b, in press b). Shy individuals report increased cacosmia (Bell et al 1995b); and cacosmics have elevated scores for shyness in prior research (Bell et al 1993a, c, 1994a, in press b). Many skeptics of chemical sensitivity and cacosmia postulate that subjective belief systems and causal misattribution rather than objectifiable effects explain self-reported illness from low-level chemicals and foods (Sparks et al 1994; Staudenmayer and Selner 1990; Terr 1993); however, community cacosmics (10-30% of the population) report various symptoms and medical/psychiatric histories similar to those of MCS patients, but do not necessarily attribute their health problems to chemicals, foods, or drugs (Bell et al 1993a, b, c, 1994a, b, 1995a, in press b). Thus, the original recruitment procedure permitted identification of cacosmics who had no underlying agenda for the outcome of the study. Unlike many industrial workers and SBS and MCS patients, these subjects had nothing to "prove" about the effects of food on sleep or the severity of any illness. Cacosmia appears to be an individual difference trait found in both functioning and disabled populations (Bell and Schwartz in submission). Especially in view of the open nature of the food exposures, these subjects would

BIOLPSYCHIATRY 1996;40:123-133

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have no a priori belief that milk or soy could have negative impact on their health. They were not applying for disability, worker's compensation, or personal injury litigation that could bias their motivations for participation.

Procedure On initial contact, potential subjects completed the 20item Jones-Briggs Social Reticence Scale. Those who rated either -->57 for the high shy or --<36 for the low shy group were enrolled; scores had to remain in the criterion ranges (Bell et al 1993d) on repeat questionnaire administration immediately prior to their participation in the study. Additional questionnaires included the SCL-90-R (Clinical Psychometric Research, Inc., Towson, MD) (see also Morrow et al 1993), Taylor Manifest Anxiety Scale (Bendig 1956--trait anxiety), Geriatric Depression Scale (Yesavage et al 1983--self-report depression measure with no somatic symptom bias), and the Marlowe-erowne Social Desirability Scale (Crowne and Marlowe 1960). The Marlowe-Crowne is a measure of repressive defensiveness, i.e., the tendency to deny negative information about oneself, a psychological trait that some skeptics believe characterizes MCS patients (Sparks et al 1994; Staudenmayer and Selner 1990). Other measures were an Environmental Health Screening Questionnaire, including five items rated on a fivepoint frequency scale from never (1) to always (5) on illness from perfume or cologne, pesticide or insecticide, drying paint, new carpet, and car exhaust (Cacosmia Index total score was the sum of the ratings for the five chemicals, possible range 5-25--Bell et al 1993c, 1994a), the Simon et al (1990) chemical sensitivity lifestyle change questionnaire (four true/false items), a five-point Likert rating scale for frequency of "trouble sleeping'at night (1 = never; 5 = always), a checklist of physiciandiagnosed medical/psychiatric conditions, and diet history forms. They also completed the Folstein Mini-Mental State Examination (Folstein et al 1975) (inclusion criteria included a score of ->25/30) and the Cain Olfactory Identification Test (Cain et al 1988) (the 10 test items included baby powder, chocolate, cinnamon, coffee, lemon, mothballs, onion, peanut butter, Ivory soap, and Vicks VapoSteam). The rationale for the Cain test was that past research has not found differences in olfactory sensory ability between MCS patients and controls despite the apparently hyperosmic quality of cacosmia (Doty et al 1988); no previous studies have examined olfactory sensory ability in older community cacosmics. All subjects underwent an in-person medical/psychiau'ic assessment (by IRB) prior to participation in the laboratory portion of the study.

