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Metabotropic glutamate receptors modulate feedback inhibition in a developmentally regulated manner in rat dentate gyrus.

We investigated group II metabotropic glutamate receptor (mGluR) modulation of glutamatergic input onto hilar-border interneurones and its regulation of feedback inhibition in the dentate gyrus. Selective activation of group II mGluRs with (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) depressed mossy fibre (MF)-evoked excitatory drive to these interneurones with significantly greater depression in juvenile than adult rats. During 20 Hz MF stimulus trains, EPSCs became depressed. Depression during the early, but not later part of the train was significantly greater in juvenile than adult rats and was blocked by the mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495). In dentate granule cells from juvenile rats polysynaptic feedback IPSCs, but not monosynaptic IPSCs, were strongly suppressed by DCG-IV. DCG-IV also suppressed feedback inhibition of perforant path-evoked population spikes. In contrast, in adult animals DCG-IV did not significantly depress feedback inhibition. During 20 Hz stimulus trains in juvenile animals the summation of polysynaptic, but not monosynaptic IPSCs was suppressed by synaptically activated group II mGluRs. Blockade of these mGluRs with LY341495 significantly increased the area and duration of the summated IPSC, causing greater feedback inhibition of granule cell firing. In contrast, in adult animals LY341495 did not alter feedback inhibition following the stimulus train. These findings indicate that group II mGluRs modulate excitatory drive to interneurones in a developmentally regulated manner and thereby modulate feedback inhibition in the dentate gyrus.

Amino Acids↗

Stabilizing PID controllers for a single-link biomechanical model with position, velocity, and force feedback.

In this paper we address the problem of PID stabilization of a single-link inverted pendulum-based biomechanical model with force feedback, two levels of position and velocity feedback, and with delays in all the feedback loops. The novelty of the proposed model lies in its physiological relevance, whereby both small and medium latency sensory feedbacks from muscle spindle (MS), and force feedback from Golgi tendon organ (GTO) are included in the formulation. The biomechanical model also includes active and passive viscoelastic feedback from Hill-type muscle model and a second-order low-pass function for muscle activation. The central nervous system (CNS) regulation of postural movement is represented by a proportional-integral-derivative (PID) controller. Padé approximation of delay terms is employed to arrive at an overall rational transfer function of the biomechanical model. The Hermite-Biehler theorem is then used to derive stability results, leading to the existence of stabilizing PID controllers. An algorithm for selection of stabilizing feedback gains is developed using the linear matrix inequality (LMI) approach.

Adaptation, Physiological↗

Learning to produce speech with an altered vocal tract: the role of auditory feedback.

Modifying the vocal tract alters a speaker's previously learned acoustic-articulatory relationship. This study investigated the contribution of auditory feedback to the process of adapting to vocal-tract modifications. Subjects said the word /tas/ while wearing a dental prosthesis that extended the length of their maxillary incisor teeth. The prosthesis affected /s/ productions and the subjects were asked to learn to produce "normal" /s/'s. They alternately received normal auditory feedback and noise that masked their natural feedback during productions. Acoustic analysis of the speakers' /s/ productions showed that the distribution of energy across the spectra moved toward that of normal, unperturbed production with increased experience with the prosthesis. However, the acoustic analysis did not show any significant differences in learning dependent on auditory feedback. By contrast, when naive listeners were asked to rate the quality of the speakers' utterances, productions made when auditory feedback was available were evaluated to be closer to the subjects' normal productions than when feedback was masked. The perceptual analysis showed that speakers were able to use auditory information to partially compensate for the vocal-tract modification. Furthermore, utterances produced during the masked conditions also improved over a session, demonstrating that the compensatory articulations were learned and available after auditory feedback was removed.

Adult↗

Effects of frequency-shifted feedback on the pitch of vocal productions.

Previous investigations into the effects of distorted auditory feedback on vocalizations have been limited to manipulations of intensity, background noise, temporal delay, or to selective filtering of frequency. The current study reports the results of real-time shifts of the frequency components of auditory feedback. Subjectively, such shifts are perceived primarily as an alteration in the fundamental frequency (F0) of the speech. Subjects performed a variety of tasks under conditions where they received either normal auditory feedback or frequency-shifted feedback. Under normal feedback conditions, subjects maintained approximately constant F0 as instructed. With frequency-shifted feedback, subjects attempted to compensate for the shift by adjusting their F0 up or down such that the resulting feedback appeared to be "normal."

