Background: Defined by thyroid-pituitary feedback control, clinical diagnosis of hypothyroidism and hyperthyroidism has become synonymous with TSH measurement. We combined in silico analysis and in vivo data to explore the central influences on thyroidal T3 production. Materials & methods:A system of five coupled first-order nonlinear parameterised ordinary differential equations (ODEs) is used to model the feedback control of TSH and TRH by thyroid hormones together with the feedforward control of thyroidal T3 secretion and enzymatic T4-T3 conversion. Dependencies of the stable equilibrium solutions of this ODE system, that is the homeostasis of the underlying physiological process, on the system parameters were investigated whether they accounted for clinical observations. Results: During the modelled transition to hypothyroidism, central control imposed an increasing influence in maintaining serum FT3 levels, compared to peripheral conversion efficiency. Numerical continuation analysis revealed dependencies of T3 production on different elements of TSH feedforward control. While T4-T3 conversion provided the main T3 source in euthyroidism, this was overtaken by increasing glandular T3 secretion when thyroid reserve declined. The computational results were in good agreement with data from untreated patients with autoimmune thyroiditis. Conclusions: Dependencies revealed in the expression of control differ in thyroid health and disease, using a physiologically based mathematical model of combined feedback-feedforward control of the hypothalamic-pituitary-thyroid regulation.Strong T3-protective mechanisms of the control system emerge with declining thyroid function, when glandular T3 secretion becomes increasingly influential over conversion efficiency. This has wide-ranging implications for the utility of TSH in clinical decision-making. K E Y W O R D Sautoimmune thyroiditis, mathematical model, personalised medicine, set point, subclinical hypothyroidism, T3 secretion

IntroductionThe movement disorder in Parkinson disease (PD) results from depletion of the catecholamine dopamine in the brain's nigrostriatal system (1). PD also entails profound deficiency of the closely related catecholamine norepinephrine (NE) in the heart (2). Other Lewy body diseases -pure autonomic failure (PAF) and dementia with Lewy bodies -also involve severely decreased myocardial NE contents (3).The cardiac sympathoneural lesion in these diseases probably is important clinically. Thus, neuroimaging evidence of cardiac noradrenergic deficiency in PD is associated with cognitive impairment (4), exercise intolerance (5), olfactory dysfunction (6), rapid eye movement behavior disorder (7), visual hallucinations (8), falls from neurogenic orthostatic hypotension (9), fatigue (10), and shortened survival (11).One might presume that the myocardial NE depletion in these disorders directly and solely reflects loss BACKGROUND. Lewy body diseases, a family of aging-related neurodegenerative disorders, entail loss of the catecholamine dopamine in the nigrostriatal system and equally severe deficiency of the closely related catecholamine norepinephrine in the heart. The myocardial noradrenergic lesion is associated with major nonmotor symptoms and decreased survival. Numerous mechanisms determine norepinephrine stores, and which of these are altered in Lewy body diseases has not been examined in an integrated way. We used a computational modeling approach to assess comprehensively pathways of cardiac norepinephrine synthesis, storage, release, reuptake, and metabolism in Lewy body diseases. Application of a potentially novel kinetic model identified a pattern of dysfunctional steps contributing to norepinephrine deficiency. We then tested predictions from the model in a new cohort of Parkinson disease patients.

Endocrine regulation in the hypothalamic-pituitary-thyroid (HPT) axis is orchestrated by physiological circuits which integrate multiple internal and external influences. Essentially, it provides either of the two responses to overt biological challenges: to defend the homeostatic range of a target hormone or adapt it to changing environmental conditions. Under certain conditions, such flexibility may exceed the capability of a simple feedback control loop, rather requiring more intricate networks of communication between the system’s components. A new minimal mathematical model, in the form of a parametrized nonlinear dynamical system, is here formulated as a proof-of-concept to elucidate the principles of the HPT axis regulation. In particular, it allows uncovering mechanisms for the homeostasis of the key biologically active hormone free triiodothyronine (FT3). One mechanism supports the preservation of FT3 homeostasis, whilst the other is responsible for the adaptation of the homeostatic state to a new level. Together these allow optimum resilience in stressful situations. Preservation of FT3 homeostasis, despite changes in FT4 and TSH levels, is found to be an achievable system goal by joining elements of top-down and bottom-up regulation in a cascade of targeted feedforward and feedback loops. Simultaneously, the model accounts for the combination of properties regarded as essential to endocrine regulation, namely sensitivity, the anticipation of an adverse event, robustness, and adaptation. The model therefore offers fundamental theoretical insights into the effective system control of the HPT axis.

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