The influence of continuous prenatal exposure to valproic acid on physical, nociceptive, emotional and psychomotor responses during adolescence in mice: Dose-related effects within sexes.

Clinical findings show that the use of valproic acid (VPA) during pregnancy increases the risk of birth defects and autism spectrum disorder in offspring. Although there is a consensus that monitoring of potential long-term outcomes of VPA exposure is needed, especially in undiagnosed individuals, preclinical studies addressing this issue are rare. The present study examined the effects of continuous intrauterine exposure to a wide dose range of VPA (50, 100, 200, and 400 mg/kg/day) on the physical and behavioral response in peripubertal mice as a rodent model of adolescence. Body weight and the hot plate test [on postnatal days (PND) 25 and 32], the elevated plus-maze test (on PND35), and the open field test (on PND40) served to examine physical growth, the supraspinal reflex response to a painful thermal stimulus and conditional learning, anxiety-like/risk-assessment behavior, as well as novelty-induced psychomotor activity, respectively. VPA exposure produced the following responses: (i) a negative effect on body weight, except for the dose of 100 mg/kg/day in both sexes; (ii) an increase in the percentage of animals that responded to the thermal stimulus above the defined cut-off time interval and the response latency in both sexes; (iii) dose-specific changes within sexes in behavior provoked by a novel anxiogenic environment, i.e., in females less anxiety-like/risk-assessment behavior in response to the lowest exposure dose, and in males more pronounced anxiety-like/risk-assessment behavior after exposure to the highest dose and 100 mg/kg/day; (iv) dose-specific changes within sexes in novelty-induced psychomotor activity, i.e., in females a decrease in stereotypy-like activity along with an increase in rearing, and in males a decrease in stereotypy-like activity only. These findings show that continuous intrauterine exposure to VPA produces maladaptive functioning in different behavioral domains in adolescence and that the consequences are delicate to assess as they are dose-related within sexes.

Inner Ear Malformations in Congenital Deafness Are Not Associated with Increased Risk of Breech Presentation.

BackgroundThere is speculation that an immature vestibular system may be associated with breech presentation at delivery. Our aim was to determine whether syndromes with congenital inner ear malformations were accompanied by a higher frequency of breech presentation/malpresentations than in the general population (2%-3%). Methods: A review was conducted for published literature using PubMed/MEDLINE (1936-2016), to determine frequency of breech presentation and transverse lie in cases with congenital deafness (Michel aplasia, Wildervanck syndrome, Mondini-Alexander dysplasia, Waardenburg syndrome, CHARGE syndrome, Large vestibular aqueductal syndrome, Pendred syndrome, Oculo-aurico-vertebral spectrum, Jervel and Lange-Nielsen syndrome, Usher syndrome, and Scheibe dysplasia) and vestibular nerve aplasia. Results: Identified were total of 122 cases. The frequency of breech presentation was 1.64%, and of transverse lie 1.64%, giving a total of 3.28% malpresentations. Conclusion: The results of the study suggest that congenital malformations of the vestibular apparatus are not associated with the increased risk of breech presentation at delivery.

Chronic Polyhydramnios: A Medical Entity Which Could Be a Model of Muscle Development in Decreased Mechanical Loading Condition.

Polyhydramnios is a condition related to an excessive accumulation of amniotic fluid in the third trimester of pregnancy and it can be acute and chronic depending on the duration. Published data suggest that during muscle development, in the stage of late histochemical differentiation decreased mechanical loading cause decreased expression of myosin heavy chain (MHC) type 1 leading to slow-to-fast transition. In the case of chronic polyhydramnios, histochemical muscle differentiation could be affected as a consequence of permanent decreased physical loading. Most affected would be muscles which are the most active i.e., spine extensor muscles and muscles of legs. Long-lasting decreased mechanical loading on muscle should cause decreased expression of MHC type 1 leading to slow-to-fast transition, decreased number of muscle fiber type I especially in extensor muscles of spine and legs. Additionally, because MHC type 1 is present in all skeletal muscles it could lead to various degrees of hypotrophy depending on constituting a percentage of MHC type 1 in affected muscles. These changes in the case of preexisting muscle disorders have the potential to deteriorate the muscle condition additionally. Given these facts, idiopathic chronic polyhydramnios is a rare opportunity to study the influence of reduced physical loading on muscle development in the human fetus. Also, it could be a medical entity to examine the influence of micro- and hypogravity conditions on the development of the fetal muscular system during the last trimester of gestation.

