Psychological Stress Perturbs Epidermal Permeability Barrier Homeostasis: Implications for the Pathogenesis of Stress-Associated Skin Disorders

Background  A large number of skin diseases, including atopic dermatitis and psoriasis,appear to be precipitated or exacerbated by psychological stress. Nevertheless,the specific pathogenic role of psychological stress remains unknown. In 3different murine models of psychological stress, it was recently shown thatpsychological stress negatively impacts cutaneous permeability barrier functionand that coadministration of tranquilizers blocks this stress-induced deteriorationin barrier function.

Objectives and Methods  The relationship between psychological stress and epidermal permeabilitybarrier function was investigated in 27 medical, dental, and pharmacy studentswithout coexistent skin disease. Their psychological state was assessed with2 well-validated measures: the Perceived Stress Scale and the Profile of MoodStates. Barrier function was assessed simultaneously with the stress measuresat periods of presumed higher stress (during final examinations) and at 2assumed, lower stress occasions (after return from winter vacation [approximately4 weeks before final examinations] and during spring vacation [approximately4 weeks after final examinations]).

Results  The subjects as a group demonstrated a decline in permeability barrierrecovery kinetics after barrier disruption by cellophane tape stripping, inparallel with an increase in perceived psychological stress during the highervs the initial lower stress occasions. During the follow-up, presumed lowerstress period, the subjects again displayed lower perceived psychologicalstress scores and improved permeability barrier recovery kinetics, comparableto those during the initial lower stress period. Moreover, the greatest deteriorationin barrier function occurred in those subjects who demonstrated the largestincreases in perceived psychological stress.

Conclusion  These studies provide the first link between psychological status andcutaneous function in humans and suggest a new pathophysiological paradigm,ie, stress-induced derangements in epidermal function as precipitators ofinflammatory dermatoses.

ALTHOUGH psychological stress appears to be capable of provoking, exacerbating,and propagating disease,^1-3the possible causal relationship is obscured, at least in part, because chronicdisease itself can lead to an increase in perceived stress. Moreover, theinfluence of psychological stress on disease is often perceived as being eithertoo subjective or nonquantifiable for scientific assessment.⁴Yet, a number of studies point to a possible pathogenic link between psychologicalstress and disease. For example, sustained psychological stress is associatedwith alterations in both humoral and cellular immune responses.^5-12Furthermore, there is increasing evidence that psychological stress can influencethe progression and survival of patients with cancer.^8,13-16Likewise, reduced psychological stress appears both to decrease medicationrequirements and to improve organ function in systemic inflammatory disorders.¹⁷

Among dermatoses, atopic dermatitis,^18-21psoriasis,^22-27and a variety of other dermatoses are anecdotally linked to psychologicalstress.^2,24,28-30Psychological stress also is associated with delayed wound healing in bothhumans³¹ and a murine model.³²It also is widely accepted that optimal management of these skin conditionsrequires consideration of coexistent emotional factors.²⁰Accordingly, stress-reduction techniques, such as meditation, biofeedback,and hypnosis, may benefit some patients with these disorders.^20,33-37

It is noteworthy that some of the most common skin disorders that arecommonly associated with increased psychological stress, eg, psoriasis, eczema,and healing wounds,³⁸ are characterized by defectivecutaneous permeability barrier function. For example, even the apparentlyuninvolved skin of patients with atopic dermatitis demonstrates increasedtransepidermal water loss (TEWL), and barrier function deteriorates stillfurther in involved skin sites.^39,40Psoriatic lesions also display abnormalities in TEWL,^41,42and the severity of lesional phenotype in psoriasis correlates directly withthe extent of the barrier abnormality.⁴³ Recentstudies suggest that a barrier abnormality, coupled with epidermal injury,provokes or sustains these cutaneous disorders through activation of an epidermalinitiated cytokine cascade.^44,45

Our laboratory has explored the potential pathogenic link between psychologicalstress and permeability barrier homeostasis. In 3 different murine modelsof psychological stress, Denda et al^46,47recently demonstrated defects in barrier function that were reversed by thesystemic coadministration of anxiolytic agents. In the present study, we assessedwhether increased levels of psychological stress in medical, dental, and pharmacystudents are paralleled by alterations in permeability barrier homeostasis.We found that increased psychological stress during examination periods, awell-accepted stress model, is associated with a reversible deteriorationin transcutaneous water permeability. These findings point to a potentialpathogenic link between psychological stress, permeability barrier homeostasis,and the induction, exacerbation, and propagation of inflammatory skin disorders.