Feedback↗

Effect of monaural and binaural altered auditory feedback on stuttering frequency.

The effect of monaural and binaural alterations in auditory feedback on stuttering frequency was investigated. Eleven participants who stutter read aloud under nonaltered auditory feedback (NAF) and monaural and binaural conditions of frequency altered feedback [(FAF), on-quarter octave shift upward] and delayed auditory feedback [(DAF), 50-ms delay] at a normal speech rate. Relative to the NAF condition, reductions in stuttering frequency of approximately 60%-75% were found with the altered auditory feedback conditions. Post hoc single-df comparisons revealed a reduction in stuttering frequency with altered auditory feedback versus NAF (p < 0.0001), a greater reduction in stuttering frequency for binaural compared to monaural altered auditory feedback (p = 0.028), and nonsignificant differences in stuttering frequencies for right versus left monaural conditions (p = 0.54) and DAF versus FAF (p = 0.70).

Adolescent↗

The mechanical action of proprioceptive length feedback in a model of cat hindlimb.

Postural regulation is an important part of a variety of motor tasks, including quiet standing and locomotion. Muscle length feedback, both the autogenic length feedback arising from a muscle's own spindles, and heterogenic length feedback, arising from its agonists and antagonists, is a strong modulator of muscle force and well suited to postural maintenance. The effects of this reflex feedback on 3-D force generation and limb mechanics are not known. In this paper, we present a mechanical model for relating 3-D changes in cat hindlimb posture to changes in muscle lengths. These changes in muscle length are used to estimate changes in both intrinsic muscle force generation and muscle activation by length feedback pathways. Few muscles are found to have directly agonist mechanical actions, and most differ by more than 20 degrees. Endpoint force fields are largely uniform across the space investigated. Both autogenic and heterogenic feedback contribute to whole limb resistance to perturbation, autogenic pathways being most dramatic. Length feedback strongly reinforced a restoring force in response to endpoint displacement.

Animals↗

Effect of feedback on test ordering behaviour of general practitioners.

OBJECTIVE: To assess the effect of feedback on the test ordering behaviour of general practitioners. DESIGN: Comparison of requests at two diagnostic centres, and internal comparison between tests which were discussed in feedback and tests which were not. SETTING: A diagnostic centre in Maastricht giving feedback and another elsewhere in the Netherlands (laboratory A) not giving feedback. SUBJECTS: All 85 general practitioners in the region of Maastricht, and all general practitioners in the region of laboratory A. MAIN OUTCOME MEASURES: Numbers of tests requested by general practitioners. RESULTS: Requests at the Maastricht diagnostic centre decreased soon after the onset of feedback whereas there was a persistent increase in requests at laboratory A. Tests that were discussed showed the strongest decrease (maximum 40%), though tests that were not discussed decreased as well (maximum 27%). CONCLUSIONS: Feedback on diagnostic requests may exert a strong influence on request behaviour. Four years after the onset of feedback the effects were still noticeable.

Clinical Laboratory Techniques↗

Retrieval feedback in MEDLINE.

OBJECTIVE: To investigate a new approach for query expansion based on retrieval feedback. The first objective in this study was to examine alternative query-expansion methods within the same retrieval-feedback framework. The three alternatives proposed are: expansion on the MeSH query field alone, expansion on the free-text field alone, and expansion on both the MeSH and the free-text fields. The second objective was to gain further understanding of retrieval feedback by examining possible dependencies on relevant documents during the feedback cycle. DESIGN: Comparative study of retrieval effectiveness using the original unexpanded and the alternative expanded user queries on a MEDLINE test collection of 75 queries and 2,334 MEDLINE citations. MEASUREMENTS: Retrieval effectivenesses of the original unexpanded and the alternative expanded queries were compared using 11-point-average precision scores (11-AvgP). These are averages of precision scores obtained at 11 standard recall points. RESULTS: All three expansion strategies significantly improved the original queries in terms of retrieval effectiveness. Expansion on MeSH alone was equivalent to expansion on both MeSH and the free-text fields. Expansion on the free-text field alone improved the queries significantly less than did the other two strategies. The second part of the study indicated that retrieval-feedback-based expansion yields significant performance improvements independent of the availability of relevant documents for feedback information. CONCLUSIONS: Retrieval feedback offers a robust procedure for query expansion that is most effective for MEDLINE when applied to the MeSH field.