Early physical and motor development of mouse offspring exposed to valproic acid throughout intrauterine development.

Clinical research has identified developmental delay and physical malformations in children prenatally exposed to the antiepileptic drug (AED) valproic acid (VPA). However, the early signs of neurodevelopmental deficits, their evolution during postnatal development and growth, and the dose effects of VPA are not well understood. The present study aimed to examine the influence of maternal exposure to a wide dose range (50, 100, 200 and 400mg/kg/day) of VPA during breeding and gestation on early physical and neuromotor development in mice offspring. Body weight gain, eye opening, the surface righting reflex (SRR) and tail suspension test (TST) were examined in the offspring at postnatal days 5, 10 and 15. We observed that: (1) all tested doses of VPA reduced the body weight of the offspring and the timing of eye opening; (2) offspring exposed to VPA displayed immature forms of righting and required more time to complete the SRR; (3) latency for the first immobilization in the TST is shorter in offspring exposed to higher doses of VPA; however, mice in all groups exposed to VPA exhibited atypical changes in this parameter during the examined period of maturation; (4) irregularities in swinging and curling activities were observed in animals exposed to higher doses of VPA. This study points to delayed somatic development and postponed maturation of the motor system in all of the offspring prenatally exposed to VPA, with stronger effects observed at higher doses. The results implicate that the strategy of continuous monitoring of general health and achievements in motor milestones during the early postnatal development in prenatally VPA-exposed offspring, irrespectively of the dose applied, could help to recognize early developmental irregularities.

Spectral and fractal measures of cerebellar and cerebral activity in various types of anesthesia.

The features of rat cerebral and cerebellar electrocortical activity (ECoG) under different types of anaesthesia (nembutal, ketamine or zoletil) were examined by the distribution of spectral entropy across frequency bands of ECoG and by calculation of fractal dimension determined on the basis of Higuchi's algorithm. Spectral entropy, as a measure of activity, in the case of cerebrum had greater values than the spectral entropy of cerebellum in low frequency ranges, regardless of the type of applied anesthetic. Various anesthetics evoked different effects on spectral entropy of electrocortical activity: spectral entropy of delta range greatly dominated under nembutal anesthesia, while ketamine or zoletil appeared to affect the spectral entropy of higher frequency ranges. The pronounced effect of ketamine or zoletil anesthesia on spectral entropy of higher frequency was confirmed by the higher values of Higucihi's fractal dimension (FD) of ECoGs, with a tendency of higher FD values in cerebellar activity than cerebral activity.

Fractal dimension values of cerebral and cerebellar activity in rats loaded with aluminium.

Aluminium interferes with a variety of cellular metabolic processes in the mammalian nervous system and its intake might increase a risk of developing Alzheimer's disease (AD). While cerebral involvement even at the early stages of intoxication is well known, the role of cerebellum is underestimated. Our aim was to investigate cerebral and cerebellar electrocortical activity in adult male rats exposed to chronic aluminium treatment by nonlinear analytic tools. The adult rats in an aluminium-treated group were injected by AlCl(3), intraperitoneally (2 mg Al/kg, daily for 4 weeks). Fractal analysis of brain activity was performed off-line using Higuchi's algorithm. The average fractal dimension of electrocortical activity in aluminium-treated animals was lower than the average fractal dimension of electrocortical activity in the control rats, at cerebral but not at cerebellar level. The changes in the stationary and nonlinear properties of time series were more expressed in cerebral electrocortical activity than in cerebellar activity. This can be useful for developing effective diagnostic and therapeutic strategies in neurodegenerative diseases.

