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Original Article |

Decreased Memory Performance in Healthy Humans Induced by Stress-Level Cortisol Treatment FREE

John W. Newcomer, MD; Gregg Selke, BA; Angela K. Melson, MA; Tamara Hershey, PhD; Suzanne Craft, PhD; Katherine Richards, BA; Amy L. Alderson, MA
[+] Author Affiliations

From the Department of Psychiatry, Washington University School of Medicine (Drs Newcomer and Hershey, Mr Selke, and Mss Melson and Richards), and the Department of Psychology, Washington University (Dr Newcomer and Ms Alderson), St Louis, Mo; and the Department of Psychiatry and Behavioral Science, University of Washington, and the Geriatric Research, Education, and Clinical Center, Seattle/American Lake Veterans Affairs Medical Center, Seattle, Wash (Dr Craft).


Arch Gen Psychiatry. 1999;56(6):527-533. doi:10-1001/pubs.Arch Gen Psychiatry-ISSN-0003-990x-56-6-yoa8291.
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Background  Glucocorticoids (GCs) can regulate hippocampal metabolism, physiologic functions, and memory. Despite evidence of memory decreases during pharmacological GC treatment, and correlations between memory and cortisol levels in certain disease conditions, it remains unclear whether exposure to the endogenous GC cortisol at levels seen during physical and psychological stress in humans can inhibit memory performance in otherwise healthy individuals.

Methods  Randomized, double-blind, placebo-controlled comparison of 2 fixed oral doses of cortisol (40 mg/d and 160 mg/d using split doses to approximate circadian rhythm) given for 4 days to matched groups of healthy subjects (n=51). Lower-dose treatment approximated cortisol exposure during mild stress, whereas the higher dose approximated cortisol exposure during major stress. Cognitive testing and plasma sampling were done at baseline, after 1 and 4 days of treatment, and after a 6-day washout period, hypothesizing dose-dependent decreases in verbal declarative memory.

Results  Cortisol treatment at the higher dose produced reversible decreases in verbal declarative memory without effects on nonverbal memory, sustained or selective attention, or executive function. A significant interaction between time and treatment condition for paragraph recall was explained by treatment-induced differences in performance after 4 treatment days, with lower immediate and delayed recall performance during higher-dose cortisol treatment compared with lower-dose treatment and placebo.

Conclusions  Several days of exposure to cortisol at doses and plasma concentrations associated with physical and psychological stress in humans can—similar to pharmacological GC treatment—reversibly decrease specific elements of memory performance in otherwise healthy individuals.

Figures in this Article

GLUCOCORTICOIDS (GCs), which are produced by the stress-responsive hypothalamic-pituitary-adrenal axis, can regulate neuronal metabolism, physiologic functions, and gene expression in the brain, particularly the hippocampus. A range of evidence1 supports the role of the hippocampus in declarative memory performance, with recent interest2 in a role for hippocampal synaptic plasticity as a memory substrate. Glucocorticoid actions on the hippocampus include involution of the dendritic processes of hippocampal neurons,3 inhibition of activity-dependent synaptic changes such as long-term potentiation,4 site-preferential inhibition of glucose transport in vitro,5 and glucose metabolism in humans in vivo.6 Type 2 GC receptors have a lower affinity for the endogenous human GC cortisol than do type 1 receptors and thus tend to be activated by peak levels associated with stress rather than by basal GC concentrations.7 Effects on glucose transport5 and suppressant effects on neuronal excitability8 are also mediated by type 2 receptors.

Investigators912 reported adverse effects of GC exposure on cognitive functions associated with hippocampal integrity in the rodent, including recent evidence13 for GC-induced impairments in the retrieval of learned material. Investigators1416 also reported dose-dependent facilitating effects of GC treatment on elements of memory function. However, the implications of these findings for memory performance in humans is complicated by varying species, dose level and timing, and variable task characteristics across the studies. In humans, case-control study designs indicate decreased memory performance during prednisone treatment of asthmatic children17 and decreased verbal declarative memory in prednisone-treated patients vs matched medical control subjects.18 Investigators1929 also reported inverse correlations between memory performance and plasma concentrations of cortisol in patients with Cushing syndrome, dementia of the Alzheimer type, schizophrenia, and depression. Various cognitive impairments have been reported in Cushing syndrome, with preferential involvement of memory functions.24,30,31 However, the interpretation of these results is limited by nonrandomized treatment assignments, noncausal associations, or additional disease factors that can decrease performance.

Results of double-blind, randomized, placebo-controlled experiments with healthy humans indicate that use of pharmacological doses of the preferential type 2 GC receptor ligands dexamethasone and prednisone can decrease verbal declarative memory performance.32,33 However, the interpretation of dexamethasone or prednisone treatment effects as a model of cortisol effects or human stress remains problematic. This is because of uncertainty about whether treatment-induced impairments result from increased brain GC receptor binding or from an alternate possibility: that treatment-induced suppression of cortisol secretion, combined with the slow entry of dexamethasone and prednisone into the brain (in contrast to the rapid availability of cortisol),34,35 could result in decreases in brain GC receptor binding. Based on the results of animal studies noted previously1416 suggesting that GC agonists may sometimes enhance memory performance, decreases in hippocampal GC receptor binding might alternatively underlie the decreased performance observed during dexamethasone or prednisone treatment. This uncertainty, and differences in the binding of dexamethasone vs cortisol to type 1 vs type 2 hippocampal GC receptors, limits the utility of dexamethasone and similar ligands in modeling the effects of cortisol or stress in humans.

