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January 2001

Psychological Stress Perturbs Epidermal Permeability Barrier HomeostasisImplications for the Pathogenesis of Stress-Associated Skin Disorders

Author Affiliations

Copyright 2001 American Medical Association. All Rights Reserved.Applicable FARS/DFARS Restrictions Apply to Government Use.2001

Arch Dermatol. 2001;137(1):53-59. doi:10.1001/archderm.137.1.53

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 al46,47recently 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.

Subjects and methods
Experimental subjects and study design

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.

Psychological stress assays

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.

Measurements of permeability barrier homeostasis

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.

Analytical methods

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.

Perceived stress during the different periods

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).

Figure 1.
A,Total mood disturbance on theProfile of Mood States (POMS). B, Mean Perceived Stress Scale (PSS) scoresfor students during the indicated psychological stress period. The P values refer to the results of the post hoc tests. LS1 indicateslow stress 1; HS, high stress; and LS2, low stress 2 (see the "ExperimentalSubjects and Study Design" subsection of the "Subjects and Methods" sectionfor further explanation of the pyschological stress periods).

A,Total mood disturbance on theProfile of Mood States (POMS). B, Mean Perceived Stress Scale (PSS) scoresfor students during the indicated psychological stress period. The P values refer to the results of the post hoc tests. LS1 indicateslow stress 1; HS, high stress; and LS2, low stress 2 (see the "ExperimentalSubjects and Study Design" subsection of the "Subjects and Methods" sectionfor further explanation of the pyschological stress periods).

Change Over Time in the POMS Subscale Scores*
Change Over Time in the POMS Subscale Scores*
Barrier recovery during the different periods

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.

Figure 2.
Mean percentage of permeabilitybarrier recovery at 3, 6, and 24 hours for students during the indicated psychologicalstress period. LS1 indicates low stress 1; HS, high stress; and LS2, low stress2 (see the "Experimental Subjects and Study Design" subsection of the "Subjectsand Methods" section for further explanation of the pyschological stress periods).Differences in mean percent recoveries between the LS1 and LS2 intervals arenonsignificant at both time points. P<.001 for comparisonsbetween LS1 and HS and between HS and LS2 at 3, 6, and 24 hours.

Mean percentage of permeabilitybarrier recovery at 3, 6, and 24 hours for students during the indicated psychologicalstress period. LS1 indicates low stress 1; HS, high stress; and LS2, low stress2 (see the "Experimental Subjects and Study Design" subsection of the "Subjectsand Methods" section for further explanation of the pyschological stress periods).Differences in mean percent recoveries between the LS1 and LS2 intervals arenonsignificant at both time points. P<.001 for comparisonsbetween LS1 and HS and between HS and LS2 at 3, 6, and 24 hours.

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.

Relationship of changes in psychological stress to changes in barrierhomeostasis

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.

Figure 3.
Relationship of changes in levelsof stress with changes in barrier homeostasis. Data shown are for the Profileof Mood States (POMS) (A) and the Perceived Stress Scale (PSS) (B) instrumentsadministered at the initial low-stress (LS1) vs high-stress (HS) period vsbarrier recovery rates at 3 hours. TMD indicates total mood disturbance (seethe "Experimental Subjects and Study Design" subsection of the "Subjects andMethods" section for further explanation of the pyschological stress periods).

Relationship of changes in levelsof stress with changes in barrier homeostasis. Data shown are for the Profileof Mood States (POMS) (A) and the Perceived Stress Scale (PSS) (B) instrumentsadministered at the initial low-stress (LS1) vs high-stress (HS) period vsbarrier recovery rates at 3 hours. TMD indicates total mood disturbance (seethe "Experimental Subjects and Study Design" subsection of the "Subjects andMethods" section for further explanation of the pyschological stress periods).

Effects of specific stressors on barrier recovery

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 psoriasis70-75;(2) both of these neuropeptides are known keratinocyte mitogens53,76-78;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

Figure 4.
Diagram illustrating the potentialinterplay of psychological stress, endogenous glucocorticoids, barrier homeostasis,and disease pathogenesis.

Diagram illustrating the potentialinterplay of psychological stress, endogenous glucocorticoids, barrier homeostasis,and disease pathogenesis.

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).

