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Division of Endocrinology (J.D.V.), Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202; Endocrine Section (A.I.), Medical Service, Salem Veterans Affairs Medical Center, Salem, Virginia 24153; and Department of Psychiatry and Behavioral Sciences (D.N., N.T., F.C., B.J.C.), Duke University Medical Center, Durham, North Carolina 27710
Address all correspondence and requests for reprints to: Johannes D. Veldhuis, M.D., Division of Endocrinology, Department of Internal Medicine, P.O. Box 800202, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202. E-mail: JDV{at}virginia.edu
Abstract
To explore the mechanisms of homeostatic adaptation of the hypothalamo-pituitary-adrenal axis to an experimental low-feedback condition, we quantitated pulsatile (ultradian), entropic (pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion during high-dose metyrapone blockade (2 g orally every 2 h for 12 h, and then 1 g every 2 h for 12 h). Plasma ACTH and cortisol concentrations were sampled concurrently every 10 min for 24 h in nine adults. The metyrapone regimen reduced the amplitude of nyctohemeral cortisol rhythm by 45% (P = 0.0013) and delayed the time of the cortisol maximum (acrophase) by 7.1 h (P = 0.0002). Attenuated cortisol negative feedback stimulated a 7-fold increase in the mean (24-h) plasma ACTH concentration, which rose from 24 ± 1.6 to 169 ± 31 pg/ml (ng/liter) (P < 0.0001). Augmented ACTH output was driven by a 12-fold amplification of ACTH secretory burst mass (integral of the underlying secretory pulse) (21 ± 3.1 to 255 ± 64 pg/ml; P < 0.0001), yielding a higher percentage of ACTH secreted in pulses (53 ± 3.5 vs. 92 ± 1.3%; P < 0.0001). There were minimal elevations in basal (nonpulsatile) ACTH secretion (by 50%; P = 0.0049) and ACTH secretory burst frequency (by 36%; P = 0.031). The estimated half-life of ACTH (median, 22 min) and the calculated ACTH secretory burst half-duration (pulse event duration at half-maximal amplitude) (median, 23 min) did not change. Hypocortisolemia evoked remarkably more orderly subordinate patterns of serial ACTH release, as quantitated by the approximate entropy statistic (P = 0.003). This finding was explained by enhanced regularity of successive ACTH secretory pulse mass values (P = 0.032). In contrast, there was no alteration in serial ACTH interpulse-interval (waiting-time) regularity. At the level of 24-h ACTH rhythmicity, cortisol withdrawal enhanced the daily rhythm in ACTH secretory burst mass by 29-fold, elevated the mesor by 16-fold, and delayed the acrophase by 3.4 h from 0831 h to 1154 h (each P < 10-3).
In summary, short-term glucocorticoid feedback deprivation primarily (>97% of effect) amplifies pulsatile ACTH secretory burst mass, while minimally elevating basal/nonpulsatile ACTH secretion and ACTH pulse frequency. Reduced cortisol feedback paradoxically elicits more orderly (less entropic) patterns of ACTH release due to emergence of more regular ACTH pulse mass sequences. Cortisol withdrawal concurrently heightens the amplitude and mesor of 24-h rhythmic ACTH release and delays the timing of the ACTH acrophase. In contrast, the duration of underlying ACTH secretory episodes is not affected, which indicates that normal pulse termination may be programmed centrally rather than imposed by rapid negative feedback. Accordingly, we hypothesize that adrenal glucocorticoid negative feedback controls hypothalamo-pituitary-adrenal axis dynamics via the 3-fold distinct mechanisms of repressing the mass of ACTH secretory bursts, reducing the orderliness of the corticotrope release process, and modulating the intrinsic diurnal rhythmicity of the hypothalamo-corticotrope unit.