Twenty-seven students who were randomly chosen from a larger group ofstudents attending the University of California, San Francisco, School ofMedicine, Pharmacy, or Dentistry provided informed consent to participateas paid volunteers in a study on the effects of psychological stress on permeabilitybarrier function in normal skin. The study subjects, who ranged in age from23 to 27 years (mean age, 24.4 years), represented a broad cross section oftheir respective student bodies.

The subjects were in good health and free of preexisting primary skindisease, and none was receiving sedatives, antidepressants, psychotherapy,or exogenous steroid hormones (however, 12 of the 21 women were taking oralcontraceptives). Since prior studies showed that barrier recovery kineticsare not affected by sex or race,⁴⁸ no subjectswere excluded based on these criteria.

We assessed permeability barrier function in parallel with completionof 2 standard self-report inventories for psychological stress at 3 occasions:(1) an initial period of presumed lower stress (LS1), ie, shortly after returnfrom winter vacation (January 1999); (2) a period of presumed higher stress(HS), approximately 4 weeks later, during final examination week (February1999); and (3) a recurrent period of presumed lower stress (LS2), approximately4 weeks after the HS period, shortly after return from spring vacation. Becauseof scheduling difficulties, only a limited number of students (n = 17) wereavailable for reexamination at the LS2 period. These students did not differfrom the group as a whole, as examined during the other 2 periods. Becauseof prolonged cold weather during the winter of 1999, both outdoor temperaturesand humidity levels remained comparable in San Francisco, from January throughmid-March 1999.

The extent of perceived psychological stress and related anxiety wereassessed using 2 self-report measures: the Profile of Mood States (POMS) andthe Perceived Stress Scale (PSS). The POMS is a 65-point, descriptive ratingscale that identifies and assesses transient fluctuations in mood state.⁴⁹ The POMS consists of 6 individual subscales: Tension-Anxiety,Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, andConfusion-Bewilderment. The total score of the POMS, referred to as total mood disturbance, represents a summation of the 6subscale scores. In contrast, the PSS is a 14-item scale that assesses globalperceptions of psychological stress, and measures the extent to which thesubject appraises situations in his or her life as unpredictable, uncontrollable,and/or overloading.⁵⁰ Both measures are widelyemployed, have strong normative data, and are psychometrically credible interms of their reliability and validity. Moreover, there is strong evidencefor their validity and usefulness for the measurement of psychological experiencesthat together or separately reflect psychological stress. The PSS and thePOMS were administered to subjects at each of the 3 designated time points,immediately prior to assessment of permeability barrier function (see below).For both instruments, higher scores indicate greater levels of psychologicalstress. Since students in all 3 professional schools (medical, dental, andpharmacy) exhibited comparable changes in stress during the LS1-HS-LS2 intervals,subsequent analyses considered the group as a unit.