Previous efforts to directly study the effects of cortisol on memory performance in humans have been limited to brief (60 minutes), single-dose (10- to 50-mg) treatments.3638 These study designs do not model the longer duration of hypercortisolemia relevant to most stress- and disease-related human events and prevent an assessment of memory performance over the time course expected for genomic GC actions. These earlier studies produced mixed or negative results for immediate recall or, in one report, decreases in delayed recall, raising questions about the contribution of non-GC effects to these variable changes in performance. This background motivated the present study, in which we hypothesized that 4 days of randomized, double-blind, placebo-controlled cortisol (hydrocortisone) treatment—modeling the hypercortisolemia associated with stress in humans—could produce dose-dependent decreases in verbal declarative memory performance.

Total daily oral cortisol doses for this study were selected to approximate 24-hour cortisol secretion during mild to maximal physiologic stress, based on data from medical and surgical populations.3944 In general, oral cortisol doses required to produce targeted secretion levels are somewhat higher than measured endogenous secretion, caused by incomplete bioavailability associated with first-pass hepatic metabolism. Lower-dose treatment was selected to approximate cortisol output in the range between mild physiologic stress (eg, laparoscopy)—producing approximately 25-mg/d cortisol per day—and moderate physiologic stress (eg, nonlaparoscopic cholecystectomy)—producing approximately 50-mg/d cortisol per day. Higher-dose treatment was selected to approximate cortisol output during major physiologic stress (eg, colectomy or aortobifemoral bypass)—producing approximately 100- to 150-mg/d cortisol per day, with maximal levels of 200 to 300 mg/d per day. The targeted range of plasma cortisol concentrations for this study was similarly based on previously observed values associated with various physical and psychological stressors, for example: 276 to 828 nmol/L (10-30 ug/dL) for minor surgical procedures41,45; 690 nmol/L (25 ug/dL) for the Trier Social Stress Test46; 828 to 1104 nmol/L (30-40 ug/dL) for more extended surgical procedures such as nonlaparoscopic cholecystectomy or hysterectomy41; and 1104 to 1517 nmol/L (40-55 ug/dL) for severe sepsis, multiple trauma, or following major abdominal surgery.41,47,48

SUBJECTS

All subjects gave written informed consent for their participation in a protocol approved by the Washington University School of Medicine Human Studies Committee, St Louis, Mo. Subjects aged 18 to 30 years were recruited using local advertisements and were screened for general medical health, including psychiatric disorders, using the Diagnostic Interview for Genetic Studies.49 Subjects were excluded for the presence of clinically significant medical or psychiatric disease, including (1) type 1 or 2 diabetes mellitus, hypertension, any major surgery within the previous 6 months, any cardiac condition causing documented hemodynamic compromise, any respiratory condition causing documented or clinically recognized hypoxia, fever, dehydration, nausea, epilepsy, other endocrine disease, body weight less than 80% ideal body weight, any other medical condition requiring more than 7 days of hospitalization in the past 4 weeks, pregnancy or higher-dose estrogen therapy, narcotic therapy, corticosteroid or spironolactone therapy, and psychotropic therapy; (2) any Axis I psychiatric disorder, including any substance use disorders; and (3) mental retardation as determined by DSM-IV criteria. Twenty-five men and 26 women were assigned to the higher-dose cortisol (7 men and 8 women), lower-dose cortisol (8 men and 8 women), and placebo (10 men and 10 women) groups. Complete data were available for most of the cognitive analyses for all 51 subjects, with complete plasma data for 50 of them at baseline and 49 of them over all sampling times. Clinical characteristics of the sample were as follows (mean±SD): age, 22.2±2.8 years; body mass index (calculated as weight in kilograms divided by the square of the height in meters, 23.0±3.9; and education, 15.5±1.96 years. No significant differences across treatment groups were detected for age (F2,48=0.003; P=.99); body mass index (F2,48=1.03; P=.36); education (F2,48=0.49; P=.61); Wechsler Adult Intelligence Scale–Revised information (F2,48=0.65; P=.53), vocabulary (F2,48=0.75; P=.48) and block design (F2,47=0.33; P=.72) subscale scores; handedness (F2,47=0.66; P=.52); or baseline cortisol (F2,47=1.30; P=.28), insulin (F2,47=0.007; P=.99), or glucose (F2,47=0.04; P=.96) plasma concentrations.

PROCEDURE

This study was a randomized, double-blind, placebo-controlled comparison of 2 fixed oral doses of cortisol (hydrocortisone), 160 mg/d and 40 mg/d, given over 4 days. All subjects received 1 of the 2 oral hydrocortisone doses or placebo using matched capsules given in divided doses (7 AM and 7 PM), with an approximately 3:2 dose ratio (higher dose, 100:60 mg; lower dose, 25:15 mg) to approximate circadian changes in endogenous cortisol secretion. As in a previous study with dexamethasone,32 plasma sampling and blinded cognitive testing were performed at baseline (day 0), after 1 and 4 days of treatment (days 1 and 4), and after a 6-day washout period (day 10). All assessments were performed at approximately 4 PM, with no food intake after 1 PM. Plasma samples were stored at −70°C before assay. Plasma cortisol50 and insulin51 levels were measured by radioimmunoassay. Plasma glucose level was measured with a glucose oxidase method (Beckman Glucose Analyzer 2; Beckman Instruments, Fullerton, Calif).