THE STRESS-ADAPTIVE HYPOTHALAMO-PITUITARY-ADRENAL (HPA) axis manifests prominently pulsatile (ultradian), pattern-specific (entropic), and rhythmic (24-h circadian) features (1, 2, 3, 4, 5, 6, 7). In principle, corticotropin secretory dynamics reflect the ensemble effects of interactions among all components of the axis (Keenan, D. M., and J. D. Veldhuis, unpublished observations). In particular, intermittent output of hypothalamic arginine vasopressin (AVP) and CRH triggers episodic ACTH release, which in turn stimulates time-varying secretion of cortisol. Cortisol imposes negative feedback to restrain AVP/CRH and ACTH secretion (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47). Inferentially, this closed-loop network of time-delayed interactions, rather than any single component acting in isolation, coordinates the orderly dynamics of AVP/CRH, ACTH, and cortisol release (Keenan, D. M., and J. D. Veldhuis, unpublished observations).
In view of the foregoing multisite, interactive, time-lagged and nonlinear features of HPA axis regulation, intuitive predictions of neuroregulatory adaptations are extremely difficult (Keenan, D. M., and J. D. Veldhuis, unpublished observations). Thus, the present investigation directly quantitates observed homeostatic reactivity of the human hypothalamo-corticotrope unit to experimentally enforced low glucocorticoid feedback. To this end, we carried out a 4-fold analysis of the basal, pulsatile, pattern-sensitive, and 24-h rhythmic modes of ACTH secretory control under normal and reduced cortisol feedback.
Materials and Methods
Human subjects
Nine volunteers (five men and four women) participated in this study, after providing written informed consent approved by the Duke University School of Medicine. The median (range) values for age were 39 (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48) yr in women and 51 (38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62) yr in men; body mass indices were 27 (23, 24, 25, 26, 27, 28, 29, 30, 31) kg/m2 in women and 25 (21, 22, 23, 24, 25, 26, 27, 28, 29) kg/m2 in men. Subjects had conventional work and sleeping patterns with no recent transmeridian travel, dieting or weight gain, intercurrent psychosocial stress, medication use, drug or alcohol abuse, neuropsychiatric illness, or acute or chronic systemic disease. A complete medical history, physical examination, and structured psychiatric interview screening for substance abuse and disorders of mood, eating, behavior, personality and/or psychosis were unremarkable. Biochemical tests of hematological, renal, hepatic, metabolic, and endocrine function were normal. Pregnancy tests and urinary drug screening were negative. No volunteer was receiving hormones or had been exposed to any glucocorticoids recently.
Volunteers were admitted to the inpatient General Clinical Research Center at 1900 h. A catheter was placed in a forearm vein at 2000 h, and subjects rested quietly until sampling began 4 h later. Beginning at midnight, volunteers were given oral placebo capsules every 2 h for 24 h (baseline, day 1) and then metyrapone every 2 h for 24 h (experimental, day 2). The dosing schedule of metyrapone was based on pilot studies of tolerability. Subjects received 1000 mg orally every 2 h for six doses, followed by 500 mg every 2 h for six additional doses administered with milk and crackers. Meals were provided at 0730, 1200, and 1800 h. Sleep, activity and any symptoms were noted every 10 min. Blood samples (1.6 ml) were withdrawn at 10-min intervals in chilled EGTA-containing tubes, centrifuged at 4 C to separate plasma, and frozen at -70 C before assay. Total blood loss was 489 ml. Volunteers were compensated for their participation. No subject experienced significant side effects.
Hormone assays
Plasma ACTH concentrations were assayed in each sample in duplicate by two-site monoclonal immunoradiometric assay using a robotics-assisted system (Nichols Institute Diagnostics, San Juan Capistrano, CA), exactly as characterized earlier (20, 47, 52). Assay sensitivity was 5 pg/ml (= ng/liter) with median intra-assay coefficients of variation (CVs) of 8.5% (ACTH concentration, 5–30 pg/ml), 4.8% (30–100 pg/ml), and 6.3% (100–600 pg/ml). All samples from a given subject were assayed together to eliminate interassay variance, which averaged less than 10%. The specificity of the immunoradiometric assay was reported previously (20, 47, 52). Cortisol was assayed in duplicate by solid-phase RIA (Diagnostic Products Inc., Los Angeles, CA), which had a sensitivity of 0.14 µg/dl, intra-assay CVs of 7.7% (serum cortisol concentration, 2–10 µg/dl) and 6.0% (10–30 µg/dl), and an interassay CV of less than 8.8% (to convert µg/dl cortisol to nmol/liter, multiply by 27.6) (20, 21, 22, 23, 53, 54, 55, 56). For deconvolution analysis (see below), all replicated samples (n = 289) in any given series were used to define a continuous (power function) relationship between the measured hormone concentration and the within-sample variance (57, 58, 59).