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On enrollment, subjects gave one blood sample for analysis by a commercial radioallergosorbent test (RAST) method for immunoglobulin E (IgE) and an enzymelinked immunosorbent assay (ELISA) technique for immunoglobulin G (IgG) specific antibodies to milk (Immuno Laboratories, Inc., Ft. Lauderdale, Florida 33311); these results were reported on a 0 - 6 basis for IgE and 0 - 4 basis for IgG (higher values indicate increased antibody levels). The rationale for the IgE and IgG measurements was that either or both types of antibodies have been implicated in a subset of food sensitivities, including those of insomniac infants (Kahn et al 1988), depressives (Sugerman et al 1982), and rheumatoid arthritics (van de Laar et al 1992). Other investigators have found no evidence for immunological involvement in MCS cacosmics (Jewett et al 1990; Parker et al 1990; Rix et al 1984; Simon et al 1993). Subjects then participated in an 8-week protocol involving 2 initial weeks of their customary baseline diet (with ad lib dairy products), followed by 3 weeks each of dairy-containing and non-dairy-containing diets in randomly assigned, counterbalanced order. As part of the dairy diet, subjects consumed 24 ounces per day of 1% low-fat milk and a multivitamin; as part of the nondairy diet, they consumed 24 ounces per day of a soy-based nondairy substitute product (First Alternative) and a multivitamin. Diet plans were otherwise matched for nutrient intake, including wheat gluten, on the basis of the individual's baseline diet. On the last 2 days of each of the three diet conditions (Baseline, Dairy, Nondairy), subjects underwent standardized computerized and polygraphically recorded sleep studies at the Sleep Research Laboratory in the University of Arizona Department of Psychology. Subjects were permitted to go to sleep ad lib and were awakened, if not already awake, at 7:00 AM. Electroencephalogram (EEG) electrodes were affixed at central and occipital scale sites (C3, C4, O1, and 02) using mastoid references (A1 and A2). Electro-oculogram (EOG), bipolar mentalis and submentalis chin electromyogram (EMG), and two-lead clavicle electrocardiogram (EKG) leads were employed. Leg EMG electrodes were placed on the fight and left anterior tibialis muscles. Combined nasal and oral thermistors were affixed on the upper lip to record respiratory airflow. Elastic belts with piezo-crystal sensors were placed around the chest and abdomen to record respiratory effort. A transcutaneous, infrared finger probe was attached to record pulse oximetry. All biological signals were recorded with Grass Instruments Model 8-16 EEG machines. For EEG and EOG signals, high-pass and low-pass filters were set to 0.3 Hz and 35 Hz, respectively. For chin and leg EMG channels, high-pass and low-pass filters were set to 10 Hz and 70 Hz, respectively.

I.R. Bell et al

At 1 hour before subjects' estimated bedtimes and at 0730 hours, after awakening in the morning, they consumed an 8-ounce glass of refrigerated beverage (1% lowfat milk for baseline and dairy days; First Alternative for nondairy days). Additional testing (reported elsewhere) included morning measurements of body impedance, performance on a divided attention vigilance task, and blood sampling 90 min after the morning beverages for measurement of plasma betaendorphin (see Bell et al in press a) and milk-derived beta-casomorphins (by radioimmunoassay--Hamel et al 1985). Differences from ideal weight were calculated on the basis of age, gender, height, and weight from standardized weight tables (Master et al 1960). For purposes of the present study, after completion of the data collection process, cacosmia group membership was assigned on the basis of the median split for the overall sample on the Cacosmia Index score to low chemical odor intolerance (LOCAC) (score -< 6) or high chemical odor intolerance (HICAC) (score > 6). For data analysis, demographic and questionnaire scores were initially compared using one-way analyses of variance for continuous variables and chi-square tests for categorical variables (with Yates' correction for 2 × 2 comparisons). Relationships between specific sleep variables and self-report measures were assessed with multiple linear regression. Polysomnographic records were visually scored (Rechtschaffen and Kales 1968). Scorers were trained until they had interrater reliability in excess of 0.90. Sleep scorers were blind to the dietary condition, night in the study, and any descriptive characteristics of the subjects (e.g., gender, shyness status, cacosmia status). Raw sleep data were entered in the computerized Somnibus Sleep Stage Scoring System (Houpt and Houpt; Behavioral Cybernetics, Cambridge, MA 02139). Each of the sleep variables for the six nights was analyzed using repeated measure multivariate analysis of variance (MANOVA), with cacosmia group as a between-subjects factor. The reliance on multivariate statistics for the sleep data reduced the indication for application of the Bonferroni correction for multiple comparisons. Notably, statisticians also point out the risks of making type II errors while trying to limit type I errors with the conservative Bonferroni correction, especially in exploratory work such as the present study (Rothman 1986). Statistical analyses were performed using SPSS-PC + and SPSS for Windows. Given the focus of this study on cacosmia, sleep findings were also assessed for any contribution of the original recruitment bias (high or low shyness) by using Social Reticence Scale scores as a continuous covariate in follow-up analyses. Results for shyness group per se and of diet effects will be reported elsewhere.