Feedback↗

Adaptation of handwriting size under distorted visual feedback in patients with Parkinson's disease and elderly and young controls.

OBJECTIVE: The ability to use visual feedback to control handwriting size was compared in patients with Parkinson's disease (PD), elderly people, and young adults to better understand factors playing a part in parkinsonian micrographia. METHODS: The participants wrote sequences of eight cursive l loops with visual target sizes of 0.5 and 2 cm on a flat panel display digitiser which both recorded and displayed the pen movements. In the pre-exposure and postexposure conditions, the display digitiser showed the actual pen trace in real time and real size. In the distortion exposure conditions, the gain of the vertical dimension of the visual feedback was either reduced to 70% or enlarged to 140%. RESULTS: The young controls showed a gradual visuomotor adaptation that compensated for the visual feedback distortions during the exposure conditions. They also showed significant after effects during the postexposure conditions. The elderly controls marginally corrected for the size distortions and showed small after effects. The patients with PD, however, showed no trial by trial adaptations or after effects but instead, a progressive amplification of the distortion effect in each individual trial. CONCLUSION: The young controls used visual feedback to update their visuomotor map. The elderly controls seemed to make little use of visual feedback. The patients with Parkinson's disease rely on the visual feedback of previous or of ongoing strokes to programme subsequent strokes. This recursive feedback may play a part in the progressive reductions in handwriting size found in parkinsonian micrographia.

Aged↗

A model of combined feedforward and feedback control of coronary blood flow.

Recent evidence shows that norepinephrine affects coronary blood flow not only by alpha-receptor-mediated vasoconstriction and by feedback metabolic vasodilation that occurs as a result of myocardial beta-receptor activation, but also by the direct activation of coronary vascular beta-receptors that increase flow in a feedforward manner. The implications of combined feedforward and feedback control in maintaining the balance between metabolism and flow were investigated in the present mass balance model. Feedback was represented by a closed loop and was based on the hypothesis that the regulated variables are myocardial PO2 and PCO2 and that divergence of these variables from their operating point values functions as the metabolic error signals that manipulate coronary vascular smooth muscle and flow to match metabolism. alpha-Receptor-mediated vasoconstriction and beta-receptor-mediated vasodilation are represented by feedforward open loops that are activated simultaneously with increases in metabolism. The postulated control schemes of 1) metabolic feedback control alone, 2) feedback plus alpha- and beta-adrenergic feedforward control, and 3) feedback plus beta-adrenergic feedforward control were able to simulate the steady-state increase in coronary flow and the decrease in coronary venous PO2 that occurs during comparable experimental conditions. The simulations demonstrate that 1) the speed and accuracy of the flow response improve as beta-adrenergic feedforward control is added and alpha-adrenergic feedforward control is removed from the control scheme, 2) high feedback gain also improves the accuracy of the flow response, but the penalty is instability, and 3) a lag in alpha-adrenergic feedforward control improves the stability of the coronary response.

Animals↗

Resetting of tubuloglomerular feedback: evidence for a humoral factor in tubular fluid.

Experiments were performed on chronically salt-loaded rats to determine whether resetting of tubuloglomerular feedback is caused by changes in the sensitivity of the juxtaglomerular apparatus itself or by changes of tubular fluid composition. The feedback response was quantified in both salt-loaded and salt-deplete rats by measuring early proximal flow rate (EPF) during loop perfusion at 40, 10, and 0 nl/min using tubular fluid harvested from both groups and with Ringer solution. In salt-loaded rats endogenous tubular fluid produced only a small feedback response (EPF40-0 = 1.9 +/- 1.5 nl/min), whereas exogenous tubular fluid from salt-deplete rats or Ringer solution produced normal feedback responses (EPF40-0 = 15.4 +/- 2.0 and 10.6 +/- 1.7 nl/min, respectively). In salt-deplete rats, endogenous tubular fluid and Ringer solution produced feedback responses of similar magnitude (EPF40-0 = 14.2 +/- 1.8 and 13.0 +/- 2.0 nl/min, respectively) but exogenous tubular fluid from salt-loaded rats elicited only a small feedback response (EPF40-0 = 1.5 +/- 1.6 nl/min), indistinguishable from that seen in salt-loaded rats with endogenous tubular fluid. It is concluded that an inhibitory factor in the tubular fluid of chronically salt-loaded rats causes a reduction in tubuloglomerular feedback response.