Deconvolution analysis
Multiparameter deconvolution analysis was used to quantitate underlying basal and pulsatile ACTH secretion and estimate the corresponding (endogenous) half-life (57, 58, 60). Daily pulsatile secretion is the product of secretory burst (pulse) frequency and the mean mass released per burst. The mass secreted per burst is the analytical integral of the secretory pulse. The latter is determined by its amplitude (maximal secretory rate) and half-duration (duration of the burst at half-maximal amplitude). Basal ACTH secretion was calculated as time-invariant interpulse release. Secretory pulse identification required that the estimated secretory-burst mass exceed zero by 95% joint statistical confidence intervals.
Approximate entropy (ApEn) analysis
ApEn was used as a model-free and scale-independent regularity measure to quantify the serial orderliness of the hormone time series (50, 51, 61, 62). ApEn comprises a family of two-parameter statistics defined by ApEn (m, r), where m is a run length and r is a de facto tolerance width (see 49, 63, 64, 65 for practical examples). We used m = 1 and r = 20% of each intraseries SD here, as previously validated for neurohormone profiles of this length (n = 145 samples) (48, 66). ApEn monitors the consistency of subpattern recurrence in data series, unlike conventional pulse detection or the analysis of circadian rhythmicity. Higher ApEn values denote greater relative disorderliness (or less pattern regularity), as reported for GH, ACTH, and PRL time series in acromegaly, Cushing’s disease, and prolactinomas (63, 67, 68); GH secretion profiles in mid-to-late puberty and in children or adults given (aromatizable) sex-steroid hormones (65, 69, 70, 71); GH release in women compared with men (65, 69, 72); and ACTH, LH, GH, cortisol, testosterone, and insulin release in aging humans (49, 64, 73, 74, 75).
Because ApEn is also dependent on N (series length), comparisons are valid for fixed N, as applied here. In addition, we decorrelated ApEn from N when quantifying irregularity in pulse-mass and interpulse-interval (successive waiting-time) sequences by computing the ratio of the observed ApEn value for each series to the mean ApEn derived from 1000 random shufflings of the same series. Thus, ApEn ratios of unity approach mean empirical randomness for any given sequence, whereas values less than 1.0 denote more orderly sequences.
Cosinor analysis
The 24-h rhythmicity of plasma ACTH and cortisol concentrations, as well as of pertinent deconvolution-derived ACTH and cortisol secretory measures (e.g. secretory burst mass and interburst intervals), was quantitated by cosinor analysis, as described earlier (21, 76). This procedure entails unweighted regression of a cosine function of 1440 min periodicity on the observed time series. Ninety-five percent group statistical confidence intervals were determined for the fitted amplitude (50% of the nadir-zenith difference), mesor (cosine mean), and acrophase (clocktime of calculated maximum value).
Statistical analysis
A paired two-tailed t test with unknown variance was applied to compare log-transformed measures in the control and metyrapone study sessions. P < 0.05 was construed as statistically significant. Data are presented as the mean ± SEM (median).
Results
Cortisol concentration profiles
On the baseline day, there was no indication of situational
stress, as evidenced by the low plasma cortisol values at midnight
(Fig. 1
). Metyrapone administration
prevented the morning surge of cortisol. Values remained well below
baseline until late afternoon. This reversal followed exposure of the
adrenal gland to extremely high ACTH concentrations (see below). Mean
(24-h) plasma cortisol concentrations were unchanged at 4.6 ±
0.45 (metyrapone) vs. 5.7 ± 0.43 (control).
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).
Diurnal variations in cortisol secretory burst mass were damped by
45%, and the diurnal variation in cortisol interburst intervals was
abolished during metyrapone administration (Table 2).
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Plasma ACTH concentration profiles are illustrated for one subject
in Fig. 1
. Baseline ACTH secretion was consistent with the absence of
situational stress. Fig. 2 shows the
dispersion of mean and integrated (24-h) plasma ACTH concentrations in
all nine subjects studied during placebo and metyrapone administration.