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Table 1. Demographic and Psychological Variables in Low and High Cacosmia Groups LOCAC (n = 15) (mean _+ SD)

HICAC (n = 15) (mean _+ SD)

Age (years) Gender (% women) Difference from ideal weight (lb.) Folstein Mini-Mental State Exam (0-30)

69.3 4- 7.0 73% 9.4 _+ 21.7 29.4 _+ 0.9

68.0 _+ 5.5 73% 11.9 4- 31.3 29.1 4- 1.2

Cacosmia Index score (5-25) Social Reticence Scale score (20-100)

5.1 -+ 0.4 53.8 -+ 26.3

11.7 4- 2.9" 52.4 _+ 22.0

8.3 4- 1.3

8.1 _+ 1.4

0.1 _+ 0.3 0.5 - 0.6 1.5 4- 1.3

0 0.7 4- 0.9 1.4 4- 1.2

204 4- 164

123 _+ 136

4.8 + 6.6 3.9 4- 3.9

5.8 _+ 6.2 6.3 -+ 4.5

22.2 _+ 4.4

17.1 _+ 5.4 b

0.13 + 0.4

0

Cain Olfactory Identification Test

(O-lO) Antimilk lgE antibodies ( 0 - 6 ) Antimilk IgG antibodies ( 0 - 4 ) Caffeinated beverages on lab days (mean #) Plasma beta-casomorphin-7 on dairy diet Geriatric Depression Scale ( 0 - 3 0 ) Taylor Manifest Anxiety (short form) ( 0 - 2 0 ) Marlowe~Crowne Social Desirability ( 0 - 3 3 ) Simon Lifestyle Change ( 0 - 4 ) Symptom Checklist 90 (revised) Depression Anxiety Phobic anxiety Interpersonal sensitivity Somatization Paranoia Psychoticism Obsessive-compulsiveness Hostility

4.6 2.2 0.2 2.9 5.5 1.3 1.6 4.5 1.3

_+ 5.8 -+ 2.7 -+ 0.6 4- 2.6 4- 5.5 _+ 1.4 + 2.0 4- 3.7 4- 1.4

7.7 3.9 0.4 6.7 6.6 2.8 2.2 8.2 2.1

-+ 6.2 -+ 4.5 -+ 0.9 -+ 5.1 b 4- 7.4 _+ 2.4 C _+ 3.9 -+ 6.8 -+ 2.2

MANOVA over the nine SCL-90-R subscales using Cacosmia Group as a factor. Group main effect: Hotellings F(9,17) = 2.8, p - .034. p < .0001; b p < .05; c .05 < p < . 10, for one-way analyses of variance and post hoc univariate F tests for MANOVA. a

Results Two women subjects did not complete the protocol because of inability to comply with dietary intake requirements. The remaining 30 subjects (mean age 68.7 _+ 6.2 years; 73% women) were divided for analyses as detailed above into LOCAC (n = 15) and HICAC (n = 15) groups. Table I summarizes the descriptive data. The LOCAC and HICAC subjects did not differ on age, gender distribution, Mini-Mental State scores, olfactory identification ability, milk-specific IgE or IgG antibodies, plasma beta-casomorphins, or scores on the Social Reticence Scale, Taylor Manifest Anxiety Scale, Geriatric Depression Scale, or the