Analysis of Variance↗

Electrical feedback in the cone pedicle: a computational analysis.

One of the fundamental principles of neuroscience is that direct electrical interactions between neurons are not possible without specialized electrical contacts, gap junctions, because the transmembrane resistance of neurons is typically much higher than the resistance of the adjacent extracellular space. However it has been proposed that in the retina direct electrical interactions between cones and second-order neurons occur due to the specific morphology of the cone synaptic terminal. This electrical mechanism could potentially explain the phenomenon of "negative feedback" from horizontal cells to cones and the recent finding that the tips of horizontal cell dendrites contain hemichannels has rekindled interest in the idea. We quantitatively evaluated the possibility that hemichannels and/or glutamate channels mediate electrical feedback from horizontal cells to cones. The calculations show that it is unlikely that an electrical mechanism plays a significant functional role because 1) the necessity of preserving adequate cone-to-horizontal-cell synaptic transmission limits the extracellular space resistance and the horizontal-cell dendritic transmembrane resistances to values at which the effectiveness of electrical feedback is very low and its electrical effect on the cone presynaptic membrane is negligible, 2) electrical feedback is most effective in the dark and weaker during light adaptation, which contradicts the experimental data, and 3) electrical negative feedback is associated with much stronger electrical positive feedback from horizontal cells to cones, a phenomenon that has never been reported. Therefore it is likely that negative feedback from horizontal cells to cones is chemical in nature.

Animals↗

Dynamically interacting processes underlie synaptic plasticity in a feedback pathway.

Descending feedback is a common feature of sensory systems. Characterizing synaptic plasticity in feedback inputs is essential for delineating the role of feedback in sensory processing. In this study, we demonstrate that multiple interacting processes underlie the dynamics of synaptic potentiation in one such sensory feedback pathway. We use field recording and modeling to investigate the interaction between the transient high-magnitude potentiation (200-300%) elicited during tetanic stimulation of the feedback pathway and the lower magnitude posttetanic potentiation (PTP; ~30%) that slowly decays on cessation of the tetanus. The amplitude of the observed transient potentiation is graded with stimulus frequency. In contrast, the induction of PTP has a stimulus frequency threshold between 1 and 5 Hz, and its amplitude is independent of stimulus frequency. We suggest that the threshold for PTP induction may be linked to a minimum level of sustained potentiation (MSP) during repetitive trains of stimuli. We have developed a novel model that describes the interaction between the transient plasticity observed during train stimulation and the generation of PTP. The model combines a multiplicative, facilitation-depression-type (FD) model that describes the transient plasticity, with an enzymatic network that describes the dynamics of PTP. The model links transient plasticity to PTP through an input term that reflects MSP. The stratum fibrosum-pyramidal cell (StF-PC) synapse investigated in this study is the terminus of a feedback pathway to the electrosensory lateral line lobe (ELL) of a weakly electric gymnotiform fish. Dynamic plasticity at the StF-PC synapse may contribute to the putative role of this feedback pathway as a sensory searchlight.

Action Potentials↗

A comparative voltage and current-clamp analysis of feedback and feedforward synaptic transmission in the striatal microcircuit in vitro.

Striatal spiny projection (SP) neurons control movement initiation by integrating cortical inputs and inhibiting basal ganglia outputs. Central to this control lies a "microcircuit" that consists of a feedback pathway formed by axon collaterals between GABAergic SP neurons and a feedforward pathway from fast spiking (FS) GABAergic interneurons to SP neurons. Here, somatically evoked postsynaptic potentials (PSPs) and currents (PSCs) were compared for both pathways with dual whole cell patch recording in voltage- and current-clamp mode using cortex-striatum-substantia nigra organotypic cultures. On average, feedforward inputs were 1 ms earlier, more reliable, and about twice as large in amplitude compared with most feedback inputs. On the other hand, both pathways exhibited widely varying, partially overlapping amplitude distributions. This variability was already established for single FS neurons targeting many SP neurons. In response to precisely timed action potential bursts, feedforward and feedback inputs consistently showed short-term depression < or =50-70% in voltage-clamp, although feedback inputs also displayed strong augmentation in current-clamp in line with previous reports. The augmentation of feedback inputs was absent in gramicidin D perforated-patch recording, which also showed the natural reversal potential for both inputs to be near firing threshold. Preceding depolarizing feedback inputs during the down state did not consistently change subsequent postsynaptic action potentials. We conclude that feedback and feedforward inputs have their dominant effect during the up-state. The reversal potential close to the up-state potential, which supports shunting operation with millisecond precision and the strong synaptic depression, should enable both pathways to carry time-critical information.

