Alternations in the Cardiovascular Autonomic Regulation and Growth Factors in Autism.

Autism spectrum disorder (ASD) represents a serious neurodevelopmental disorder associated with autonomic nervous system dysregulation. The aim was to study complex cardiovascular autonomic regulation using heart rate variability (HRV) and systolic blood pressure variability (SBPV) linear/non-linear analysis at rest and during orthostasis, and to assess plasma levels of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) in autistic children. Twenty-five ASD boys and 25 age and gender-matched children at the age 7-15 years were examined. After venous blood taking, continuous ECG and blood pressure biosignals were recorded at rest and during orthostasis. Evaluated parameters: RR intervals, high- and low-frequency band of HRV spectral analysis (HF-HRV, LF-HRV), symbolic dynamics parameters 0V%, 1V%, 2LV%, 2UV%, low- and high-frequency band of SBPV (LF-SBPV, HF-SBPV), systolic, diastolic, mean blood pressure, EGF, VEGF plasma levels. RR intervals were significantly shortened and the HF-HRV, LF-SBPV, HF-SBPV parameters were significantly lower at rest, the HF-HRV and LF-SBPV remained lower during orthostasis in autistic children compared to controls (p<0.05). EGF plasma levels were significantly lower in ASD compared to controls (p=0.046). No significant differences were found in remaining parameters. Our study revealed tachycardia, cardiovagal underactivity, and blunted sympathetic vasomotor regulation at rest and during orthostasis in autistic children. Additionally, complex heart rate dynamics are similar in autistic children than controls. Furthermore, EGF was reduced in autistic children without significant correlations with any autonomic parameters. We suggest that the abnormal complex cardiovascular reflex control could contribute to understanding the pathway linking autonomic features and autism.

Complex sympathetic regulation in adolescent mitral valve prolapse.

Mitral valve prolapse (MVP) belongs to cardiac disorders characterized by impaired closure of mitral leaflets. We studied adolescent group of patients with MVP suffering from symptomatology that cannot be explained by mitral regurgitation alone. Several studies suggested that symptoms can be explained by autonomic, in particular sympathetic-linked dysfunction. Thus, we assessed non-invasive sympathetic indices of blood pressure and heart rate variability and electrodermal activity (EDA). Fifty-three adolescents with MVP (age: 15.1+/-0.4 years) and 43 healthy age- and gender-matched adolescents (age: 14.9+/-0.4 years) were examined. Blood pressure, heart rate and EDA were continuously recorded during 6-min rest. Evaluated parameters were: low frequency band of systolic blood pressure variability, systolic, diastolic and mean blood pressure, mean RR interval, cardiac sympathetic indices: symbolic dynamics (0V%), left ventricular ejection time (LVET), pre-ejection period (PEP), and EDA. Our findings revealed significantly higher systolic, diastolic, and mean blood pressure values, shortened mean RR interval, increased 0V%, and shortened LVET in MVP patients vs. controls (p=0.028, p<0.001, p=0.002, p<0.001, p=0.050, p<0.001; respectively). Our study revealed enhanced cardiovascular sympathetic regulation in adolescent MVP patients. We suggest that evaluation of non-invasive sympathetic parameters could represent potential biomarkers for early diagnosis of cardiovascular complications associated with MVP already at adolescent age.

Eye pupil - a window into central autonomic regulation via emotional/cognitive processing.

If the eyes are windows into the soul, then the pupils represent at least the gateway to the brain and can provide a unique insight into the human mind from several aspects. The changes in the pupil size primarily mediated by different lighting conditions are controlled by the autonomic nervous system regulated predominantly at the subcortical level. Specifically, parasympathetically-linked pupillary constriction is under the Edinger-Westphal nucleus control and sympathetically-mediated pupillary dilation is regulated from the posterior hypothalamic nuclei. However, the changes in the pupil size can be observed at resting state even under constant lighting, these pupillary changes are mediated by global arousal level as well as by various cognitive factors. In this context, autonomic pathways modulating changes in the pupil size in response to the different light levels can be influenced by multiple central descending inputs driving pupillary changes under steady lighting conditions. Moreover, as the pupillary response is involved in emotional (task-evoked pupillary dilation as an index of emotional arousal) and cognitive (task-evoked pupillary dilation as an index of cognitive workload) stimulation, it can be used to detect the impact of mutual subcortical and cortical structures (i.e. overlapping brain structures included in autonomic, emotional and cognitive regulation) on the pupillary innervation system. Thus, complex understanding of the baseline pupil size´ and pupillary dynamics´ mechanisms may provide an important insight into the central nervous system functioning pointing to the pupillometry as a promising tool in the clinical application.