COGNITIVE MEASURES

Paragraph recall was used as a valid52 and sensitive measure of verbal declarative memory53,54 that has also proved to be sensitive to GC effects in previous reports.32 Additional tasks were used to explore the effect of cortisol on other elements of cognitive function, as described in the following paragraph. Different versions of each cognitive task, matched for difficulty, were administered on each study day. In addition, 2 different sets of the task battery that offered the different task versions in 2 different orders across study days were counterbalanced across subjects within each treatment group to avoid any nonrandom bias from affecting study results. The tasks were presented in a fixed order in both sets: paragraph recall (immediate), delayed match to sample, modified Stroop color-word task, continuous performance task, paragraph recall (delayed), verbal fluency, spatial delayed response, and delayed match to sample.

Immediate and delayed paragraph recall are dependent on cognitive abilities such as encoding, retrieval, and organizational and learning strategies. Subjects hear recorded short narratives that were constructed using an established method used for the Wechsler Memory Scale–Revised Logical Memory Test,55 with 44 pieces of information followed by audiotaped immediate and delayed (30 minutes) verbatim recall. Two paragraphs are given during each test session, with all paragraphs comparable in recall difficulty. Scores for correct verbatim recall and commission errors (ie, intrusions or confabulations) are tabulated, based on a modification of established scoring methods.56 A computerized delayed match to sample task was used to measure nonverbal recognition performance based on previous work on animals57,58 and humans with hippocampal lesions.59 Subjects see 10 consecutive presentations of 2 geometric line drawings (a total of 20 drawings) followed by a 312-minute delay filled with a digit span task. After the delay, subjects are presented with 10 recognition trials with 1 target and 2 distracter drawings per trial. Number of correct responses per total possible responses and reaction time were calculated for analysis. A multiple version modification of the Stroop color-word task60 was used as a measure of selective attention. Total time to complete each condition and number of incorrect responses per condition were analyzed. Sustained attention was measured using a computer-generated continuous performance task that presents a rapid, continual sequence of letters. Subjects must press a key whenever a specific letter appears on the screen. Accuracy and reaction time are measured. A word list generation (verbal fluency) task was used as a measure of verbal executive function.61 The total number of correct responses was analyzed. A spatial delayed response task was used to measure nonverbal spatial recall at 5 and 120 seconds. Memory for spatial location has been well researched in primates, and this method was modified for use with humans, as previously described.62 In general, delays longer than 15 to 30 seconds on similar tasks may be sensitive to medial temporal dysfunction.6365 Mean error (distance from a target on a computer screen) was calculated for each subject at each type of trial (5-second delay, 120-second delay, and cue-present [no recall] trials).

ANALYSIS

Comparability of the different treatment groups (ie, age and body mass index) was tested using analysis of variance (ANOVA). The main hypothesis concerning treatment effects on verbal declarative memory performance was tested using ANOVA to evaluate the repeated measures of paragraph performance across baseline and both treatment days, including a between-subject factor for treatment condition and a within-subject factor for recall condition (eg, immediate vs delayed). Treatment effects on plasma cortisol concentrations (and other plasma variables) were similarly tested to confirm the anticipated treatment effects on plasma cortisol level and to evaluate possible confounds to the primary analysis. Because of sex differences in plasma cortisol concentrations (see "Results" section), sex was added as a between-subject factor to the ANOVA testing the main hypothesis (including or excluding sex from this model did not alter the significance of the primary results), and a subsequent analysis of the covariance model included plasma cortisol concentrations. Treatment effects on other cognitive measures were similarly tested to evaluate secondary hypotheses concerning the specificity of treatment effects for verbal declarative memory. To adjust for any nonhomogeneity of covariance for the repeated within-subject effects, we used P values that were adjusted using the Huynh-Feldt (H-F) method; all tests required little or no adjustment. Significant effects (critical P=.05) were further evaluated using comparisons across individual treatment days and individual treatment conditions as appropriate. Analyses were performed using statistical software programs (Statview and SuperAnova; SAS Institute Inc, Cary, NC).

Cortisol treatment produced reversible decreases in verbal declarative memory performance. The initial ANOVA testing the main hypothesis indicated a significant interaction between time and treatment condition for paragraph recall performance (F4,94=2.49; P<.05 by H-F) (Figure 1). Although an expected main effect of recall condition (immediate vs 30-minute delayed: F1,47=180.3; P<.001 by H-F) was detected, there was no significant interaction between recall condition, treatment condition, and time (F4,94=0.77; P=.55 by H-F). These results indicate that the significant effect of treatment on paragraph performance similarly affected immediate and delayed recall over time (Figure 1). Total recall performance differed across groups after 4 treatment days (F2,48=3.82; P=.029), with lower performance on higher-dose dose treatment compared with lower-dose treatment (F1,48=4.09; P<.05) and placebo (F1,48=7.19; P=.01). No difference in recall performance was detected across treatment groups at baseline (F2,48=0.06; P=.94) or after 1 treatment day (F2,48=0.25; P=.78). The addition to the model of a covariate term for plasma cortisol concentrations increased the strength of interaction between time and treatment condition (F4,91=3.15; P=.018 by H-F), reflecting the additional contribution of plasma cortisol level variance within each treatment condition to overall paragraph performance.

Place holder to copy figure label and caption
Figure 1.