Action Potentials↗

Effects of inhibitory feedback in a network model of avian brain stem.

The avian auditory brain stem consists of a network of specialized nuclei, including nucleus laminaris (NL) and superior olivary nucleus (SON). NL cells show sensitivity to interaural time difference (ITD), a critical cue that underlies spatial hearing. SON cells provide inhibitory feedback to the rest of the network. Empirical data suggest that feedback inhibition from SON could increase the ITD sensitivity of NL across sound level. Using a bilateral network model, we assess the effects of SON feedback inhibition. Individual cells are specified as modified leaky-integrate-and-fire neurons with time constants and thresholds that vary with inhibitory input. Acoustic sound level is reflected in the discharge rates of the model auditory-nerve fibers, which innervate the network. Simulations show that with SON inhibitory feedback, ITD sensitivity is maintained in model NL cells over a threefold range in auditory-nerve discharge rate. In contrast, without SON feedback inhibition, ITD sensitivity is significantly reduced as input rates are increased. Feedback inhibition is most beneficial in maintaining ITD sensitivity at high-input rates (simulating high sound levels). With SON inhibition, ITD sensitivity is maintained for both interaurally balanced inputs (simulating an on-center sound source) and interaurally imbalanced inputs (simulating a lateralized source). Further, the empirically observed temporal build-up of SON inhibition and the presence of reciprocal inhibitory connections between the ipsi- and contralateral SON both improve ITD sensitivity. In sum, our network model shows that inhibitory feedback can substantially increase the sensitivity and dynamic range of ITD coding in the avian auditory brain stem.

Action Potentials↗

Patterns of synaptic activity in forward and feedback pathways within rat visual cortex.

1. The laminar and temporal distribution of synaptic activity supplied by forward and feedback connections between different areas of rat visual cortex was determined with the use of current source density (CSD) analysis in in vitro slices. In forward connections, synaptic potentials were evoked by electrically stimulating area 17 and recording in the extrastriate area LM (lateromedial), that ranks at the second hierarchical level, one step above primary visual cortex. For activating feedback connections, the location of stimulating and recording electrodes was reversed. 2. The synaptic interactions in reciprocal intracortical circuits are excitatory, and they are mediated through glutamate receptors that are blocked by kynurenic acid. 3. Forward connections from area 17 to area LM provide input to all layers including a strong input to layer 4. In contrast, feedback input to layer 4 is weak and is mainly directed to superficial and deep layers. This laminar distribution closely resembles that seen anatomically. 4. Both forward and feedback connections evoke distinct temporal patterns of synaptic activation in different layers. Although onset and peak latencies are slightly shorter in the forward than in the feedback pathway, the difference is not statistically significant. 5. The spatiotemporal distribution of synaptic activation by forward connections resembles the pattern evoked by geniculocortical inputs. Feedback connections show greater similarities to long-range connections within area 17, although they are not identical. Our results support the notion derived from anatomic and in vivo physiological studies that forward and feedback pathways belong to functionally distinct cortical circuits.

Animals↗

Independent feedback control of horizontal and vertical amplitude during oblique saccades evoked by electrical stimulation of the superior colliculus.