Simon lifestyle change questionnaire. HICAC were significantly lower than LOCAC in defensiveness measured on the Marlowe-Crowne. Multivariate analysis of variance over the nine subscales of the SCL-90-R showed a significant main effect for the HICAC group (p = .034), derived primarily on post hoc univariate analyses from a significantly higher score for interpersonal sensitivity and a trend toward higher paranoia. Over all subjects, Social Reticence Scale scores were highly correlated with other measures of negative affectivity, i.e., with the Taylor Manifest Anxiety score (r = .7, p < .0001) and the Geriatric Depression Scale (r = .7, p < .0001). No subject reported a physician diagnosis of MCS, chronic fatigue syndrome, or multiple food sensitivities. Twenty-one of the 30 subjects reported no chronic medication use; and, among those taking medications, the groups did not differ systematically. Drugs included mainly antihypertensives and various vitamin/mineral supplements in their baseline diet. Groups did not differ overall or as a function of diet type on mean caffeine intake reported on the laboratory days (MANOVA p > .10, for Cacosmia Group main effects and for the group by diet interaction). HICAC rated the frequency of subjective insomnia higher than did the LOCAC, but the difference did not reach significance (HICAC: 3.1 -+ 1.0 vs. LOCAC: 2.5 -+ 1.1, F(1,28) = 2.1, p = .16). Table 2 gives the cacosmia group mean comparisons for the objective sleep measures. Over the six nights, HICAC had significantly less total sleep time (in minutes and as a percentage of total dark time, i.e., lower sleep efficiency) and lower total stage REM (percentage of total sleep period) than did the LOCAC. In turn, HICAC experienced more wakefulness (as wake after sleep onset in minutes and as higher percentage of the sleep period). HICAC also exhibited a trend toward a longer latency from sleep onset to REM sleep. Sleep latencies and sleep architecture were otherwise similar between the LOCAC and HICAC groups. Figure 1 demonstrates a significant interaction between cacosmia group membership and diet type on total sleep time (in minutes). As expected from the initial novelty of the laboratory setting, both HICAC and LOCAC groups had relatively low total sleep times on baseline diets; but the HICAC subjects also had low sleep times on the dairy diet, whereas the LOCAC subjects had more sleep On both dairy and nondairy diets as compared with their baseline diet [Hotelling's F(2,27) = 4.5, p = .02]. HICAC and LOCAC groups did not differ significantly overall on indices of sleep apnea (apneas per hour of sleep), respiratory disturbance (apneas and hypopneas per hour of sleep), or periodic leg movements (Table 2); however, the HICAC showed a trend toward their highest, whereas the LOCAC tended to have their lowest, respiratory disturbance index on the dairy diet (p = .06) (Figure 2). The

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Table 2. Means over Six Recorded Nights of Polysomnographic Variables in Low and High Cacosmia Group

General measures Total dark time (rain) Total sleep time (min) Sleep efficiency (%) W a k e after sleep onset (rain) Apnea Index (apneas/hour sleep) Respiratory Disturbance Index Periodic Limb Movement Index Latency measures Lights out to Stage 1 (min) Lights out to Stage 2 (min) Sleep onset to REM (min) Stages (% total sleep period) Stage 1 Stage 2 Stage 3 Stage 4 Slow wave (stages 3 + 4) REM Total waking Total movement

Group x Diet, p=0.06

~8

LOCAC

HICAC

(n = 15)

(n = 15)

(mean +_ SD)

(mean _+ SD)

