Clinical and morphological correlates of impulse control disorders in Parkinson's disease

Poremećaj kontrole impulsa (PKI) zahvata i do jedne četvrtine svih obolelih od Parkinsonove bolesti (PB) i prouzrokuje značajne teškoće u psihološkom, socijalnom i finansijskom smislu za pacijente. Patofiziologija poremećaja je i dalje nedovoljno razjašnjena. Punding je deo spektra poremećaja kontrole impulse, ali ima određene karakteristike koje ga izdvajaju iz ove grupe, a koje se posebno odnose na repetitivnu prirodu poremećaja uprkos izostanku nagrade, što čini interesantnim istraživanja sistema nagrade kod ovih bolesnika. Ciljevi: Ispitati kliničke, psihijatrijske i kognitivne karakteristike obolelih od PB sa PKI; ispitati postojanje strukturnih i funkcionalnih izmena mozga primenom multimodalnog magnetnorezonantnog (MR) snimanja mozga kod obolelih od PB koji su razvili PKI (PB-PKI+) u poređenju sa onima koji nisu (PB-PKI-) i sa zdravim kontrolama; ispitati strukturne i funkcionalne izmene mozga kod pacijenata sa pundingom (PB-Pun+) u poređenju sa PB-PKI- i sa zdravim kontrolama, sa posebnim osvrtom na funkciju habenula i amigdala kao modulatora sistema nagrade. Materijal i metode: Uključili smo 320 pacijenata sa PB koji su detaljno klinički obrađeni i ispitani na prisustvo bilo kog PKI. Potom smo 85 od ovih pacijenata u drugi deo studije (35 PB-PKI+) i 50 zdravih kontrola koji su svi uradili magnetno rezonatno (MR) snimanje mozga i pri tome su dobijeni trodimenzionalni T1 snimci, difuzioni tenzor (DT) snimci, i funkcionalna MR u mirovanju. Procenili smo debljinu kotreksa pomoću morfometrije zasnovane na površini, supkortikalne volumene, DT MR merenja pomoću pristupa zasnovanog na regionima od interesa i traktografije i ispitali funkcionalnu MR u mirovanju koristeći slobodan pristup. Dalje istraživanje je uključilo 52 pacijenta (22 PB-Pun+ i 30 PB-PKI-) i 30 zdravih kontrola kod kojih je ispitana funkcionalna konektivnost u mirovanju habenule i amigdale bilateralno koristeći pristup zasnovan na “semenu”. Kod ovih pacijenata smo procenili i volumene habenule i amigdale i mere kortikalne debljine. Najzad, kod 49 od ovih pacijenata (21 PB-Pun+) i 28 zdravih kontrola smo odredili DT mere koristeći traktografiju. Rezultati: Jedan ili više PKI dijagnostikovan kod 22,5% naših ispitanika. Najčešći PKI među njima je bio punding koji je razvilo 11,6% osoba, Pacijenti koji su imali PKI su bili češće muškog pola, imali su raniji početak bolesti, duže trajanje bolesti i duže su bili na antiparkinsonoj terapiji, koja je bila i u višim dnevnim dozama...Impulse control disorders (ICDs) affect up to one quarter of patients with Parkinson's disease (PD), causing severe psychological, social, and financial disstress. Patophysiological background of the disorder is still elusive. Punding is part of impulse-control disorder spectrum, but has some distinguishing features, in particular related to its repetitive nature despite lack of reward that bring in focus investigations of alterations of the reward system in this disorder. Aims: To investigate clinical, psychiatric and cognitive characteristics of patients with ICDs in PD; to investigate structural and functional alterations of the brain, by means of multimodal brain magnetic resonance imaging (MRI); to investigate in particular structural and functional alterations of the brain in patients with punding, with particular interest in function of habenula and amygdale as modulators of the reward system. Methods: We included 320 patients with PD that were investigated for the presence of the any of the ICDs. We included 85 of these patients in the second part of the study (35 with ICDs) and 50 healthy volounteers, that underwent three-dimensional T1-weighted, diffusion tensor (DT), and resting state functional MRI (RS fMRI). We assessed cortical thickness with surface-based morphometry, subcortical volumes, DT MRI metrics using region of interest and tractography approaches, and RS fMRI using a model free approach. We further assessed 52 patients (22 with punding) and 30 healthy controls in whom RS fMRI of the habenula and amygdala bilaterally was assessed using a seed-based approach. Habenula and amygdala volumes and cortical thickness measures were obtained. Finally, we obtained DT metrics by using tractography approach in 49 of these patients (21 with punding) and 28 healthy controls. Results: We diagnosed one or more ICDs in 22,5% of PD patients, most often punding in 11,6% of them. PD-ICD patients were more often males, with an earlier disease onset, longer disease and treatment duration, and higher levodopa daily dosage. Additionally, PD-ICD patients had more depressive and anxiety symptoms and increased impulsivity. Independent factors associated with ICD occurrence were male gender, earlier disease onset and higher score on Beck’s depression inventory..