Cortisol-induced decreases in verbal memory performance (n=51). A similar effect of treatment conditions over time was observed for immediate and delayed paragraph recall. Recall performance differed across treatment groups after 4 days in the immediate and delayed recall conditions (asterisk indicates comparison point F2,48=4.04; P=.02 and F2,48=3.29; P=.05, respectively), with decreased immediate and delayed recall performance in the high-dose treatment group compared with the lower-dose (F1,48=4.54; P=.04 and F1,48=3.34; P=.07, respectively) and placebo (F1,48=7.50; P=.009 and F1,48=6.26; P=.02, respectively) groups. Error bars represent SE.

Graphic Jump Location

Inspecting the paragraph recall performance of individual subjects in the higher-dose cortisol treatment group relative to the mean performance of the placebo group, 14 of 15 individuals (93%) taking higher-dose cortisol experienced a decrease in performance below placebo levels between 1 and 4 days of treatment (mean decrease from placebo level at day 4, 21.9±16.6 bits of paragraph data, in which each bit is 1 "content" word, eg, noun, verb, adjective, or adverb). No similar effects of treatment were observed on any other cognitive task in our test battery, including tests of sustained and selective attention, verbal executive function, nonverbal object recognition, and nonverbal spatial recall at 5 and 120 seconds (Table 1). No difference in paragraph performance was detected across treatment groups after a 6-day treatment washout (F2,48=1.44; P=.25) (Figure 1), indicating a reversible effect on performance. In the placebo and lower-dose cortisol treatment groups, similar to results with placebo in our previous studies, paragraph performance increased over time because of predicted practice effects or procedural learning.

Table Graphic Jump LocationPerformance on Cognitive Measures During Placebo-Controlled Cortisol Treatment in 51 Healthy Adults*

Cortisol treatment also produced expected stable increases in 4 PM plasma cortisol concentrations in the higher-dose treatment condition, resembling levels associated with moderate surgical stress and the psychological stress of the Trier Social Stress Test (Figure 2). Plasma cortisol concentrations were higher overall in women (main effect of sex: F1,43=7.53; P=.009), without sex differences in response to treatment conditions (sex × treatment condition × time: F4,86=1.15; P=.34 by H-F). No sex differences were detected in overall paragraph recall performance (main effect of sex: F1,47=1.87; P=.18) or in the effect of cortisol treatment conditions on recall performance (sex × treatment condition × time: F4,90=1.71; P=.16 by H-F). However, this may reflect a type II error related to the relatively small female sample size within each treatment group. No main effect of, or relevant interactions with, plasma cortisol concentrations on paragraph performance was detected. Cortisol treatment produced a mild increase in plasma glucose concentrations (treatment condition × time: F4,90=7.51; P<.001 by H-F). However, this was explained by a peak increase in glucose concentrations on study day 1 in the 160-mg/d condition only, without a temporal relationship to the memory effect. Plasma glucose concentrations varied across study days 0, 1, and 4 in the 160-mg/d condition (F2,26=12.64; P<.001 by H-F; mean±SD, 4.8±0.4 [86.5±7.1], 5.9±1.0 [106.8±17.6], and 5.5±0.7 mmol/L [98.7±12.5 mg/dL], respectively). Plasma glucose concentrations did not change over repeated sampling in either the placebo (F2,36=1.43; P=.25 by H-F) or the 40-mg/d (F2,30=0.62; P=.54 by H-F) condition. Plasma insulin concentrations did not vary significantly across the different treatment conditions (treatment condition × time: F4,92=1.55; P=.20). Testing the effect of plasma glucose and insulin concentrations on paragraph performance, no significant interaction between treatment condition, time, and either plasma glucose level or insulin level was detected.

Place holder to copy figure label and caption
Figure 2.

Treatment-induced changes in plasma cortisol concentrations (n=49). Treatment conditions resulted in stable stress-level elevation of plasma cortisol concentrations (time × treatment condition: F4,86=10.72; P<.001 by Huynh-Feldt), explained by differences after 1 (F2,48=8.62; P≤.001) and 4 (F2,47=13.46; P<.001) treatment days, with higher concentrations in those taking 160 mg/d compared with those taking 40 mg/d and placebo (P<.002, both days, by Bonferroni and Dunn tests). Error bars represent SE.

Graphic Jump Location

The results of this study indicate that several days of exposure to cortisol at doses and plasma concentrations associated with physical and psychological stress in humans can reversibly decrease verbal declarative memory function in otherwise healthy humans. The results extend previous studies32 in humans using pharmacological GC treatments such as dexamethasone, and previously reported associations1929 between memory performance and plasma cortisol concentrations in patients with Cushing syndrome, dementia of the Alzheimer type, schizophrenia, and depression. The results are directly relevant to the interpretation of decreased memory performance during periods of extended stress in humans, in which plasma cortisol elevations are present throughout memory encoding and retrieval processes. Memory performance was decreased only by a cortisol treatment condition resembling moderate to maximal stress levels—not mild stress—suggesting that cortisol-induced memory decreases may not occur in most individuals under mildly stressful circumstances. Future studies should carefully define the dose or plasma concentration threshold for cortisol-induced memory impairment in healthy humans.