Plasma ACTH concentrations rose by a mean of 7-fold in response to
metyrapone intervention (P <
10-4) and peaked later (see below).
|
). Feedback
interruption amplified the daily pulsatile ACTH secretion rate by
18.5-fold (P < 10-4) and the
total (pulsatile plus basal) ACTH secretion rate commensurately
(P < 10-4). The percentage of
total daily ACTH secretion that was pulsatile increased from 53 ±
3.5 (53) (placebo) to 92 ± 1.3 (91)
(metyrapone; P < 10-4).
Accordingly, at least 97% of the total increase in ACTH secretion in
response to metyrapone occurred in the pulsatile component.
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, ApEn of ACTH fell significantly and
consistently during metyrapone intervention, which denotes more orderly
ACTH secretory patterns (P = 0.002).
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).
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, A and B). Metyrapone
elevated the amplitude and mesor of the 24-h rhythm in ACTH secretory
burst mass by 28- and 15-fold, respectively (both P <
0.001), and tended to delay the acrophase (by a mean of 3.4 h;
P = 0.07). Cortisol depletion did not significantly
influence the amplitude or acrophase, but reduced the mesor, of the
24-h rhythm in ACTH interpulse intervals (P < 0.025),
consistent with the small rise in ACTH secretory-burst frequency (see
above).
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, withdrawal of cortisol
negative feedback heightened the orderliness (reduced the mean ApEn
ratio) of serial ACTH pulse-mass values (P = 0.032). In
contrast, the regularity (mean ApEn ratio) of serial ACTH
interpulse-interval lengths was unaltered; viz., 0.945
± 0.018 (0.943) control vs. 0.939 ± 0.024 (0.941)
metyrapone (P = NS).
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The present interventional analysis of normal HPA axis dynamics identifies an ensemble of distinctive neuroregulatory mechanisms that mediate unleashing of ACTH secretion by low glucocorticoid negative feedback. In particular, statistical analyses unveiled prominent (12-fold) and specific amplification of ACTH secretory burst mass (integral of the secretory pulse), with only minimal elevations in basal (nonpulsatile) ACTH secretion (50% increase) and ACTH pulse frequency (36% rise). Augmented ACTH secretory burst mass drove at least 97% of stimulated ACTH output during cortisol deprivation. Both the calculated half-life of endogenous ACTH and the half-duration of ACTH secretory bursts were unaffected by the low feedback condition. The lack of effect of low cortisol feedback on the half-duration of ACTH secretory bursts (duration of the secretory pulse at half- maximal amplitude) indicates that under normal conditions their duration is centrally programmed rather than terminated by rapid feedback by the resultant rise in circulating cortisol. The ApEn of plasma ACTH concentration profiles fell significantly, thereby quantitating greater patterned orderliness of the ACTH release process in the low feedback state (see below). The mesor (mean) and amplitude of 24-h rhythmic (mean to zenith increment) ACTH output rose markedly and the acrophase (timing of maximum) of ACTH secretory burst mass was delayed by 3.4 h. From the foregoing findings, we infer that glucocorticoid normal negative feedback in healthy adults primarily: 1) represses the mass of ACTH released per burst, 2) decreases the orderliness of ACTH secretion patterns, 3) reduces the mesor and amplitude of the diurnal ACTH rhythm, and 4) modulates the timing of the nyctohemeral variation in the hypothalamo-corticotrope unit.
We started glucocorticoid withdrawal at midnight and used a higher dose
of metyrapone than is usual in clinical testing of adrenocortical
insufficiency (77). This modified regimen was adopted to
ensure low plasma cortisol concentrations throughout the earlier
morning surge of ACTH secretion. Given the hazard of adrenal
steroidogenic blockade in adrenally compromised patients, we emphasize
that the present protocol was applied investigationally to healthy
inpatient volunteers under continuing nursing surveillance. At this
dosage schedule, metyrapone reduced the (24-h) mean serum cortisol
concentration to less than 5.0 µg/dl, limited the amplitude of the
nyctohemeral serum cortisol concentration rhythm to 2.0 µg/dl,
blunted the 24-h rhythm in cortisol secretory burst mass by 45%, and
abolished the diurnal variation in cortisol interpulse intervals. Thus,
this experimental schedule of high-dose metyrapone administration
substantially limited cortisol feedback for 15–18 h, after which some
breakthrough of cortisol production occurred (Fig. 1). Unexpectedly,
markedly elevated ACTH output continued at that time. The latter could
suggest that glucocorticoid feedback on the hypothalamo-pituitary
corticotrope unit was impaired after the intense period of
hypersecretion of ACTH. In comparable animal studies, there is a marked
increase in AVP and CRH release in portal blood as well as a rise in
the AVP/CRH ratio after more than 12 h of pharmacological
adrenalectomy (78). Combined AVP and CRH stimulation can
be associated with impaired glucocorticoid feedback on ACTH release
(79). As a practical matter, greater inhibition of 24-h
cortisol biosynthesis is unlikely to be attained in human volunteers
given metyrapone orally.