Students kept their arms and forearms free of topical emollients forat least 1 week before each testing period. The LS1 and LS2 measurements wereobtained on the nondominant forearm, and the HS assessments were obtainedon the dominant forearm to avoid any residual effects of tape stripping. Inpreliminary studies, barrier recovery was found to be similar on the dominantand the nondominant forearms. Using an evaporimeter (Servo Med; Varberg, Sweden),basal TEWL was assessed at 3 sites on the volar surface of the forearm atdistances between 4 and 10 cm below the antecubital fossa. Measurements wereobtained in a temperature-controlled room (24°C) and were recorded ingrams per square meter per hour.⁵¹ Relativehumidity ranged between 31% and 45%, and atmospheric pressure ranged from7.1 to 11.6 mm Hg during measurement periods. Each of the 3 sites was individuallydisrupted by a minimally invasive, nonpainful method, ie, sequential applicationsof cellophane tape (Tuck; Tesa Tuck Inc, New Rochelle, NY). Transepidermalwater loss rates were assessed over the same sites after each group of 5 successivetape strippings until a TEWL level of 20 to 30 g/m² per hour wasattained (a total of 15 or 20 strippings was required in all cases). The TEWLthen was assessed over each of the 3 sites at 0, 3, 6, and 24 hours afterbarrier disruption. The 2 sites that displayed TEWL values closest to eachother were used for further data analysis (see below). Data from the mostproximal vs the most distal sites presumably differed more because of knowndifferences in barrier function over proximal vs distal forearm skin.

Since we used repeated measures on the same subjects, we used multivariateanalysis of variance to test whether (1) perceived stress increased duringfinals and (2) skin barrier recovery at 3, 6, and 24 hours differed betweenthe HS period and both LS periods. If significant main effects were detected,then post hoc t tests were conducted to determinethe source of these differences. Correlations were computed to show that changesin perceived stress (as measured by the POMS and the PSS) from LS1 to HS areassociated with changes in 3-hour skin barrier recovery from LS1 to HS. Arandom regression analysis was conducted to determine whether HS POMS subscalescores predicted 3-, 6-, and 24-hour skin barrier recovery at LS1 and HS afterLS1 POMS subscale scores were controlled for.

Psychological stress levels and permeability barrier function were assessedfirst in all 27 subjects shortly after their return from winter vacation,the LS1 period. To test the hypothesis that the perceived psychological stressof examinations results in decompensation of permeability barrier homeostasis,we reevaluated the same parameters in the same subjects 6 weeks later, ie,during final examination week, the HS period. During the HS period, the subjectsas a group perceived a significant increase in psychological stress relativeto the LS1 period on both the POMS and the PSS (Figure 1; P<.001 and P<.05 for the POMS and the PSS, respectively). Moreover, the increasesin stress scores extended to all subscales of the POMS; ie, most subjectsreported significantly higher levels of anger, confusion, depression, fatigue,tension, and reduced vigor (Table 1; P≤.02). We also examined perceived levels of stressand barrier repair approximately 4 weeks later, after the students had returnedfrom spring vacation. Seventeen of the original 27 students agreed to returnfor this third evaluation (LS2). On both the PSS and the POMS, these studentsdisplayed psychological stress levels that were significantly lower than thoserecorded during the HS period (Figure 1; P<.05 and P<.001 for thePSS and the POMS, respectively). In fact, stress levels, as measured by bothinstruments, returned to levels similar to those of the LS1 period (Figure 1). Moreover, all 6 subscales of thePOMS also demonstrated significantly reduced scores during the LS2 periodcompared with the HS period (Table 1; P≤.01 for each component).

We simultaneously assessed permeability barrier homeostasis in thesesubjects. Under basal conditions, ie, prior to experimental disruption bytape stripping, there were no differences in permeability barrier functionat the LS1, HS, or LS2 period and very low intersubject and intrasubject variability(not shown). Similarly, barrier integrity, as measured by the number of tapestrippings required to disrupt the permeability barrier to less than 20 g/m² of water loss, did not differ significantly among subjects under HSvs LS. However, in contrast to basal TEWL levels, after an acute insult (tapestripping), repeated-measures analysis revealed significant changes in therates of barrier recovery across the 3 periods. Post hoc analysis revealedthat barrier recovery slowed significantly at 3, 6, and 24 hours in the subjectsas a whole during the HS period compared with recovery rates during both LS1and LS2 periods (Figure 2; F = 18.87; df = 12.2; P<.001). In contrast,there were no significant differences at these 3 time points between the LS1and the LS2 periods. The greatest differences in rates of barrier recoverywere at the 3-hour point during the HS period vs the LS1 period. Thus, anincrease in perceived psychological stress was associated with delayed barrierrecovery after acute permeability barrier disruption in the subjects as agroup.