Selye  H The general adaptation syndrome and the diseases of adaptation.  J Clin Endocrinol. 1946;6117- 230Google ScholarCrossref
Panconesi  EHautmann  G Psychophysiology of stress in dermatology: the psychobiologic patternof psychosomatics.  Dermatol Clin. 1996;14399- 421Google ScholarCrossref
Spiegel  D Healing words: emotional expression and disease outcome.  JAMA. 1999;2811328- 1329Google ScholarCrossref
Cohen  SWilliamson  GM Stress and infectious disease in humans.  Psychol Bull. 1991;1095- 24Google ScholarCrossref
Glaser  RKiecolt-Glaser  JKSpeicher  C  et al.  Stress, loneliness, and changes in herpesvirus latency.  J Behav Med. 1985;8249- 260Google ScholarCrossref
Glaser  RRice  JSheridan  J  et al.  Stress-related immune suppression: health implications.  Brain Behav Immun. 1987;17- 20Google ScholarCrossref
Glaser  RKiecolt-Glaser  JKMalarkey  WBSheridan  JF The influence of psychological stress on the immune response to vaccines.  Ann N Y Acad Sci. 1998;840649- 655Google ScholarCrossref
Palmblad  JE Stress-related modulation of immunity: a review of human studies.  Cancer Detect Prev. 1987;157- 64Google Scholar
O'Leary  A Stress, emotion, and human immune function.  Psychol Bull. 1990;108363- 382Google ScholarCrossref
Bonneau  RHSheridan  JFFeng  NGGlaser  R Stress-induced suppression of herpes simplex virus (HSV)–specificcytotoxic T lymphocyte and natural killer cell activity and enhancement ofacute pathogenesis following local HSV infection.  Brain Behav Immun. 1991;5170- 192Google ScholarCrossref
Kiecolt-Glaser  JKGlaser  RGravenstein  SMalarkey  WBSheridan  J Chronic stress alters the immune response to influenza virus vaccinein older adults.  Proc Natl Acad Sci U S A. 1996;933043- 3047Google ScholarCrossref
Sheridan  JFDobbs  CJung  J  et al.  Stressed-induced neuroendocrine modulation of viral pathogens and immunity.  Ann N Y Acad Sci. 1998;840803- 808Google ScholarCrossref
Shavit  YTerman  GWMartin  FCLewis  JWLiebeskind  JCGale  RP Stress, opioid peptides, the immune system, and cancer.  J Immunol. 1985;135(2 suppl)834s- 837sGoogle Scholar
Spiegel  DBloom  JRKraemer  HCGottheil  E Effect of psychosocial treatment on survival of patients with metastaticbreast cancer.  Lancet. 1989;2888- 891Google ScholarCrossref
Spiegel  DSephton  SETerr  AIStites  DP Effects of psychosocial treatment in prolonging cancer survival maybe mediated by neuroimmune pathways.  Ann N Y Acad Sci. 1998;840674- 683Google ScholarCrossref
Fawzy  FIFawzy  NWHyun  CS  et al.  Malignant melanoma: effects of an early structured psychiatric intervention,coping, and affective state on recurrence and survival 6 years later.  Arch Gen Psychiatry. 1993;50681- 689Google ScholarCrossref
Smyth  JMStone  AAHurewitz  AKaell  A Effects of writing about stressful experiences on symptom reductionin patients with asthma or rheumatoid arthritis: a randomized trial.  JAMA. 1999;2811304- 1309Google ScholarCrossref
Ullman  KCMoore  RWReidy  M Atopic eczema: a clinical psychiatric study.  J Asthma Res. 1977;1491- 99Google ScholarCrossref
Faulstich  MEWilliamson  DA An overview of atopic dermatitis: toward a bio-behavioural integration.  J Psychosom Res. 1985;29647- 654Google ScholarCrossref
Koblenzer  CSKoblenzer  PJ Chronic intractable atopic eczema: its occurrence as a physical signof impaired parent-child relationships and psychologic developmental arrest:improvement through parent insight and education.  Arch Dermatol. 1988;1241673- 1677Google ScholarCrossref
Kodama  AHorikawa  TSuzuki  T  et al.  Effect of stress on atopic dermatitis: investigation in patients afterthe Great Hanshin Earthquake.  J Allergy Clin Immunol. 1999;104173- 176Google ScholarCrossref
Reiss  F Psoriasis and stress.  Dermatology. 1956;11371- 78Google ScholarCrossref
Baughman  RSobel  R Psoriasis, stress, and strain.  Arch Dermatol. 1971;103599- 605Google ScholarCrossref