Respiratory Sinus Arrhythmia as an Index of Cardiac Vagal Control in Mitral Valve Prolapse.

Respiratory sinus arrhythmia (RSA), i.e. heart rate (HR) variations during inspiration and expiration, is considered as a noninvasive index of cardiac vagal control. Mitral valve prolapse (MVP) could be associated with increased cardiovascular risk; however, the studies are rare particularly at adolescent age. Therefore, we aimed to study cardiac vagal control indexed by RSA in adolescent patients suffering from MVP using short-term heart rate variability (HRV) analysis. We examined 12 adolescents (girls) with MVP (age 15.9±0.5 years) and 12 age and gender matched controls. Resting ECG was continuously recorded during 5 minutes. Evaluated HRV indices were RR interval (ms), rMSSD (ms), pNN50 (%), log HF (ms(2)), peak HF (Hz) and respiratory rate (breaths/min). RR interval was significantly shortened in MVP group compared to controls (p=0.004). HRV parameters-rMSSD, pNN50 and log HF were significantly lower in MVP compared to controls (p=0.017, p=0.014, p= 0.015 respectively). Our study revealed reduced RSA magnitude indicating impaired cardiac vagal control in MVP already at adolescent age that could be crucial for early diagnosis of cardiovascular risk in MVP.

Impact of prenatal hypoxia on the development and behavior of the rat offspring.

The healthy development of the fetus depends on the exact course of pregnancy and delivery. Therefore, prenatal hypoxia remains between the greatest threats to the developing fetus. Our study aimed to assess the impact of prenatal hypoxia on postnatal development and behavior of the rats, whose mothers were exposed to hypoxia (10.5 % O2) during a critical period of brain development on GD20 for 12 h. This prenatal insult resulted in a delay of sensorimotor development of hypoxic pups compared to the control group. Hypoxic pups also had lowered postnatal weight which in males persisted up to adulthood. In adulthood, hypoxic males showed anxiety-like behavior in the OF, higher sucrose preference, and lower levels of grimace scale (reflecting the degree of negative emotions) in the immobilization chamber compared to the control group. Moreover, hypoxic animals showed hyperactivity in EPM and LD tests, and hypoxic females had reduced sociability compared to the control group. In conclusion, our results indicate a possible relationship between prenatal hypoxia and changes in sociability, activity, and impaired emotion regulation in ADHD, ASD, or anxiety disorders. The fact that changes in observed parameters are manifested mostly in males confirms that male sex is more sensitive to prenatal insults.

A mixture of diethylhexyl, diisononyl and dibutyl phthalate decreased anogenital distance, postnatal testosterone levels, and changed social behavior in Wistar rats.

Phthalates are chemicals interfering with the function of testosterone and are suspected to play a role in the emergence of neurodevelopmental diseases. This could be due to interference with brain development for which optimal testosterone levels are essential. We investigated the effect of prenatal and early postnatal exposure to a phthalate mixture on the anogenital distance (AGD), plasma testosterone levels and social behavior in rats. Pregnant rats were exposed to a mixture of diethylhexyl, diisononyl and dibutyl phthalate, each at a dose of 4.5 mg/kg/day, from gestational day 15 to postnatal day 4. A social interaction test was performed to assess sociability in the three ontogenetic stages (weaning, puberty, adulthood). AGD was measured in adulthood to assess changes in prenatal testosterone levels. Plasma testosterone levels were measured in adults by a radioimmunoassay. The total frequency and time of socio-cohesive interactions were decreased in phthalate exposed females in weaning, puberty and adulthood. Phthalate exposed males showed a decrease in the frequency of social interactions in weaning only. Shorter anogenital distance was observed in adult males exposed to phthalates. Decreased testosterone levels were observed in the exposed group in both sexes. Our results suggest that early developmental phthalate exposure may play an important role in the hormonal and behavioral changes associated with several neurodevelopmental diseases.

Central autonomic regulation assessed by pupillary light reflex is impaired in children with attention deficit hyperactivity disorder.