1. In early local feedback models for controlling horizontal saccade amplitude, a feedback signal of instantaneous eye position is continuously subtracted from a reference signal of desired eye position at a comparator. The output of the comparator is dynamic motor error, the remaining distance the eyes must rotate to reach the saccadic goal. When feedback reduces dynamic motor error to zero, the saccade stops on target. Two classes of local feedback model have been proposed for controlling oblique saccades (i.e., saccades with both horizontal and vertical components). In "independent comparator" models, separate horizontal and vertical comparators maintain independent representations of horizontal and vertical dynamic motor error. Thus, once an oblique desired displacement signal is established, the horizontal and vertical amplitudes of oblique saccades are under independent feedback control. In "vectorial comparator" models, output cells in the motor map of the superior colliculus act as site-specific vectorial comparators. For a given oblique desired displacement, a single comparator controls the amplitudes of both components. Because vectorial comparator models do not maintain separate representations of horizontal and vertical dynamic motor error, they cannot exert independent control over the component amplitudes of oblique saccades. 2. We tested differential predictions of these two types of models by electrically stimulating sites in the superior colliculus of rhesus monkey immediately after either vertical or horizontal visually guided saccades. We have shown previously that, despite the fixed site of collicular stimulation, the amplitude of the visually guided saccades systematically alters the amplitude of the corresponding component (horizontal or vertical) of stimulation-evoked saccades. However, in the present study, we examined the effect of the visually guided saccades on the amplitude of the orthogonal component of stimulation-evoked saccades. 3. For a fixed site of collicular stimulation, vectorial comparator models predict that the initial visually guided saccade will influence both components of the ensuing stimulation-evoked saccade via the single feedback comparator. By contrast, independent comparator models permit the independent manipulation of the horizontal and vertical amplitudes of these oblique stimulation-evoked saccades. 4. In total, we collected data from 15 collicular stimulation sites. Immediately after either horizontal or vertical visually guided saccades of different amplitudes, we measured the horizontal and vertical amplitudes of saccades evoked by stimulation of the intermediate or deep layers of the superior colliculus. For each site, the duration, frequency, and current of the stimulation train were held constant. 5. Under these conditions, stimulation-evoked saccades followed visually guided saccades with short latency (18.1 +/- 6.7 ms, mean +/- SD). For every stimulation site tested, although the amplitude of the component of stimulation-evoked saccades corresponding to the direction of the preceding saccade (horizontal or vertical) varied systematically, the amplitude of the orthogonal component was roughly constant. 6. Thus the horizontal and vertical amplitudes of oblique stimulation-evoked saccades can be manipulated independently. Moreover, the peak velocity-amplitude relationships, the instantaneous velocity profiles, and the ratio of horizontal and vertical velocities and durations were very similar to those of visually guided saccades. 7. Independent comparator models can readily account for the ability to manipulate the amplitude of one component of oblique saccades without affecting the other. However, two-dimensional local feedback models that cannot exert independent control over the horizontal and vertical amplitudes of oblique saccades should be carefully reevaluated.

Animals↗

Decreased hypothalamic-pituitary-adrenal axis sensitivity to cortisol feedback inhibition in human aging.

Aging-related reduction in the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis to glucocorticoid feedback inhibition has been demonstrated in rodents, but aging effects on glucocorticoid feedback inhibition in humans are unclear. This study assessed the influence of aging on the sensitivity of the human HPA axis to feedback inhibition induced by cortisol. Endogenous cortisol feedback inhibition was removed by treatment with metyrapone, which reduces cortisol synthesis by inhibiting 11 beta-hydroxylase. Feedback inhibition was then reintroduced by infusing exogenous cortisol. Sixteen young (26 +/- 1 years old) and 16 older (70 +/- 2 years old) subjects underwent three study conditions in random order. In the two cortisol infusion conditions, oral metyrapone treatment was followed by intravenous infusion of 0.03 mg/kg/h (83 nmol/kg/h) or 0.06 mg/kg/h (166 nmol/kg/h) cortisol for 150 min. Feedback sensitivity was estimated by the latency to and extent of decline of plasma ACTH concentration during and following the cortisol infusion. In a placebo condition, placebo tablets were substituted for metyrapone and normal saline infusion was substituted for cortisol. Blood samples were drawn twice prior to and at 15-min intervals for 4 h following the onset of the infusions, and plasma was assayed for 11-deoxycortisol, cortisol and ACTH. Plasma cortisol suppression and ACTH and 11-deoxycortisol elevations did not differ between age groups after metyrapone. Older subjects exhibited delayed and blunted ACTH responses to infused cortisol. Within older subjects, the ACTH response to the higher dose cortisol infusion was blunted in older women compared to older men. These data provide direct evidence for reduced responsiveness to glucocorticoid feedback inhibition in human aging.

Adrenal Glands↗