461.1 386.3 84.0 52.8 1.4 3.9 23.9

452.6 346.3 76.8 74.9 1.1 6.5 22.8

+ ± ± ± ± ± ±

48.7 41.7 6.1 26•9 3.5 7.4 27.5

+ 37.9 ± 35.2" --_ 7.0" ~ 30.7 b ~ 1.5 ± 12.8 + 25.6

13.6 47.7 5.6 2.1 7.7 18.1 15.4 1.3

_ 10.1 _+ 9.2 _ 5.4 ~ 3.3 + 7.3 + 4.5 + 6.8 ± 1.0

12.1 ± 6,5 15.9 ± 7.9 116.4 + 46.5" 13.4 45.1 3.8 3.6 7.4 15.0 22.8 1,9

___ 13.6 + 12.9 + 4.2 + 5.6 ± 7.0 ± 3.1 b ± 7.8" ±_ 3.0

above interaction between group and diet on total sleep time remained significant even after covarying for respiratory disturbance index [F(2,55) = 3.4, p = .04]. All of the above findings remained significant after repeating the analyses with Social Reticence Scale score as a covariate, with the exception of the wake after sleep onset observation, which became a trend (p = .09). 400,

......................

; •

380 . . . . . . . . .

~. ~..i ...............

o

E37e,

-

~-i. . . . . . . . . . .

=

i

I 360

340

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

/

Baseline

..................

NonDairy

Ill

53 ~,

-

Baseline

I

1

NonDairy

Dairy

Diet Type ,! ~,- LOCAC --,=-HICAC I

10.1 _ 6.1 13,9 _+ 9.0 90.2 _+ 29.0

Sleep efficiency = (total sleep time/total dark time) x 100. Respiratory Disturbance Index reflects the sum of apneas and hypopneas per hour of sleep (a value of >--5 can have clinical significance)• Repeated measure multivariate MANOVAS over six-night values for each variable, using Cacosmia Group as a factor; probability of group main effects: ap < .0l; bp < .05; c.05 < p < .10.

390

~7

"--_11113

.............

Dairy

Figure l. Cacosmic elderly have lowest total sleep ttme baseline and dairy diets.

on

F i g u r e 2. H i g h e r r e s p i r a t o r y d i s t u r b a n c e elderly on milk.

index in cacosmic

Average total sleep time over all diets and days tended to be negatively correlated with self-reported difficulty sleeping over all subjects (r -- - . 3 , p = . 11). Groups did not differ significantly for beta-casomorphin-7 levels during any of the diets (main effect for Group, p = .6; Group X Diet interaction, p = .4). Table 3 shows the mean scores for the Profile of Mood States (POMS) subscales by group at bedtime in the laboratory during each diet. The significant main effects for cacosmia group on multivariate repeated measures analyses of variance for each of the subscales demonstrated that HICAC had more Confusion-Bewilderment (self-perceived cognitive inefficiency), Anger-Hostility, and Tension-Anxiety than did L O C A C throughout the study. None of the Cacosmia Group × Diet interactions was significant. Confusion-Bewilderment showed a trend toward the lowest score for HICAC on Nondairy and for L O C A C on Dairy. No POMS subscales correlated significantly with their respective total sleep times for the same night. The only significant correlation for REM% indicated that greater Confusion-Bewilderment was associated with less REM% on the Dairy diet (r = - . 3 8 , p = .036); this finding would be nonsignificant with the application of the Bonferroni correction (requiring p < .003). Our previous studies have suggested a low correlation in young adults of cacosmia with depression (e.g., r = . 15, n = 794, p = .000), anxiety (r = .18, n = 794, p = .000), somatization (r ~ .24, n = 795, p = .000), and the general severity index (r = .18, n = .782, p = .000) of the SCL-90-R (Bell et al in press b). None of the parallel correlations reached significance in the present study with its much smaller sample size (cacosmia with SCL-90-R depression: r = .35, p = .07; anxiety: r = .23, p = .2; somatization: r = .03, p = .9; general severity index: r = .33, p = .097). It is nevertheless a plausible hypothesis

Sleep Disturbance in Cacosmic Elderly

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Table 3. Means (_+ Standard Deviations) for Profile of Mood States Subscales by Group and Diet (Averaged over Two Nights per Diet) Baseline HICAC

