The pulsatile release of cortisol from the adrenal glands is controlled by a hierarchical system that involves corticotropin releasing hormone (CRH) from the hypothalamus, adrenocorticotropin hormone (ACTH) from the pituitary, and cortisol from the adrenal glands. Determining the number, timing, and amplitude of the cortisol secretory events and recovering the infusion and clearance rates from serial measurements of serum cortisol levels is a challenging problem. Despite many years of work on this problem, a complete satisfactory solution has been elusive. We formulate this question as a non-convex optimization problem, and solve it using a coordinate descent algorithm that has a principled combination of (i) compressed sensing for recovering the amplitude and timing of the secretory events, and (ii) generalized cross validation for choosing the regularization parameter. Using only the observed serum cortisol levels, we model cortisol secretion from the adrenal glands using a second-order linear differential equation with pulsatile inputs that represent cortisol pulses released in response to pulses of ACTH. Using our algorithm and the assumption that the number of pulses is between 15 to 22 pulses over 24 hours, we successfully deconvolve both simulated datasets and actual 24-hr serum cortisol datasets sampled every 10 minutes from 10 healthy women. Assuming a one-minute resolution for the secretory events, we obtain physiologically plausible timings and amplitudes of each cortisol secretory event with R (2) above 0.92. Identification of the amplitude and timing of pulsatile hormone release allows (i) quantifying of normal and abnormal secretion patterns towards the goal of understanding pathological neuroendocrine states, and (ii) potentially designing optimal approaches for treating hormonal disorders.
We study the use of the FitzHugh-Nagumo (FHN) model for capturing neural spiking. The FHN model is a widely used approximation of the Hodgkin-Huxley model that has significant limitations. In particular, it cannot produce the key spiking behavior of bursting. We illustrate that by allowing time-varying parameters for the FHN model, these limitations can be overcome while retaining its low-order complexity. This extension has applications in modeling neural spiking behaviors in the thalamus and the respiratory center. We demonstrate the use of the FHN model from an estimation perspective by presenting a novel parameter estimation method that exploits its multiple time-scale properties, and compare the performance of this method with the extended Kalman filter in several illustrative examples. We demonstrate that the dynamics of the spiking threshold can be recovered even in the absence of complete specifications for the system.
Existing mathematical models for cortisol secretion do not describe the entire cortisol secretion process, from the neural firing of corticotropin releasing hormone (CRH) in the hypothalamus to cortisol concentration in the plasma. In this paper, we lay the groundwork to construct a more comprehensive model, relating CRH, Adrenocorticotropic hormone (ACTH), and cortisol. We start with an existing mathematical model for cortisol secretion, and combine it with a simplified neural firing model that describes CRH and ACTH release. This simplified neural firing model is obtained using the extended FitzHugh-Nagumo (FHN) model, which includes a time-varying spiking threshold . A key feature of our model is the presence of a feedback loop from cortisol secretion to ACTH secretion.
In this paper, we revisit the issue of the utility of the FitzHugh-Nagumo (FHN) model for capturing neuron firing behaviors. It has been noted (e.g., see ) that the FHN model cannot exhibit certain interesting firing behaviors such as bursting. We illustrate that, by allowing time-varying parameters for the FHN model, one could overcome such limitations while still retaining the low order complexity of the FHN model. We also highlight the utility of the FHN model from an estimation perspective by presenting a novel parameter estimation method that exploits the multiple time scale feature of the FHN model, and compare the performance of this method with the Extended Kalman Filter through illustrative examples.
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