Fava  GAPerini  GISantonastaso  PFornasa  CV Life events and psychological distress in dermatologic disorders: psoriasis,chronic urticaria and fungal infections.  Br J Med Psychol. 1980;53277- 282Google ScholarCrossref
Arnetz  BBFjellner  BEneroth  PKallner  A Stress and psoriasis: psychoendocrine and metabolic reactions in psoriaticpatients during standardized stressor exposure.  Psychosom Med. 1985;47528- 541Google ScholarCrossref
Gaston  LLassonde  MBernier-Buzzanga  JHodgins  SCrombez  JC Psoriasis and stress: a prospective study.  J Am Acad Dermatol. 1987;1782- 86Google ScholarCrossref
Mazzetti  MMozzetta  GCSoavi  E  et al.  Psoriasis, stress, and psychiatry: psychodynamic characteristics ofstressors.  Acta Derm Venereol Suppl (Stockh). 1994;18662- 64Google Scholar
Rostenberg Jr  A The role of psychogenic factors in skin disease.  Arch Dermatol. 1960;8181- 83Google ScholarCrossref
Whitlock  FA Psychophysiological Aspects of Skin Disease.  London, England WB Saunders Co Ltd1976;1- 40
O'Sullivan  RLLipper  GLerner  EA The neuro-immuno-cutaneous-endocrine network: relationship of mindand skin.  Arch Dermatol. 1998;1341431- 1435Google ScholarCrossref
Kiecolt-Glaser  JKMarucha  PTMalarkey  WBMercado  AMGlaser  R Slowing of wound healing by psychological stress.  Lancet. 1995;3461194- 1196Google ScholarCrossref
Padgett  DAMarucha  PTSheridan  JF Restraint stress slows cutaneous wound healing in mice.  Brain Behav Immun. 1998;1264- 73Google ScholarCrossref
Frankel  FHMisch  RC Hypnosis in a case of long-standing psoriasis in a person with characterproblems.  Int J Clin Exp Hypn. 1973;21121- 130Google ScholarCrossref
Hughes  HHEngland  RGoldsmith  DA Biofeedback and psychotherapeutic treatment of psoriasis: a brief report.  Psychol Rep. 1981;4899- 102Google ScholarCrossref
Gaston  LCrombez  JCJoly  J  et al.  Efficacy of imagery and meditation techniques in treating psoriasis.  Imaginative Cognit Pers. 1988;8125- 38Google ScholarCrossref
Winchell  SAWatts  RA Relaxation therapies in the treatment of psoriasis and possible pathophysiologicmechanisms.  J Am Acad Dermatol. 1988;18101- 104Google ScholarCrossref
Kabat-Zinn  JWheeler  ELight  T  et al.  Influence of a mindfulness meditation-based stress reduction interventionon rates of skin clearing in patients with moderate to severe psoriasis undergoingphototherapy (UVB) and photochemotherapy (PUVA).  Psychosom Med. 1998;60625- 632Google ScholarCrossref
Suetaki  TSasai  SZhen  Y-XOhi  TTazami  H Functional analysis of the stratum corneum in scars: sequential studiesafter injury and comparison among keloids, hypertrophic scars, and atrophicscars.  Arch Dermatol. 1996;1321453- 1458Google ScholarCrossref
Shahidullah  MRalffle  EJRimmer  ARFrain-Bell  W Transepidermal water loss in patients with dermatitis.  Br J Dermatol. 1969;81722Google ScholarCrossref
Yoshiike  TAikawa  YSindhvananda  J  et al.  Skin barrier defect in atopic dermatitis: increased permeability ofthe stratum corneum using dimethyl sulfoxide and theophylline.  J Dermatol Sci. 1993;592- 96Google ScholarCrossref
Felsher  ZRothman  S The insensible perspiration of the skin in hyperkeratotic disorders.  J Invest Dermatol. 1945;6271- 278Google ScholarCrossref
Grice  KABettley  FR Skin water loss and accidental hypothermia in psoriasis, ichthyosis,and erythroderma.  BMJ. 1967;4195- 198Google ScholarCrossref
Ghadially  RReed  JTElias  PM Stratum corneum structure and function correlates with phenotype inpsoriasis.  J Invest Dermatol. 1996;107558- 564Google ScholarCrossref
Elias  PMAnsel  JCWood  LCFeingold  KR Signaling networks in barrier homeostasis: the mystery widens.  Arch Dermatol. 1996;1321505- 1506Google ScholarCrossref
Elias  PMWood  LCFeingold  KF Epidermal pathogenesis of inflammatory dermatoses.  Am J Contact Dermat. 1999;10119- 126Google Scholar