Nondairy LOCAC

HICAC

Dairy LOCAC

HICAC

LOCAC

Depression ~

4.9 -+ 4.7

1.6 _+ 2.2

4.3 -+ 6.5

1.8 + 2.9

4.9 _+ 6.7

1.5 _+ 2.6

C o n f u s i o n - b e w i l d e r m e n t b'c

5.3 -+ 3.0

3.5 -+ 2.7

4.6 +- 2.7

2.9 ± 2.2

5.3 -+ 3.0

2.5 ± 1.7

Anger-hostilityb Tension-anxiety b

5.6 + 5.5 6.0 ± 3.8

2.1 _+ 3.0 3.0 -+ 2.4

3.1 + 3.3 5.1 -+ 3.8

1.8 _+ 2.6 2.1 -+ 1.9

4.3 _+ 4.6 5.4 -+ 4.1

1.4 _ 1.9 2.1 -+ 2.3

5.8 -+ 5.4 17.6 -+ 5.5

7.2 -+ 6.2 21.8 + 7.4

4.9 -+ 5.4 18.2 -+ 6.8

6.2 ± 5.7 21.9 -+ 7.7

5.7 -+ 6.2 16.9 + 7.2

5.8 ± 4.4 22.7 -+ 6.7

Fatigue Vigor ~

Compare: mean POMS raw scores for patients with psychophysiological disorders: Depression 14.0; Confusion 8.4; Anger 8.1; Tension 15.9; Fatigue 8.1; Vigor 12.3. [Source: McNair DM, Lorr M, Droppleman LF (1981): EDITS Manual for the Profile of Mood States. San Diego: Educational and Industrial Testing Service]. Main effects for HICAC vs. LOCAC Group overall: ~' .05 < p < .10; bp < .05. Interaction of Cacosmia Group × Diet: " .05 < p < .10.

that the variable of cacosmia itself might be explained by psychological variables and thereby obscure the role of such factors in the sleep findings. To assess this possibility, two separate stepwise multiple regression analyses used Cacosmia Index score as the dependent measure, (i) with the two subscales of the SCL-90-R on which groups differed (Interpersonal Sensitivity and Paranoia), the Mariowe-Crowne Social Desirability Scale, the Geriatric Depression Scale, and the Taylor Manifest Anxiety Scale from the present study as independent measures (prelaboratory, screening status); or (ii) with all six mean POMS subscale scores over the six sleep laboratory nights as independent measures (in-laboratory status). In (i), the SCL-90-R Interpersonal Sensitivity subscale accounted for 26% of the variance in the Cacosmia Index (beta = .51, t = 2.7, p = .01); none of the other screening scales entered the equation. In (ii), the POMS Confusion-Bewilderment subscale accounted for 35% of the variance in the Cacosmia Index (beta = .99, t = 3.9, p = .0006); none of the other POMS subscales entered the equation. To assess the ability of cacosmia versus specific psychological variables to account for the sleep findings, two separate multiple linear regression analyses with mean total sleep time (in minutes) and mean REM (percentage sleep period) averaged over the six nights as dependent variables were performed for all subjects in the sample. Each regression forced in the Social Reticence Scale, SCL-90-R Interpersonal Sensitivity subscale, and mean POMS Confusion-Bewilderment subscale scores, followed by the Cacosmia Index, as independent measures. The rationale for selection of independent measures derived from the original recruitment procedure in the case of shyness (Social Reticence Scale) and from the results of the regressions above using Cacosmia Index as dependent measure. None of the psychological variables accounted for a significant portion of the variance in total sleep time (all p > .2) or REM% (all p > .8). In contrast, the Cacosmia Index accounted for 23% of the variance in

mean total sleep time (beta = - . 4 7 , t = - 2 . 0 , p = .05) and 21% of the variance in mean REM% (beta = - . 5 1 , t = - 2 . 2 , p = .04).