The mean cortisol-induced memory decrease, approximating a 1-SD reduction from placebo-level performance, is clinically relevant. Similar 1-SD changes in performance on the Logical Memory passages (paragraph recall) of the Wechsler Memory Scale–Revised would lower an individual's age-normalized classification of paragraph recall performance by 1 level (eg, high-average decreased to average or low-average decreased to borderline).55 The results of this study indicate a reversible effect of increased GC exposure on memory performance under such treatment conditions, consistent with previous results using dexamethasone.32 The preferential effect of treatment on immediate and delayed verbal declarative memory performance, without effects on other differentiated elements of cognitive function, also replicates the previous results with dexamethasone, suggesting preferential GC effects on encoding processes or retrieval mechanisms involved in immediate and delayed recall.13 However, results of this study and the previous study with dexamethasone indicate a GC treatment effect that may also block the practice effect or procedural memory effect observed in both studies in the placebo conditions, in addition to decreasing performance for treated groups below baseline levels. We did not in either study attempt to disentangle the effects on procedural memory vs elements of declarative memory performance, leaving some open questions about exactly which elements of memory function are altered by GC treatment. Although most previous reports in humans concerning GC effects on cognitive function have involved verbal declarative memory—usually for paragraphs or semantically related word lists—other nonverbal tasks with a declarative memory component that were used in this study did not detect GC-induced changes. This may reflect a preferential GC effect on verbal memory processes or may be caused by differing task sensitivity.

Although the cortisol doses used and the measured plasma cortisol concentrations obtained were all within the range associated with the human stress response, the twice-daily oral dosing regimen may have produced post-dose peak levels that were higher than those measured at 4 PM and perhaps higher than those associated with stress. However, carefully derived human pharmacokinetic data for a 5-mg dose of oral deuterium-labeled cortisol66 indicates a peak plasma cortisol concentration of 55 nmol/L (2 µg/dL) (30 minutes after ingestion), suggesting that our highest 7 AM cortisol dose of 100 mg (20×5 mg) would produce a peak plasma cortisol concentration of approximately 1100 nmol/L (40 µg/dl), which is 20 times higher than the previously reported peak plasma cortical concentration.66 As detailed in the introduction, this is well within the range of plasma cortisol concentrations observed after moderate to major medical or surgical stress. This study was limited by the use of a single plasma sampling time on each study day, which prevented the measurement of cortisol levels throughout the entire dosing interval. Although our cortisol dosing schedule simulated a morning peak and some daily circadianlike variation in plasma levels, the study was limited by the use of only 2 dosing times to approximate physiologic cortisol secretion, with larger-than-ideal peaks and troughs in plasma cortisol levels. One such trough in plasma cortisol concentration occurred at 4 PM in the 40-mg/d dosing condition, in which levels were no longer increased above placebo levels (Figure 2). However, the biologic (vs plasma elimination) half-life of cortisol is 8 to 12 hours.67 Indeed, the lower-dose condition remained biologically active, as evidenced by negative feedback on endogenous cortisol production (eg, mean 4 PM cortisol concentration numerically lower than that for placebo) and by treatment-induced increases in plasma leptin levels.68 These observations suggest that cortisol effects on memory function, if present at this dose level, could similarly persist throughout the dosing interval.

The study was also limited by not measuring other potentially cognitively active compounds, such as epinephrine, norepinephrine, corticotropin, and corticotropin-releasing factor, which could be relevant to cognitive impairments in various neuropsychiatric disorders. However, the time course for our treatment effect on memory, the similar memory impairment induced by stress and exogenous cortisol in a previous report,38 and the cortisol-related memory impairments noted in clinical populations all argue against a role for catecholamines or treatment-induced decreases in corticotropin or corticotropin-releasing factor levels in the explanation of our results. Nevertheless, this study provides only a partial experimental model for conditions such as pituitary Cushing disease or depression. Future studies should test the effects of altered exposure to corticotropin, corticotropin-releasing factor, and other relevant elements of the stress response, alone and in combination.

In summary, several days of exposure to cortisol at doses and plasma concentrations associated with physical and psychological stress in humans can reversibly decrease specific elements of memory performance in otherwise healthy individuals. The results suggest that a clinically significant impairment in human memory performance can occur during extended periods of moderate to severe physiologic stress. Future studies will be needed to define the plasma concentration threshold and duration of exposure required to produce this impairment in healthy and clinical populations. The results are relevant to identifying adverse physiologic conditions that can be targeted by future treatments or prevention approaches. Future research in this area can make important contributions to our understanding of the complex role of GCs and other factors regulating memory function in the human brain.

Accepted for publication March 5, 1999.

This study was supported by Independent Scientist Award MH01510 from the National Institute of Mental Health, Rockville, Md (Dr Newcomer), and grants 5M01 RR00036 and P60-DK20579 from the US Public Health Service, Bethesda, Md.

Presented as a poster at the annual meeting of the Society for Neuroscience, New Orleans, La, October 29, 1997.

We thank Brenda Rosen for secretarial support and George Vogler, PhD, Department of Biobehavioral Health, Pennsylvania State University, for statistical consultation.