It is assumed that the Attention Deficit Hyperactivity Disorder is associated with the central autonomic dysregulation, however, the studies are rare. Analysis of pupillary light reflex represents a non-invasive tool to provide information related to the central autonomic regulation; thus, we aimed to evaluate potential disturbances in the central autonomic integrity using pupillary light reflex examination in Attention Deficit Hyperactivity Disorder. We have examined 20 children with Attention Deficit Hyperactivity Disorder (10 boys, 13.0+/-2.3 years) and 20 age/gender-matched healthy subjects. Pupillary light reflex was examined at rest for both eyes using Pupillometer PLR-2000 (NeurOptics, USA). Evaluated parameters were: diameter of the pupil before the application of light stimulus and after illumination at the peak of the constriction, the percentual change of the pupil diameter during constriction, average constriction velocity, maximum constriction velocity and average dilation velocity. We found significantly lower percentual change of the pupil diameter during constriction for both eyes in Attention Deficit Hyperactivity Disorder group compared to controls (right eye: -25.81+/-1.23 % vs. -30.32+/-1.31 %, p<0.05, left eye: -25.44+/-1.65 % vs. -30.35+/-0.98 %, p<0.05). The average constriction velocity and maximum constriction velocity were significantly shortened in left eye in Attention Deficit Hyperactivity Disorder group compared to controls (p<0.05). Our findings revealed altered pupillary light reflex indicating abnormal centrally-mediated autonomic regulation characterized by parasympathetic underactivity associated with relative sympathetic predominance in children suffering from Attention Deficit Hyperactivity Disorder.

Potential major depressive disorder biomarkers in pediatric population - a pilot study.

Mental disorders affect 10-20 % of the young population in the world. Major depressive disorder (MDD) is a common mental disease with a multifactorial and not clearly explained pathophysiology. Many cases remain undetected and untreated, which influences patients' physical and mental health and their quality of life also in adulthood. The aim of our pilot study was to assess the prediction value of selected potential biomarkers, including blood cell counts, blood cell ratios, and parameters like peroxiredoxin 1 (PRDX1), tenascin C (TNC) and type IV collagen (COL4) between depressive pediatric patients and healthy peers and to evaluate a short effect of antidepressant treatment. In this study, 27 young depressive patients and 26 non-depressed age-matched controls were included. Blood analyses and immunological assays using commercial kits were performed. Platelet count was the only blood parameter for which the case/control status was statistically significant (p=0.01) in a regression model controlling for the age and gender differences. The results from ELISA analyses showed that the case/control status is a significant predictor of the parameters PRDX1 (p=0.05) and COL4 (p=0.009) in respective regression model considering the age and gender differences between MDD patients and controls. A major finding of this study is that values of platelet count, monocyte to lymphocyte ratio, white blood cell, and monocyte counts were assessed by the Random Forest machine learning algorithm as relevant predictors for discrimination between MDD patients and healthy controls with a power of prediction AUC=0.749.

Oculometric behavior assessed by pupil response is altered in adolescent depression.

Oculometric behaviour assessed by pupil response provides important information about central autonomic activity and emotional regulation. However, studies regarding pupil response to emotional stimuli in adolescent depression are rare. We aimed to study emotional-linked pupil response in adolescent depression. Twenty depressive adolescents (average age: 15.4+/-1.2 years) and 20 age/gender-matched healthy subjects were examined. Average pupil diameter assessed by eye-tracking and pupillary light reflex were evaluated during protocol - baseline, free-view task, recovery phase. Regarding right eye, significantly greater initial pupil diameter and pupil dilation to positive pictures free-viewing (p=0.013, p=0.031, respectively), significantly slower average and maximum constriction velocity in baseline and positive pictures free-viewing (p=0.036, p=0.050, p=0.021, p=0.015, respectively), significantly slower maximum constriction velocity in recovery phase (p=0.045), and significantly faster average dilation velocity in negative pictures free-viewing (p=0.042) were observed in depressive group. Regarding left eye, significantly lower constriction percentual change in negative pictures free-viewing (p=0.044) and significantly greater baseline pupil diameter and pupil diameter at the peak of constriction in positive vs. negative pictures free-viewing (p=0.002, p=0.015, respectively) were observed in depressive group. Our study revealed discrete central autonomic dysregulation - parasympathetic hypoactivity associated with relative sympathetic dominance influenced by impairments in emotional processing already in adolescent depression.