Gait Characteristics during Dual-Task Walking in Elderly Subjects of Different Ages

Background: In older age, walking ability gradually decreases due to factors including impaired balance, reduced muscle strength, and impaired vision and proprioception. Further, cognitive functions play a key role during walking and gradually decline with age. There is greater variability in gait parameters when the demands during walking increase, in dual- and multiple-task situations. The aim of this study was to analyze gait parameters while performing a demanding cognitive and motor dual task in three different age-related healthy elderly subject groups. Method: A total of 132 healthy individuals (54 males, 78 females) were divided into three groups—55 to 65, 66 to 75, and 76 to 85 years. The subjects performed a basic walking task, dual motor task, dual mental task, and combined motor and mental task while walking. The gait parameters cycle time, stride length, swing time, and double support time were noted, as well as the variability of those parameters. Results: Cycle time was longer and stride length was shorter in the >76-year-old group than in the 51–65-year-old group in all test conditions. A comparison of all three groups did not show a significant difference in swing time, while double support time was increased in the same group. Conclusions: Changes are observed when gait is performed simultaneously with an additional motor or cognitive task. Early detection of gait disorders can help identify elderly people at increased risk of falls. Employing a dual-task paradigm during gait assessment in healthy elderly subjects may help identify cognitive impairment early in the course of the disturbance

Assessment of gait in patients with fibromyalgia during motor and cognitive dual task walking: a cross-sectional study

Background: The aim of the study was to assess gait pattern of patients diagnosed with fibromyalgia (FM) while performing demanding motor and/or cognitive dual tasks while walking. Further, idea was to explore possible correlations of dual task gait pattern alterations to patients’ functional status and presence or absence of clinical symptoms associated with FM. Methods: Twenty-four female FM patients and 24 healthy female subjects performed a basic walking task, a dual motor, a dual mental (cognitive) and a combined, dual motor and cognitive task simultaneously. Quantitative spatial (stride length) and temporal (cycle time, swing time and double support time) gait parameters were measured using GAITRite walkway system and their variability was assessed. Patients underwent clinical examination including assessment of functional status, pain and fatigue level, psychiatric and cognitive manifestations. Results: The motor, cognitive and combined dual tasks affect gait performance in FM patients. Difference in tasks between FM and healthy subjects was found as double support time prolongation. Comparison of tasks showing that cycle time in FM was longer than controls and stride length was shorter in patients for all conditions, while no changes were found in any of the gait parameters variability. Further, mental/cognitive dual tasks had a larger effect than motor tasks. Correlations were also found between depression and functional status of the patients and the gait parameters. Conclusions: Gait is affected in FM patients while dual task walking. No changes in stride-to-stride variability point that patients preserve stability in complex walking situations. Analysis of gait may provide additional information for the FM identification based on presence of clinical features and cognitive status. Correlation of dual task gait alterations with occurrence of clinical symptoms and influence of cognitive changes on gait pattern could additionally define FM subgroups

Mathematical Modeling of the Hypothalamic-Pituitary-Adrenal Axis Dynamics in Rats

The hypothalamic-pituitary-adrenal (HPA) axis is a dynamic regulatory network of biochemical reactions that integrates and synchronizes the nervous and the endocrine systems functions at the organism level. In order to describe how this vast network of biochemical interactions operates, we have developed a nonlinear eleven-dimensional stoichiometric model that concisely describes key biochemical transformations that comprise the HPA axis in rats. In a stoichiometric model of a biochemical system, the outcomes of complex biochemical pathways are succinctly described by stoichiometric relations. In this representation, substances that initiate, i.e. enter a pathway are regarded to behave as reactants; substances that are generated in a pathway are regarded to behave as products; and the rates at which products of a pathway appear are jointly proportional to the concentrations of the reactants. In order to derive rate constants for specific biochemical reaction pathways, we have resorted to our recently developed nonlinear reaction model that concisely describes biochemical transformations in the HPA axis in humans. In this way, a mathematical framework is developed to describe in the form of a system of ordinary differential equations (ODEs) the integration of biochemical pathways that constitute the HPA axis on chemical kinetics basis. This, in turn, allows us to use numerical simulations to investigate how the underlying biochemical pathways are intertwined to give an integral HPA axis response at the organism level to a variety of external or internal perturbators of the HPA dynamics. Given that the HPA axis is a nonlinear dynamical network, its response is complex and often cannot be intuitively predicted, stoichiometric modeling can be harnessed for gaining additional insights into dynamical functioning of this complex neuroendocrine system.Belgrade, Serbia, June 20-24, 2016 [http://alas.matf.bg.ac.rs/~websites/bioinfo/