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Whelan  TBSchteingart  DEStarkman  MNSmith  A Neuropsychological deficits in Cushing's syndrome. J Nerv Ment Dis. 1980;168753- 757
Link to Article
Mauri  MSinforiani  EBono  GVignati  FBerselli  MEAttanasio  RNappi  G Memory impairment in Cushing's disease. Acta Neurol Scand. 1993;8752- 55
Link to Article
Newcomer  JWCraft  SHershey  TAskins  KBardgett  ME Glucocorticoid-induced impairment in declarative memory performance in adult humans. J Neurosci. 1994;142047- 2053
Wolkowitz  OMReus  VIWeingartner  HThompson  KBreier  ADoran  ARubinow  DPickar  D Cognitive effects of corticosteroids in man. Am J Psychiatry. 1990;1471297- 1303
Meijer  OCde Lange  ECMBreimer  DDde Boer  AGWorkel  JODe Kloet  ER Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology. 1998;1391789- 1793
Link to Article
Schinkel  AHWagenaar  Evan Deemter  LMol  CABorst  P Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995;961698- 1705
Link to Article
Beckwith  BEPetros  TVScaglion  CNelson  J Dose-dependent effects of hydrocortisone on memory in human males. Physiol Behav. 1986;36283- 286
Link to Article
Fehm-Wolfsdorf  GReutter  KZenz  HBorn  JFehm  HL Are circadian variations in taste thresholds cortisol-dependent? J Psychophysiol. 1993;765- 72
Kirschbaum  CWolf  OTMay  MWippich  WHellhammer  DH Stress and drug-induced elevation of cortisol levels impair explicit memory in healthy adults. Life Sci. 1996;581475- 1483
Link to Article
Salem  MTainsh Jr  REBromberg  JLoriaux  DLChernow  B Perioperative glucocorticoid coverage. Ann Surg. 1994;219416- 425
Link to Article
Lamberts  SWJBruining  HAdeJong  FH Corticosteroid therapy in severe illness. N Engl J Med. 1997;3371285- 1292
Link to Article
Chernow  BAlexander  HRSmallridge  RCThompson  WRCook  DBeardsley  DFink  MPLake  CRFletcher  JR The hormonal responses to surgical stress. Arch Intern Med. 1987;1471273- 1278
Link to Article
Deuss  UDietrich  JKaulen  DFrey  KSpangenberger  WAllolio  BMatuszczak  MTroidl  HWinkelmann  W The stress response to laparoscopic cholecystectomy: investigation of endocrine parameters. Endoscopy. 1994;26235- 238
Link to Article
Plunkett  JJReeves  JDNgo  LBellows  WShafer  SLRoach  GHowse  JHerskowitz  AMangano  DT Urine and plasma catecholamine and cortisol concentrations after myocardial revascularization. Anesthesiology. 1997;86785- 796
Link to Article
Kehlet  HBinder  C Adrenocortical function and clinical course during and after surgery in unsupplemented glucocorticoid-treated patients. Br J Anaesth. 1973;451043- 1048
Link to Article
de Jong  FHMallios  CJansen  CScheck  PAELamberts  SWJ Etomidate suppresses adrenocortical function by inhibition of 11ß-hydroxylation. J Clin Endocrinol Metab. 1984;591143- 1147
Link to Article
Kirschbaum  CPirke  KMHellhammer  DH The "Trier Social Stress Test"—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;2876- 81
Link to Article
Naito  YFukata  JTamai  SSeo  NNakai  YMori  KImura  H Biphasic changes in hypothalamo-pituitary-adrenal function during the early recovery period after major abdominal surgery. J Clin Endocrinol Metab. 1991;73111- 117
Link to Article
Vermes  IBeishuizen  AHampsink  RMHaanen  C Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab. 1995;801238- 1242
Link to Article
Nurnberger  JICooler  CKaufmann  CAMalaspina  DFriedman  JHDePaulo  JRSimpson  SReich  TGershon  ESCloninger  CRBlehar  MTsuang  MTFaraone  SVPepple  FRMiller  MWynne  DMaxwell  MEGuroff  JKirch  DG Diagnostic Interview for Genetic Studies. Arch Gen Psychiatry. 1994;51849- 859
Link to Article
Farmer  RPierce  C Plasma cortisol determination: radioimmunoassay and competitive binding compared. Clin Chem. 1974;20411- 414
Kuzuya  HBlix  PHorwitz  DSteiner  DRubenstein  A Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes. 1977;2622- 29
Link to Article