In the present study, the low glucocorticoid feedback state imposed before the morning cortisol maximum evoked a marked rise in ACTH output and a delay in the ACTH acrophase. These data suggest that cortisol feedback controls the timing as well as the amplitude of the endogenous circadian HPA rhythm. However, an early analysis of patients with primary Addison’s disease disclosed persistence of day/night ACTH variations in the face of impoverished glucocorticoid negative feedback (80). Diurnal ACTH rhythmicity thus also might reflect glucocorticoid-independent 24-h rhythmicity of hypothalamic CRH and AVP secretion (16, 26, 81, 82, 83, 84, 85, 86, 87). Indeed, indirect animal and clinical experiments point to diurnal variations in the release of hypothalamic AVP, which is a potent ACTH secretagogue alone and synergizes with the CRH stimulus. For example, transgenic mice harboring a disrupted CRH gene and postoperatively hypocortisolemic patients with Cushing’s disease (and, thus, presumptive endogenous CRH deficiency) exposed to an unvarying infusion of CRH continue to generate 24-h rhythmic glucocorticoid output (25, 29, 30, 35, 82, 88, 89).
A striking finding in the present analysis of open-loop (feedback-withdrawn) corticotrope secretion is the consistent decline in ACTH ApEn. Analytically, this decrement denotes a quantifiably more orderly corticotrope release process. Thus, on mathematical grounds, the fall in ACTH ApEn signifies altered CRH/AVP-ACTH coupling in the setting of muted cortisol negative feedback (48, 49, 63, 67, 68). Biostatistical considerations in simpler reductionist mathematical models predict that reduced interparameter linkages (e.g. less negative feedback) will account for such more regular system output (61). The calcium-PTH feedback system also manifests greater regularity of PTH secretion in response to relevant feedback withdrawal (90, 91). More orderly ACTH secretion during feedback relief was not due simply to higher plasma ACTH concentrations, because ApEn is a translation-independent and scale-invariant statistic (50, 51, 62). Interestingly, restraint of feedback signaling in some other neuroendocrine axes actually induces more disorderly hormone output patterns (56, 92, 93, 94, 95, 96). Accordingly, we infer that axis-specific neurointegrative structure dictates the particular mechanisms of regularity control.
Basal rates of ACTH secretion rose by approximately 50% and ACTH pulse frequency by 36% during experimental glucocorticoid depletion. These changes, albeit small in magnitude, occurred consistently. From the vantage of feedback control, we speculate that the observed elevation in basal/nonpulsatile corticotrope secretion arises from a reduction in cortisol’s direct inhibition of pituitary ACTH production. In contrast, the inferred increase in ACTH pulse frequency may be due to attenuation of cortisol’s putative limbo-hypothalamic repression of pulsatile AVP/CRH secretion. Alternatively, from an analytical pulse-detection perspective, the greater mass of ACTH secreted per burst during metyrapone blockade may have produced nearly confluent consecutive ACTH secretory bursts (thus elevating apparent interpulse ACTH secretion spuriously) and/or favored enhanced detection of ACTH pulsatility (thus increasing the apparent peak frequency) (60, 97, 98).