Discussion The polysomnographic data demonstrate objective sleep disturbance in cacosmic subjects from this sample. The lower sleep efficiency in HICAC than in LOCAC elderly represents a potential sleep maintenance problem. In addition, the decreased REM percent and the trend toward longer rather than shorter REM onset latency suggests that the sleep pattern of elderly cacosmics differs objectively from that of major depressives (Reynolds and Shipley 1985) or of workers with occupationally elevated levels of organophosphate pesticide exposure (Burchfiel and Duffy 1982). The trend toward increased respiratory sleep problems on Dairy in the HICAC subjects is parallel to previous reports of sleep apnea in solvent-exposed workers (Edling et al 1993; Monstad et al 1992). The lack of effect on non-REM sleep stages in this study also contrasts with the findings of Kahn et al (1988, 1989) in insomniac children with milk intolerance. These observations, together with the HICAC subjects' lack of other disturbances of sleep architecture, indicate a specific pattern of arousal relative to their LOCAC peers; however, the HICAC subjects in this study were only marginally more troubled with subjective sleep disturbance. Whether or not the data will have parallels within clinically ill cacosmic populations who complain of insomnia and blame chemicals and foods for the symptom remains to be tested. Anxiety (Nicholson and Pascoe 1990), preclinical Alzheimer's disease (Bahro et al 1993; Bell et al 1993b), and/or stimulant substances (Trampus et al 1993) could contribute to such a sleep pattern. Contrary to the assertion of certain skeptics of MCS (Staudenmayer and Selner 1990), the finding of lower Marlowe-Crowne scores in the present HICAC group would suggest a capacity to admit

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to psychopathological disturbances (Lane et al 1990) rather than to deny negative information about themselves. It is possible that the stress of the laboratory sessions (sleeping overnight in a university laboratory) brought out a correlation between cacosmia and mood variables on the POMS that was absent under the less stressful screening condition when subjects completed the SCL-90-R. Alternatively, the POMS may be more sensitive than the SCL-90-R to mood disturbance in nonclinical samples of cacosmics; however, although POMS (but not SCL-90-R) measures of anxiety and depression differed between the present HICAC and LOCAC groups, the mood scores did not correlate with the objective sleep data. The emerging evidence for a relationship between cacosmia and cognition may be a valuable clue for further research (Ryan et al 1988; Bell et al 1992). The present groups did not differ in global cognitive ability on the screening Folstein Mini-Mental Examination; however, the Confusion-Bewilderment subscale from the POMS explained over a third of the variance in the Cacosmia Index and correlated negatively with REM%. Furthermore, the present HICAC subjects exhibited an objective slowing of reaction times during a divided attention task performed after sleeping in the laboratory (Bell et al in submission). Difficulty concentrating and/or remembering is a major self-reported symptom of MCS, SBS, and chronic fatigue syndrome (Buchwald and Garrity 1994; Miller 1994). Notably, Ryan et al (1988) originally found that cacosmia accounted for 31% of the variance in verbal learning and 20% of the variance in immediate visual reproductions tests on neuropsychological assessment of solvent-exposed workers. We subsequently observed that Cacosmia Index accounted for 22% of the variance in the delayed verbal free-recall portion of the Folstein and 33% of the variance in recognition memory on the Alzheimer Disease Assessment Scale (ADAS) in elderly depressed outpatients, a cognitive pattern distinct from that usually seen in depression alone (Bell et al 1993f). The results of the current regression analyses also suggest that the construct of cacosmia as measured by the Cacosmia Index has features beyond those simply of negative affect or somatization, at least in its association with the poorer sleep quality of the older adults in this study. Another potential cause of the polysomnographic picture could be stimulant substances such as caffeine or amphetamines or the stimulant effects of exogenous opioids from milk; however, neither the cacosmia nor the shyness group reported any differences in caffeine intake on the laboratory days, and no subject reported use of prescription, over-the-counter, or recreational stimulants. While it is possible that the HICAC group exhibited a heightened or amplified reaction (Bell 1995a; Bell et al 1992, 1993b) to the same amount of caffeine or to the