Squire  LR Memory and Brain.  New York, NY Oxford University Press1987;
Butters  NSax  DMontgomery  KTarlow  S Comparison of the neuropsychological deficits associated with early and advanced Huntington's disease. Arch Neurol. 1978;35585- 589
Link to Article
Storandt  MBotwinick  JDanziger  WLBerg  LHughes  CP Psychometric differentiation of mild senile dementia of the Alzheimer's type. Arch Neurol. 1984;41497- 499
Link to Article
Wechsler  D Wechsler Memory Scale–Revised.  New York, NY Harcourt Brace Jovanovich1987;
Gangarosa  MESaykin  AJMalamut  BLGur  RC New scoring systems for the Wechsler Memory Scale. J Clin Exp Neuropsychol. 1988;101- 43
Winocur  G Effects of interference on discrimination and learning and recall by rats with hippocampal lesions. Physiol Behav. 1978;22339- 345
Link to Article
Aggleton  JPNicol  RMHuston  AEFairbairn  AF The performance of amnesic subjects on tests of experimental amnesia in animals: delayed matching-to-sample and concurrent learning. Neuropsychologia. 1988;26265- 272
Link to Article
Sidman  MStoddard  LTMohr  JP Some additional quantitative observations of immediate memory in a patient with bilateral hippocampal lesions. Neuropsychologia. 1968;6245- 254
Link to Article
Golden  CJ Stroop Color and Word Test: A Manual for Clinical and Experimental Uses.  Chicago, Ill Stoelting Co1978;
Milner  B Some effects of frontal lobectomy in man. Warren  JMAkert  KThe Frontal Granular Cortex and Behavior. New York, NY McGraw-Hill Book Co1964;313- 334
Hershey  TCraft  SGlauser  TAHale  S Short-term and long-term memory in early temporal lobe dysfunction. Neuropsychology. 1998;1252- 64
Link to Article
Alvarez  PZola-Morgan  SSquire  LR The animal model of human amnesia. Proc Natl Acad Sci U S A. 1994;915637- 5641
Link to Article
Rains  GDMilner  B Right-hippocampal contralateral-hand effect in the recall of spatial location in the tactual modality. Neuropsychologia. 1994;321233- 1242
Link to Article
Squire  LRZola-Morgan  SChen  KS Human amnesia and animal models of amnesia. Behav Neurosci. 1988;102210- 221
Link to Article
Kasuya  YIwano  MShibasaki  HFuruta  T Pharmacokinetic studies of cortisol after oral administration of deuterium-labelled cortisol to a normal human subject. Rapid Commun Mass Spectrom. 1995;1 (suppl) S29- S34
Goodman  LSGilman  A The Pharmacological Basis of Therapeutics. 6th ed. New York, NY Macmillan Publishing Co Inc1980;1480- 1482
Newcomer  JWSelke  GMelson  AKGross  JVogler  GPDagogo-Jack  S Dose-dependent cortisol-induced increases in plasma leptin concentration in healthy humans. Arch Gen Psychiatry. 1998;55995- 1000
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Cortisol-induced decreases in verbal memory performance (n=51). A similar effect of treatment conditions over time was observed for immediate and delayed paragraph recall. Recall performance differed across treatment groups after 4 days in the immediate and delayed recall conditions (asterisk indicates comparison point F2,48=4.04; P=.02 and F2,48=3.29; P=.05, respectively), with decreased immediate and delayed recall performance in the high-dose treatment group compared with the lower-dose (F1,48=4.54; P=.04 and F1,48=3.34; P=.07, respectively) and placebo (F1,48=7.50; P=.009 and F1,48=6.26; P=.02, respectively) groups. Error bars represent SE.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Treatment-induced changes in plasma cortisol concentrations (n=49). Treatment conditions resulted in stable stress-level elevation of plasma cortisol concentrations (time × treatment condition: F4,86=10.72; P<.001 by Huynh-Feldt), explained by differences after 1 (F2,48=8.62; P≤.001) and 4 (F2,47=13.46; P<.001) treatment days, with higher concentrations in those taking 160 mg/d compared with those taking 40 mg/d and placebo (P<.002, both days, by Bonferroni and Dunn tests). Error bars represent SE.