To further assess whether permeability barrier homeostasis is influencedby psychological stress, we next measured permeability barrier homeostasisduring the LS2 period. As seen in Figure 2, the kinetics of recovery returned to levels comparable to thoseof the LS1 period. These findings suggest that the apparent adverse effectsof examination-induced psychological stress on permeability barrier homeostasisare reversible during a subsequent low-stress occasion. Taken together, theseresults show a negative association between perceived psychological stressand permeability barrier homeostasis.

We then examined the relationship of changes in the level of stresswith changes in barrier homeostasis from the LS1 to the HS period. As shownin Figure 3, there was a strong correlationbetween increased stress levels and decreased barrier recovery rates (at 3hours) for the POMS (r = −0.42; P = .03), and a lesser correlation for the PSS, which did not reachstatistical significance (r = −0.33; P≤.10). Thus, the subjects who demonstrated the greatestincrease in perceived psychological stress also displayed the greatest abnormalityin barrier recovery rates.

Finally, to measure the effects of alterations in psychological stresson skin barrier recovery, we performed random regression analyses that tookinto account baseline (LS1) psychological stress, as assessed by the POMSsubscales during the LS1 period, and skin barrier recovery. The dependentvariables were 3-, 6-, and 24-hour skin barrier recovery at LS1 and HS. TheHS POMS Tension and Vigor subscales (P = .05 and P = .01, respectively) significantly predicted a delayin skin barrier recovery.

Recent studies in rodents found that imposition of 3 unrelated formsof psychological stress provokes an abnormality in permeability barrier homeostasis.^46,47 The present study is the first to findin humans that a decline in permeability barrier homeostasis parallels thesuperimposed stress of taking examinations. In the animal models, coadministrationof tranquilizers with stressors normalized permeability barrier function.⁴⁶ It is therefore plausible that the changes in psychologicalstress were responsible for the decline in barrier function demonstrated inthe present study. This conclusion is further supported by the observationthat those subjects who demonstrated the greatest increase in psychologicalstress by both the POMS and the PSS displayed the greatest impairment in barrierfunction. Moreover, barrier function returned to normal coincident with areduction of psychological stress in both assays during a subsequent vacationperiod. Furthermore, both psychological instruments that we used demonstratedsubstantial evidence of validity, because the mean responses (and the subscalesof one of them, the POMS) changed exactly as we hypothesized they would duringboth the LS and the HS periods. Yet, we do not know whether other unrelatedor less stressful stimuli would produce similar functional alterations. Thesefindings also could not be attributed to seasonal fluctuations, since neithertemperature nor humidity levels changed during the study period, and theycould not be explained by other differences among subjects, since they servedas their own controls. Furthermore, observer bias probably did not influencethese results, because each site on each subject was tape stripped equivalentlyat all time points. Finally, it is important to note that basal permeabilityrates did not change in these subjects, even with concurrent increases inpsychological stress. Thus, these studies demonstrate the importance of dynamic(in this case, the kinetics of barrier recovery), rather than static measures,to unearth potentially important differences in cutaneous function.^48,52