comparable levels of opioid beta-casomorphin-7 as found in the LOCAC group (cf. Deroche et al 1992), the present design does not permit determination of specific environmental factors that may explain the sleep differences. In support of possible sensitization of responsivity to some environmental element(s) from the study is the finding of elevated plasma beta-endorphin in these same subjects (see Bell et al in press a). Increased beta-endorphin is usually a marker for activation adrenocorticotropic hormone and the hypothalamic-pituitary-adrenal axis, and glucocorticoids are necessary for the development of amplified (sensitized) responses to stress and stimulant and opioid substances (Deroche et al 1992). Bell et al (1992, 1993b, 1994a; Bell 1994a, b; Bell and Schwartz in submission) previously proposed that cacosmics have a heightened capacity for time-dependent sensitization (TDS) to environmental substances and stressors. TDS is a form of neurobehavioral learning, i.e., the progressive amplification of responses by the passage of time between successive, intermittent exposures to a given agent (Antelman 1988; Antelman et al 1980, 1992; Caggiula et al 1989; Hooks et al 1992; Kalivas et al 1986, 1993; Post 1980, 1992; Snyder-Keller 1991; Sorg and Kalivas 1991). In contrast with the Kahn et al (1988, 1989) studies of insomnia in milk-intolerant children, the lack of group differences for both IgE and IgG milk-specific antibodies in this study tends to rule out humoral immunological mediation per se for the present diet effects on sleep. Self-reported intolerance for milk and milk products, among many other common foods, is a frequent symptom not only of MCS patients (Black et al 1990; Doty et al 1988), but also of the most severely ill cacosmics among college student (Bell et al 1993c) and community elderly (Bell et al 1993b) survey samples. In contrast, cacosmics with known milk intolerances would have been excluded from participation in this study. When meeting the inclusion criteria for this study, the present subjects reported routine use of dairy products in their customary diets. The 3-week durations of the dairy and nondairy diets should have facilitated obtaining a picture of relatively chronic as opposed to acute effects of the different dietary conditions. These data have important limitations. First, the absolute sizes of several group differences were small and require replication in larger samples with mixed age populations. They do not necessarily provide readily applicable objective indicators of "valid" versus "invalid" claims of susceptibility to low-level chemicals for individual clinical patients. The polysomnographic data are not specific to cacosmia; each of the elements is a component of sleep disturbance in other conditions (Bootzin et al 1993). Second, the cacosmic subjects in this study were by design not clinically ill MCS or SBS patients, and the present HICAC group's mean Cacosmia Index score (12)

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was six points lower than that of the HICAC community elderly subjects in a recent Bell et al study (1994a), who, unlike the present H I C A C group, showed many significant medical history and psychological scale differences from noncacosmics. It is therefore notable that the present H I C A C and L O C A C subjects differed significantly on sleep measures at all. For future research, these findings imply a potential sensitivity of polysomnography to subtle differences in the central nervous systems of HICAC versus L O C A C individuals. The size of the group differences in total sleep time, especially on the dairy diet, were in a potentially clinically significant range, even though the H I C A C group did not perceive themselves with excessively disturbed sleep. It would be essential to replicate and extend the current study, looking at the same sleep parameters in more extremely cacosmic patients with sleep and food

intolerance complaints (e.g., in MCS patients, whose Cacosmia Index mean score is 2 2 - - B e l l et al 1995a). Nonetheless, it is useful to have the current data from a nonclinical sample without inherent biases or attribution beliefs as a context for future studies, especially for prospective studies of risk factors for development of MCS. In conclusion, objective sleep measures indicate a relative sleep disturbance involving lower total sleep time and REM as well as increased waking in community elderly with moderate levels of cacosmia. The mechanisms and implications of the findings for clinical populations o f cacosmics are currently undetermined.

This research was supported by a grant from the National Dairy Board administered in cooperation with the National Dairy Council and in part by BRSG grant (University of Arizona) 2S07 RR05675-23 (PI-IRB).

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