Graphic Jump Location

Tables

Table Graphic Jump LocationPerformance on Cognitive Measures During Placebo-Controlled Cortisol Treatment in 51 Healthy Adults*

References

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Cohen  RMWeingartner  HSmallberg  SPickar  DMurphy  DL Effort and cognition in depression. Arch Gen Psychiatry. 1982;39593- 597
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Rubinow  DRPost  RMSavard  RGold  PW Cortisol hypersecretion and cognitive impairment in depression. Arch Gen Psychiatry. 1984;41279- 283
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Roy-Byrne  PPWeingartner  HBierer  LMThompson  KPost  RM Effortful and automatic cognitive processes in depression. Arch Gen Psychiatry. 1986;43265- 267
Link to Article
Whelan  TBSchteingart  DEStarkman  MNSmith  A Neuropsychological deficits in Cushing's syndrome. J Nerv Ment Dis. 1980;168753- 757
Link to Article
Mauri  MSinforiani  EBono  GVignati  FBerselli  MEAttanasio  RNappi  G Memory impairment in Cushing's disease. Acta Neurol Scand. 1993;8752- 55
Link to Article
Newcomer  JWCraft  SHershey  TAskins  KBardgett  ME Glucocorticoid-induced impairment in declarative memory performance in adult humans. J Neurosci. 1994;142047- 2053
Wolkowitz  OMReus  VIWeingartner  HThompson  KBreier  ADoran  ARubinow  DPickar  D Cognitive effects of corticosteroids in man. Am J Psychiatry. 1990;1471297- 1303
Meijer  OCde Lange  ECMBreimer  DDde Boer  AGWorkel  JODe Kloet  ER Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology. 1998;1391789- 1793
Link to Article
Schinkel  AHWagenaar  Evan Deemter  LMol  CABorst  P Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995;961698- 1705
Link to Article
Beckwith  BEPetros  TVScaglion  CNelson  J Dose-dependent effects of hydrocortisone on memory in human males. Physiol Behav. 1986;36283- 286
Link to Article
Fehm-Wolfsdorf  GReutter  KZenz  HBorn  JFehm  HL Are circadian variations in taste thresholds cortisol-dependent? J Psychophysiol. 1993;765- 72
Kirschbaum  CWolf  OTMay  MWippich  WHellhammer  DH Stress and drug-induced elevation of cortisol levels impair explicit memory in healthy adults. Life Sci. 1996;581475- 1483
Link to Article
Salem  MTainsh Jr  REBromberg  JLoriaux  DLChernow  B Perioperative glucocorticoid coverage. Ann Surg. 1994;219416- 425
Link to Article
Lamberts  SWJBruining  HAdeJong  FH Corticosteroid therapy in severe illness. N Engl J Med. 1997;3371285- 1292
Link to Article
Chernow  BAlexander  HRSmallridge  RCThompson  WRCook  DBeardsley  DFink  MPLake  CRFletcher  JR The hormonal responses to surgical stress. Arch Intern Med. 1987;1471273- 1278
Link to Article
Deuss  UDietrich  JKaulen  DFrey  KSpangenberger  WAllolio  BMatuszczak  MTroidl  HWinkelmann  W The stress response to laparoscopic cholecystectomy: investigation of endocrine parameters. Endoscopy. 1994;26235- 238
Link to Article
Plunkett  JJReeves  JDNgo  LBellows  WShafer  SLRoach  GHowse  JHerskowitz  AMangano  DT Urine and plasma catecholamine and cortisol concentrations after myocardial revascularization. Anesthesiology. 1997;86785- 796
Link to Article
Kehlet  HBinder  C Adrenocortical function and clinical course during and after surgery in unsupplemented glucocorticoid-treated patients. Br J Anaesth. 1973;451043- 1048
Link to Article
de Jong  FHMallios  CJansen  CScheck  PAELamberts  SWJ Etomidate suppresses adrenocortical function by inhibition of 11ß-hydroxylation. J Clin Endocrinol Metab. 1984;591143- 1147
Link to Article
Kirschbaum  CPirke  KMHellhammer  DH The "Trier Social Stress Test"—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;2876- 81
Link to Article
Naito  YFukata  JTamai  SSeo  NNakai  YMori  KImura  H Biphasic changes in hypothalamo-pituitary-adrenal function during the early recovery period after major abdominal surgery. J Clin Endocrinol Metab. 1991;73111- 117
Link to Article
Vermes  IBeishuizen  AHampsink  RMHaanen  C Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab. 1995;801238- 1242
Link to Article
Nurnberger  JICooler  CKaufmann  CAMalaspina  DFriedman  JHDePaulo  JRSimpson  SReich  TGershon  ESCloninger  CRBlehar  MTsuang  MTFaraone  SVPepple  FRMiller  MWynne  DMaxwell  MEGuroff  JKirch  DG Diagnostic Interview for Genetic Studies. Arch Gen Psychiatry. 1994;51849- 859
Link to Article
Farmer  RPierce  C Plasma cortisol determination: radioimmunoassay and competitive binding compared. Clin Chem. 1974;20411- 414
Kuzuya  HBlix  PHorwitz  DSteiner  DRubenstein  A Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes. 1977;2622- 29
Link to Article
Squire  LR Memory and Brain.  New York, NY Oxford University Press1987;
Butters  NSax  DMontgomery  KTarlow  S Comparison of the neuropsychological deficits associated with early and advanced Huntington's disease. Arch Neurol. 1978;35585- 589
Link to Article
Storandt  MBotwinick  JDanziger  WLBerg  LHughes  CP Psychometric differentiation of mild senile dementia of the Alzheimer's type. Arch Neurol. 1984;41497- 499
Link to Article
Wechsler  D Wechsler Memory Scale–Revised.  New York, NY Harcourt Brace Jovanovich1987;
Gangarosa  MESaykin  AJMalamut  BLGur  RC New scoring systems for the Wechsler Memory Scale. J Clin Exp Neuropsychol. 1988;101- 43
Winocur  G Effects of interference on discrimination and learning and recall by rats with hippocampal lesions. Physiol Behav. 1978;22339- 345
Link to Article
Aggleton  JPNicol  RMHuston  AEFairbairn  AF The performance of amnesic subjects on tests of experimental amnesia in animals: delayed matching-to-sample and concurrent learning. Neuropsychologia. 1988;26265- 272
Link to Article
Sidman  MStoddard  LTMohr  JP Some additional quantitative observations of immediate memory in a patient with bilateral hippocampal lesions. Neuropsychologia. 1968;6245- 254
Link to Article
Golden  CJ Stroop Color and Word Test: A Manual for Clinical and Experimental Uses.  Chicago, Ill Stoelting Co1978;
Milner  B Some effects of frontal lobectomy in man. Warren  JMAkert  KThe Frontal Granular Cortex and Behavior. New York, NY McGraw-Hill Book Co1964;313- 334
Hershey  TCraft  SGlauser  TAHale  S Short-term and long-term memory in early temporal lobe dysfunction. Neuropsychology. 1998;1252- 64
Link to Article
Alvarez  PZola-Morgan  SSquire  LR The animal model of human amnesia. Proc Natl Acad Sci U S A. 1994;915637- 5641
Link to Article
Rains  GDMilner  B Right-hippocampal contralateral-hand effect in the recall of spatial location in the tactual modality. Neuropsychologia. 1994;321233- 1242
Link to Article
Squire  LRZola-Morgan  SChen  KS Human amnesia and animal models of amnesia. Behav Neurosci. 1988;102210- 221
Link to Article
Kasuya  YIwano  MShibasaki  HFuruta  T Pharmacokinetic studies of cortisol after oral administration of deuterium-labelled cortisol to a normal human subject. Rapid Commun Mass Spectrom. 1995;1 (suppl) S29- S34
Goodman  LSGilman  A The Pharmacological Basis of Therapeutics. 6th ed. New York, NY Macmillan Publishing Co Inc1980;1480- 1482
Newcomer  JWSelke  GMelson  AKGross  JVogler  GPDagogo-Jack  S Dose-dependent cortisol-induced increases in plasma leptin concentration in healthy humans. Arch Gen Psychiatry. 1998;55995- 1000
Link to Article

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