Denda  MTsuchiya  THosoi  JKoyama  J Immobilization-induced and crowded environment-induced stress delaybarrier recovery in murine skin.  Br J Dermatol. 1998;138780- 785Google ScholarCrossref
Denda  MTsuchiya  TElias  PMFeingold  KR Stress alters cutaneous permeability barrier homeostasis.  Am J Physiol Regul Integr Comp Physiol. 2000;278R367- R372Google Scholar
Reed  JTGhadially  RElias  PM Skin type, but neither race nor gender, influence epidermal permeabilitybarrier function.  Arch Dermatol. 1995;1311134- 1138Google ScholarCrossref
McNair  DMLorr  MDropplemann  LF EITS Manual for the Profile of Mood States.  San Diego, Calif Educational and Industrial Testing Service1981;
Cohen  SWilliamson  GMSpacapan  SedOskanp  Sed Perceived stress in a probability sample of the United States.  Social Psychologyof Health. Beverly Hills, Calif Sage1988;31- 67Google Scholar
Blichmann  CWSerup  J Reproducibility and variability of transepidermal water loss measurement:studies on the Servo Med evaporimeter.  Acta Derm Venereol. 1987;67206- 210Google Scholar
Ghadially  RBrown  BESequeira-Martin  SMFeingold  KRElias  PM The aged epidermal permeability barrier: structural, functional, andlipid biochemical abnormalities in humans and a senescent murine model.  J Clin Invest. 1995;952281- 2290Google ScholarCrossref
Farber  EMLanigan  SWBoer  J The role of cutaneous sensory nerves in the maintenance of psoriasis.  Int J Dermatol. 1990;29418- 420Google ScholarCrossref
van Eck  MBerkhof  HNicolson  NSulon  J The effects of perceived stress, traits, mood states, and stressfuldaily events on salivary cortisol.  Psychosom Med. 1996;58447- 458Google ScholarCrossref
Chatterton Jr  RTVogelsong  KMLu  Y-CHudgens  GA Hormonal responses to psychological stress in men preparing for skydiving.  J Clin Endocrinol Metab. 1997;822503- 2509Google Scholar
Pruessner  JCGaab  JHellhammer  DHLintz  DSchommer  NKirschbaum  C Increasing correlations between personality traits and cortisol stressresponses obtained by data aggregation.  Psychoneuroendocrinology. 1997;22615- 625Google ScholarCrossref
Tsuchiya  THorii  I Epidermal cell proliferative activity assessed by proliferating cellnuclear antigen (PCNA) decreases following immobilization-induced stress inmale Syrian hamsters.  Psychoneuroendocrinology. 1996;21111- 117Google ScholarCrossref
Weigl  BA Immunoregulatory mechanisms and stress hormones in psoriasis.  Int J Dermatol. 1998;37350- 357Google ScholarCrossref
Allen  PIBatty  KADodd  CA  et al.  Dissociation between emotional and endocrine responses preceding anacademic examination in male medical students.  J Endocrinol. 1985;107163- 170Google ScholarCrossref
Semple  CGGray  CEBorland  WEspie  CABeastall  GH Endocrine effects of examination stress.  Clin Sci. 1988;74255- 259Google Scholar
Glaser  RPearl  DKKiecolt-Glaser  JKMalarkey  WB Plasma cortisol levels and reactivation of latent Epstein-Barr virusin response to examination stress.  Psychoneuroendocrinology. 1994;19765- 772Google ScholarCrossref
Malarkey  WBPearl  DKDemers  LMKiecolt-Glaser  JKGlaser  R Influence of academic stress and season on 24-hour mean concentrationsof ACTH, cortisol, and β-endorphin.  Psychoneuroendocrinology. 1995;20499- 508Google ScholarCrossref
Harrell  EKelly  KStutts  W Situational determinants of correlations between serum cortisol andself-reported stress measures.  Psychology. 1996;3322- 25Google Scholar
Miller  MRKasahara  M The pattern of cutaneous innervation of the human foot.  Am J Anat. 1959;105233- 256Google ScholarCrossref
Karanth  SSSpringall  DRKuhn  DMLevene  MMPolak  JM An immunocytochemical study of cutaneous innervation and the distributionof neuropeptides and protein gene product 9.5 in man and commonly employedlaboratory animals.  Am J Anat. 1991;191369- 383Google ScholarCrossref