Amplitude-specific regulation of neurohormone output is a physiological hallmark of the somatotropic and gonadotropic axes in puberty (65, 69, 99, 100, 101, 102, 103) and the basal corticotropic, somatotropic, gonadotropic, thyrotropic, and lactotropic axes in the adult (20, 21, 73, 75, 104, 105). Here, we extend the notion of pulse amplitude regulation to include feedback control of the regularity of successive pituitary secretory burst mass values. In particular, ApEn analysis disclosed statistically nonrandom ACTH pulse-mass sequences at baseline (placebo), which became more orderly during open-loop stimulation of ACTH secretion. This distinctive neuroregulatory adaptation offers a plausible basis for the greater orderliness of the plasma ACTH concentration time series during hypocortisolemia. Mechanistically, more regular successive ACTH secretory-burst output during low glucocorticoid feedback could indicate more uniform recurrent hypothalamic CRH/AVP signals and/or more consistent corticotrope-cell responsiveness to CRH/AVP inputs across the 24 h. Thus, we would infer, conversely, that physiological negative feedback by cortisol may reduce the regularity of sequential hypothalamic CRH/AVP secretion and/or erode the uniformity of corticotrope responsiveness to repeated CRH/AVP stimuli.
In contrast to the quantifiable regularity of ACTH secretory burst-mass sequences, successive ACTH pulse waiting times (interpulse-interval lengths) were nearly random (when compared with empirically random surrogate series estimated statistically by shuffling each set of interpulse interval values 1000 times). ACTH interpulse intervals remained highly irregular after interruption of cortisol negative feedback. From a physiological viewpoint, a nearly random ACTH pulse-timing mechanism may indicate a so-called renewal process (106, 107). The latter is defined when the waiting times between successive events are statistically independent, suggesting that the pulse-generator mechanism is memoriless. Other than hypothalamic GnRH (108) and CRH/AVP pulsatility (see above), no other neuroendocrine pulse-timing properties are known as yet in the human. Here, in extension of the foregoing renewal-process concept derived in closed-loop (feedback-enforced) physiological contexts, we demonstrate stability of the open-loop (feedback-withdrawn) CRH/AVP-ACTH pulsing mechanism as well.
In summary, the present clinical investigative paradigm of HPA dynamics in healthy adults unmasks prominent (>97%) and selective regulation of ACTH secretory pulse mass (and, hence, amplitude) by cortisol negative-feedback signaling with sparing of ACTH secretory-burst duration and half-life. The mean, amplitude, and timing of 24-h rhythmic corticotropin production are likewise controlled by adrenal feedback repression. Glucocorticoid negative feedback decreases orderliness of the ACTH secretory process by reducing the regularity of successive ACTH secretory burst-mass values. In contrast, ACTH pulse waiting times are nearly random and unaffected by the low feedback state. Thus, in the human, adrenal cortisol specifically restrains ACTH secretory burst mass, suppresses 24-h ACTH rhythmicity, and subdues corticotrope secretory regularity.
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We thank Patsy Craig for her skillful preparation of the manuscript; Paula P. Azimi for the deconvolution analysis, data management, and graphics; and Brenda Grisso for performance of the immunoassays. We thank Catherine Hellegers and Gina Harris, who served as study coordinators at Duke University Medical Center, and the staff and leadership of the Duke General Clinical Research Center (GCRC) for their assistance. We also thank Uwe Meya, M.D., of Ciba-Geigy (now Novartis), Basel, Switzerland, for enabling us to obtain metyrapone for this investigation. This focused report necessarily omits many primary references because of editorial constraints. The authors therefore acknowledge numerous colleagues who have made earlier foundational observations.
Footnotes
This work was supported in part by NIH Grant MO1 RR00847 to the GCRC of the University of Virginia Health Sciences Center, NICHD/NIH through cooperative agreement (U-54 HD28934) as part of the Specialized Cooperative Centers Program in Reproduction Research, NIH RO1 AG14799 (to J.D.V.) and RO1 HD 2R01MH 39593 (to B.J.C.). This work was supported by NIH Grant MO1-RR-30 to the GCRC of Duke University Medical Center and by NIH Grant P30 MH40159, Clinical Research Center for the Study of Depression in Late Life (to B.J.C.).
Present address for B.J.C.: Pacific Behavioral Research Foundation, Carmel, California 93922-3040.
Abbreviations: ApEn, Approximate entropy; AVP, arginine vasopressin; HPA, hypothalamo-pituitary-adrenal.
References
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