Wavelet and fractal analysis of rat brain activity in seizures evoked by camphor essential oil and 1,8-cineole.

We investigated the rat brain activity in acute seizures evoked by camphor essential oil or its main constituent 1,8-cineole by wavelet (primarily) and fractal analysis. Experiments were performed on anesthetized animals before and after intraperitoneal camphor oil or cineole administration. The properties of frequency bands in pre-ictal, ictal and inter-ictal stages have been determined by wavelet analysis. The domination of delta frequency band was confirmed in obtained brain activities, which participate with approximately 45% of mean relative wavelet energy (MRWE) in control signals and arise up to approximately 76% MRWE in energy spectrum during the ictal stage (after drug administration). Other frequency bands decreased during ictal stage and arised in inter-ictal stage. There was a dosedependent response of cineole effect: increase in cineole concentration leaded to the higher values of relative wavelet energy (RWE) of delta frequency band while there were slight changes of the mean fractal dimension (FD) values as a measure of system complexity.

The righting reflex from a supine to a prone position in the guinea pig fetus.

The aim of this study was to examine the righting reflex from a supine to a prone position in the albino guinea pig fetus. Ultrasound examinations of one-fetus gestations were performed in the period from the 31st to the 66th day of gestation. The experimental and control group each encompassed 6 fetuses. Fetuses were brought into supine positions relative to the gravity vector by manipulating the pregnant females into the appropriate positions. The control group received 15 mg/kg of diazepam intraperitoneally before the examination to show whether changes in fetal position occurred as the result of passive rotation. In the experimental group, each fetus was examined every other day (summary results: absent 69 times, prone position 10 times, lateral position 29 times). In the control group, each fetus was examined every five days (summary results: absent 42 times). The absence of the righting reflex in the control group was statistically significant (chi(2) = 18.66, df = 1, p = 0.000, p < 0.05). The experimental group fetuses assumed a prone position more frequently in the period from the 51st to the 66th day of gestation than in the period from the 31st to the 50th day of gestation (chi(2) = 4.17, df = 1, p = 0.0412, p < 0.05), suggesting maturation of the righting reflex.

Spectral and fractal analysis of cerebellar activity after single and repeated brain injury.

The cerebellum, even when not directly damaged, is potentially interesting for understanding the adaptive responses to brain injury. Cerebellar electrocortical activity (ECoG) in rats was studied using spectral and fractal analysis after single and repeated unilateral injury of the parietal cortex. Local field potentials of cerebellar paravermal cortex were recorded before brain injury, in the acute phase (up to 2.5 hours) after a first injury of anesthetized rats, and then before and after second, third, and, in some cases, fourth injury. Relative gamma power (32.1-128.0 Hz) and fractal dimension of ECoGs were temporarily increased after the first injury. However, there was a permanent mild increase in gamma activity and a mild increase in the fractal dimension of cerebellar activity as a chronic change after repeated remote brain injury. There was a negative linear correlation between the normalized difference in fractal dimensions and normalized difference in gamma powers of cerebellar activity only in the case of repeated brain injury. This is the first study showing that correlation between the parameters of spectral and fractal analyses of cerebellar activity can discriminate between single and repeated brain injuries, and is, therefore, a promising approach for identifying specific pathophysiological states.

Estimation of parameter kmax in fractal analysis of rat brain activity.

We recorded electrocortical activity in anesthetized rats and constructed k(max) new self-similar time series, applying Higuchi's algorithm. The aim of this study was to estimate value of the parameter k(max) in order to obtain fractal dimension values as an optimum measure of biosignal change. After our analysis, electrocortical activity recordings resulted in a family of curves f(k(max)). Three regions could be distinguished 2 < or = k(max) < 8, with a U-shape; 8 < or = k(max) < or = 30, with a steeper quasilinear increase; and k(max) > or = 30, with a smaller slope quasilinear increase. We suggest the optimum region for k(max): 8 < k(max) < 18, specifically k(max) = 8.