A New Approach in Regression Analysis for Modeling Adsorption Isotherms

Numerous regression approaches to isotherm parameters estimation appear in the literature. The real insight into the proper modeling pattern can be achieved only by testing methods on a very big number of cases. Experimentally, it cannot be done in a reasonable time, so the Monte Carlo simulation method was applied. The objective of this paper is to introduce and compare numerical approaches that involve different levels of knowledge about the noise structure of the analytical method used for initial and equilibrium concentration determination. Six levels of homoscedastic noise and five types of heteroscedastic noise precision models were considered. Performance of the methods was statistically evaluated based on median percentage error and mean absolute relative error in parameter estimates. The present study showed a clear distinction between two cases. When equilibrium experiments are performed only once, for the homoscedastic case, the winning error function is ordinary least squares, while for the case of heteroscedastic noise the use of orthogonal distance regression or Margart's percent standard deviation is suggested. It was found that in case when experiments are repeated three times the simple method of weighted least squares performed as well as more complicated orthogonal distance regression method

Modelling cholesterol effects on the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis

A mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis with cholesterol as a dynamical variable was derived to investigate the effects of cholesterol, the primary precursor of all steroid hormones, on the ultradian and circadian HPA axis activity. To develop the model, the parameter space was systematically examined by stoichiometric network analysis to identify conditions for ultradian oscillations, determine conditions under which dynamic transitions, i.e. bifurcations occur and identify bifurcation types. The bifurcations were further characterized using numerical simulations. Model predictions agree well with empirical findings reported in the literature, indicating that cholesterol levels may critically affect the global dynamics of the HPA axis. The proposed model provides a base for better understanding of experimental observations, it may be used as a tool for designing experiments and offers useful insights into the characteristics of basic dynamic regulatory mechanisms that, when impaired, may lead to the development of some modern-lifestyle-associated diseases

Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis

Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamicpituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations

Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress

Detailed dynamics of the hypothalamic-pituitary-adrenal (I-IPA) axis is complex, depending on the individual metabolic load of an organism, its current status (healthy/ill, circadian phase (day/night), ultradian phase) and environmental impact. Therefore, it is difficult to compare the HPA axis activity between different individuals or draw unequivocal conclusions about the overall status of the HPA axis in an individual using single time-point measurements of cortisol levels. The aim of this study is to identify parameters that enable us to compare different dynamic states of the HPA axis and use them to investigate self-regulation mechanisms in the HPA axis under acute and chronic stress. In this regard, a four-dimensional stoichiometric model of the HPA axis was used. Acute stress was modeled by inducing an abrupt change in cortisol level during the course of numerical integration, whereas chronic stress was modeled by changing the mean stationary state concentrations of CRH. Effects of acute stress intensity, duration and time of onset with respect to the ultradian amplitude, ultradian phase and the circadian phase of the perturbed oscillation were studied in detail. Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed

Advances in mathematical modelling of the hypothalamic-pituitary-adrenal (HPA) axis dynamics and the neuroendocrine response to stress

Stress is a physiological reaction of an organism to a demand for change that is imposed by external factors or is coming from within by way of physiological strains or self-perceived mental and/or emotional threats (internal factors). It manifests itself through the sudden release of a flood of hormones, including corticosteroids, into the blood, which rouse the body for action. Normally, stress is beneficial, but when lasting or being very strong, it causes major damage to our mind and body. Despite intense research, we still do not understand fully how the stress response axis, whose main function is to respond to challenges while maintaining the normal physiological balance, loses under prolonged exposure to stressors its capacity to maintain homeostasis. Recent applications of mathematical modelling and dynamical systems theory have enabled us to emulate complex neurochemical transformations that underlie the stress response, and help us to acquire deeper understanding of this dynamical regulatory network

The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations

Stress and alcohol use are interrelatedstress contributes to the initiation and upholding of alcohol use and alcohol use alters the way we perceive and respond to stress. Intricate mechanisms through which ethanol alters the organism's response to stress remain elusive. We have developed a stoichiometric network model to succinctly describe neurochemical transformations underlying the stress response axis and use numerical simulations to model ethanol effects on complex daily changes of blood levels of cholesterol, 6 peptide and 8 steroid hormones. Modelling suggests that ethanol alters the dynamical regulation of hypothalamic-pituitary-adrenal (HPA) axis activity by affecting the amplitude of ultradian oscillations of HPA axis hormones, which defines the threshold with respect to which the response to stress is being set. These effects are complexlow/moderate acute ethanol challenge ( LT 8mM) may reduce, leave unaltered or increase the amplitude of ultradian cortisol (CORT) oscillations, giving rise to an intricate response at the organism level, offering also a potential explanation as to why apparently discordant results were observed in experimental studies. In contrast, high-dose acute ethanol challenge (> 8mM) increases instantaneous CORT levels and the amplitude of ultradian CORT oscillations in a dose-dependent manner, affecting the HPA axis activity also during the following day(s). Chronic exposure to ethanol qualitatively changes the HPA axis dynamics, whereas ethanol at intoxicating levels shuts down this dynamic regulation mechanism. Mathematical modelling gives a quantitative biology-based framework that can be used for predicting how the integral HPA axis response is perturbed by alcohol