Some investigators believe that stress-induced release of neuroimmunesubstances adversely influences cutaneous homeostasis through activation ofimmunologic/inflammatory processes in deeper skin layers.^2,30,53However, recent studies support an alternate or parallel pathway, ie, thatstress adversely affects permeability barrier homeostasis by increasing systemicglucocorticoid levels. The following observations support this scheme: (1)in both rodents⁴⁷ and humans,^54-56the induction of psychological stress is associated with increased endogenousglucocorticoid production; (2) the adminstration of systemic glucocorticoidsadversely affects barrier homeostasis⁴⁷ andepidermal cell proliferation⁵⁷ in rodents; and(3) the coadministration of the steroid hormone receptor antagonist RU-486,along with psychological stressors, blocks development of the barrier abnormality,⁴⁷ further suggesting that glucocorticoids play an importantrole in mediating the adverse effects of stress on the skin. Other investigatorshave also shown that antagonism of glucocorticoid action reverses a psychologicalstress–induced delay in wound healing in rodents.³²Finally, the potential relevance of increased glucocorticoid production orresponsiveness for disease pathogenesis is supported further by the presenceof elevated serum cortisol levels in patients with psoriasis during acuteexacerbations²⁵ and by the clinical observationthat exogenous steroids frequently trigger flares of both psoriasis and atopicdermatitis.⁵⁸ Yet, serum and salivary cortisollevels do not always change with altered psychological stress in humans, despitesignificant outcome differences.^59-63In summary, substantial evidence supports a role for glucocorticoids in thestress-induced deterioration of barrier homeostasis, but the mechanisms bywhich glucocorticoids effect barrier homeostasis remain to be elucidated.

The peripheral nervous system and the skin are intimately connectedvia free nerve endings that extend to the epidermis.^64-66Because these afferent nerves are thought to serve as neurosecretory effectors,^67,68 descending autonomic fibers could antidromicallyrelease neuropeptides within or near the epidermis during times of increasedpsychological stress.^30,53,69A pathogenic role for neuropeptides is supported by (1) the observations thatboth substance P and vasoactive intestinal peptide levels change in the involvedskin of atopic dermatitis and psoriasis^70-75;(2) both of these neuropeptides are known keratinocyte mitogens^53,76-78;and (3) cutaneous nerves may activate Langerhans cells.^66,79Conversely, topical applications of capsaicin, which depletes neuropeptidesfrom primary sensory neurons,⁸⁰ parenteral administrationof somatostatin, a neuropeptide that inhibits the release of peptide hormonesor peripheral nerve reaction,⁸¹ and peripheralnerve resection⁸² improve lesion severity inpsoriasis.

The clinical relevance of our observations relates to the potentialrole of psychological stress-induced perturbations in the initiation or aggravationof skin diseases. Several of these disorders, including such common conditionsas atopic dermatitis, contact dermatitis, and psoriasis, are anecdotally provokedby enhanced psychological stress. Moreover, these disorders also are oftentriggered, sustained, or exacerbated by external physical insults to the epidermis.^45,46 These insults, in turn, are known tolead to enhanced synthesis and release of cytokines from the epidermis.^44,45,83 Moreover, epidermalhyperplasia, Langerhans cell activation, and inflammation develop rapidlyfollowing these acute insults.^84-86Thus, psychological stress could change the threshold for physical insults(eg, the Koebner phenomenon in psoriasis), or it could prolong the recoveryfrom such insults, resulting in enhanced epidermal mediator production. Thenet effect would be a lowered threshold for disease induction, or interferencewith disease resolution (Figure 4).^44,45 Despite the fact that the responsiblepathogenic signaling mechanisms in humans remain speculative, these studieshave important implications for the primary and ancillary management of diversedermatologic disorders, such as dishydrotic eczema, psoriasis, atopic dermatitis,contact dermatitis, and wound healing, all of which are characterized by barrierdysfunction. If the results of this pilot study are confirmed in subsequentcohorts of subjects, they would provide a potent rationale to include stress-reductionmeasures in the management of many common skin conditions.⁸⁷

Accepted for publication July 5, 2000.

This work was supported by grants AR 19098, AR39369, and AR01962 (K08)from the National Institutes of Health, Bethesda, Md; by the Medical ResearchService, Veterans Administration, Washington, DC; and by an unrestricted grantfrom Estée Lauder Inc, Melville, NY.

Ray Rosenman, MD, provided thoughtful advice, feedback, and editorialassistance, and Sue Allen provided able administrative and editorial assistance.

Corresponding author: Peter M. Elias, MD, Dermatology Service (190),Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121(e-mail: eliaspm@itsa.ucsf.edu).