Hosoi  JMurphy  GFEgan  CL  et al.  Regulation of Langerhans cell function by nerves containing calcitoningene-related peptide.  Nature. 1993;363159- 162Google ScholarCrossref
Fitzgerald  M Capsaicin and sensory neurones: a review.  Pain. 1983;15109- 130Google ScholarCrossref
Maggi  CAMeli  A The sensory-efferent function of capsaicin-sensitive sensory neurons.  Gen Pharmacol. 1988;191- 43Google ScholarCrossref
Lotti  THautmann  GPanconesi  E Neuropeptides in skin.  J Am Acad Dermatol. 1995;33482- 496Google ScholarCrossref
Giannetti  AGirolomoni  G Skin reactivity to neuropeptides in atopic dermatitis.  Br J Dermatol. 1989;121681- 688Google ScholarCrossref
Pincelli  CFantini  FMassimi  PGirolomoni  GSeidenari  SGiannetti  A Neuropeptides in skin from patients with atopic dermatitis: an immunohistochemicalstudy.  Br J Dermatol. 1990;122745- 750Google ScholarCrossref
Anand  PSpringall  DRBlank  MASellu  DPolak  JMBloom  SR Neuropeptides in skin disease: increased VIP in eczema and psoriasisbut not axillary hyperhidrosis.  Br J Dermatol. 1991;124547- 549Google ScholarCrossref
Eedy  DJJohnston  CFShaw  CBuchanan  KD Neuropeptides in psoriasis: an immunocytochemical and radioimmunoassaystudy.  J Invest Dermatol. 1991;96434- 438Google ScholarCrossref
Naukkarinen  ANickoloff  BJFarber  EM Quantification of cutaneous sensory nerves and their substance P contentin psoriasis.  J Invest Dermatol. 1989;92126- 129Google ScholarCrossref
Ostlere  LSCowen  TRustin  MH Neuropeptides in the skin of patients with atopic dermatitis.  Clin Exp Dermatol. 1995;20462- 467Google ScholarCrossref
Haegerstrand  AJonzon  BDalsgaard  CJNilsson  J Vasoactive intestinal polypeptide stimulates cell proliferation andadenylate cyclase activity of cultured human keratinocytes.  Proc Natl Acad Sci U S A. 1989;865993- 5996Google ScholarCrossref
Wilkinson  DI Mitogenic effect of substance P and CGRP on keratinocytes.  J Cell Biol. 1989;107509Google Scholar
Hsieh  S-TLin  W-M Modulation of keratinocyte proliferation by skin innervation.  J Invest Dermatol. 1999;113579- 586Google ScholarCrossref
Torii  HYan  ZHosoi  JGranstein  RD Expression of neurotrophic factors and neuropeptide receptors by Langerhanscells and the Langerhans cell–like cell line XS52: further support fora functional relationship between Langerhans cells and epidermal nerves.  J Invest Dermatol. 1997;109586- 591Google ScholarCrossref
Bernstein  JEParish  LCRapaport  MRosenbaum  MMRoenigk Jr  HH Effects of topically applied capsaicin on moderate and severe psoriasisvulgaris.  J Am Acad Dermatol. 1986;15504- 507Google ScholarCrossref
Venier  ADe Simone  CForni  L  et al.  Treatment of severe psoriasis with somatostatin: four years of experience.  Arch Dermatol Res. 1988;280(suppl)S51- S54Google Scholar
Dewing  SB Remission of psoriasis associated with cutaneous nerve section.  Arch Dermatol. 1971;104220- 221Google ScholarCrossref
Nickoloff  BJNaidu  Y Perturbation of epidermal barrier function correlates with initiationof the cytokine cascade in human skin.  J Am Acad Dermatol. 1994;30535- 546Google ScholarCrossref
Denda  MWood  LCEmami  S  et al.  The epidermal hyperplasia associated with repeated barrier disruptionby acetone treatment or tape stripping cannot be attributed to increased waterloss.  Arch Dermatol Res. 1996;288230- 238Google ScholarCrossref
Proksch  EBrasch  JSterry  W Integrity of the permeability barrier regulates epidermal Langerhanscell density.  Br J Dermatol. 1996;134630- 638Google ScholarCrossref
Proksch  EBrasch  J Influence of epidermal permeability barrier disruption and Langerhans'cell density in allergic contact dermatitis.  Acta Derm Venereol. 1997;77102- 104Google Scholar
Bilkis  MRMark  KA Mind-body medicine: practical applications in dermatology.  Arch Dermatol. 1998;1341437- 1441Google ScholarCrossref