Seasonal Variations of Neuromotor Development By 14 Months of Age: Hamamatsu Birth Cohort for Mothers and Children (HBC Study)

The present study aimed at investigating whether neuromotor development, from birth to 14 months of age, shows seasonal, cyclic patterns in association with months of birth. Study participants were 742 infants enrolled in the Hamamatsu Birth Cohort (HBC) Study and followed-up from birth to the 14th month of age. Gross motor skills were assessed at the ages of 6, 10, and 14 months, using Mullen Scales of Early Learning. The score at each assessment was regressed onto a trigonometric function of months of birth, with an adjustment for potential confounders. Gross motor scores at the 6th and 10th months showed significant 1-year-cycle variations, peaking among March- and April-born infants, and among February-born infants, respectively. Changes in gross motor scores between the 10th and 14th months also showed a cyclic variation, peaking among July- and August-born infants. Due to this complementary effect, gross motor scores at the 14th month did not show seasonality. Neuromotor development showed cyclic seasonality during the first year of life. The effects brought about by month of birth disappeared around 1 year of age, and warmer months seemed to accelerate the neuromotor development.     

An oral developmental neurotoxicity study of decabromodiphenyl ether (DecaBDE) in rats

BACKGROUND: Decabromodiphenyl ether (DecaBDE; CASRN 1163‐19‐5) is a flame retardant used in a variety of manufactured products. A single oral dose of 20.1 mg/kg administered to mice on postnatal day 3 has been reported to alter motor activity at 2, 4, and 6 months of age. METHODS: To further evaluate these results, a developmental neurotoxicity study was conducted in the most commonly used species for studies of this type, the rat, according to international validated testing guidelines and Good Laboratory Practice Standards. DecaBDE was administered orally via gavage in corn oil to dams from gestation day 6 to weaning at doses of 0, 1, 10, 100, or 1,000 mg/kg/day. Standard measures of growth, development, and neurological endpoints were evaluated in the offspring. Motor activity was assessed at 2 months of age. Additional motor activity assessments were conducted at 4 and 6 months of age. Neuropathology and morphometry evaluations of the offspring were performed at weaning and adulthood. RESULTS: No treatment‐related neurobehavioral changes were observed in detailed clinical observations, startle response, or learning and memory tests. No test substance‐related changes were noted in motor activity assessments performed at 2, 4, or 6 months of age. Finally, no treatment‐related neuropathological or morphometric alterations were found. CONCLUSIONS: Under the conditions of this study, the no‐observed‐adverse‐effect level for developmental neurotoxicity of DecaBDE was 1,000 mg/kg/day, the highest dose tested. Birth Defects Res (Part B) 92:17–35, 2011.© 2011 Wiley‐Liss, Inc.     

Motor, mental and behavioral developments in infancy are associated with fatty acid pattern in breast milk and plasma of premature infants

The objective of this study was to investigate any association between infants' early development and PUFA concentrations in early breast milk and infants' plasma phospholipids at 44 weeks gestational age. Fifty-one premature infants were included. The quality of general movement was assessed at 3 months, and motor, mental and behavioral development at 3, 6, 10 and 18 months corrected age using Bayley's Scales of Infant Development (BSID-II). Linoleic acid, the major n-6/n-3 FA ratios, Mead acid and the EFA deficiency index in early breast milk were negatively associated with development up to 18 months of age. DHA and AA, respectively, in infants' plasma phospholipids was positively, but the AA/DHA ratio negatively, associated with development from 6 to 18 months of age. Our data suggest that the commonly found high n-6 concentration in breast milk is associated with less favorable motor, mental and behavioral development up to 18 months of age.     

Actigraphic motor activity during sleep from infancy to adulthood

A secondary analysis of longitudinal and cohort studies was carried out to quantitatively investigate the motor activity pattern, recorded through actigraphy, during the first six hours of nocturnal sleep. The first study was of longitudinal nature. Ten healthy participants (four females) were monitored three times, at baseline (T1) when they were infants (mean age 7.10 ± 0.32 months), at the first follow-up examination (T2) around 4 months later (mean age 11.20 ± 0.63 months) and at the second follow-up (T3) around three years later, when they were preschoolers (mean age 4.68 ± 0.14 years). At T1, T2 and T3 each participant wore the actigraph Basic Mini-Motionlogger (Ambulatory Monitoring, Inc., Ardsley, NY, USA) over at least two consecutive nycthemeral cycles, with the aim to measure the mean hourly motor activity count. Seven- and 11-month-old infants had a higher level of motor activity over the night compared to preschoolers. Furthermore, motor activity increased as the night progressed, with a pronounced increment at both T1 and T2, while at T3 such an increase was less marked. The second study was cross-sectional and aimed to explore the motor activity pattern, using actigraphy, during the first six hours of nocturnal sleep in multiple-age healthy groups, from infancy to adulthood. We assigned participants to eight groups according to age: 20 (five females) aged around 10 months old (mean age 10.65 ± 0.67 months); 13 (nine females) aged around 4 years (mean age 4.38 ± 0.51 years); 21 (10 females) aged around 10 years (mean age 9.67 ± 0.91 years); 21 (nine females) aged around 20 years (mean age 19.33 ± 2.44 years); 20 (10 females) aged around 30 years (mean age 29.80 ± 1.99 years); 20 (15 females) aged around 40 years (mean age 40.70 ± 1.26 years); 20 (11 females) aged around 50 years (mean age 50.15 ± 2.80 years) and 20 (nine females) aged around 60 years (mean age 59.25 ± 3.23 years). The participants aged between 10 and 60 years wore the actigraph Basic Mini-Motionlogger over seven consecutive nycthemeral cycles (infants and preschoolers wore the actigraph over at least two consecutive nycthemeral cycles), with the aim to measure the mean hourly motor activity count. The results indicated a significantly higher motor activity count in 10-month-old infants compared to all the remaining age groups. Moreover, the pattern of motor activity of 10-month-old infants was different from that of all other groups, with the highest motor activity counts from the second to the sixth hour of sleep. Considered as a whole, the results of both studies converge regarding the high motor activity detected among infants, which could be explained by the presence of a maturational process that has not yet been fully completed at this stage of life. In both studies, only the motor activity of infants was above the cutoff level established for normal adults, highlighting the need to establish a specific cutoff value for infants.     

Glial activation and TNFR-I upregulation precedes motor dysfunction in the spinal cord of mnd mice

Mice homozygous for the spontaneous motor neuron degeneration mutation (mnd) show at the age of 8 months a marked impairment of the motor function and accumulation of lipofuscin granules in the cytoplasm of almost all neurons of the central nervous system.We previously reported a significant increase in GFAP protein levels in the lumbar spinal cord homogenates by western blot analysis and upregulation of TNF, a proinflammatory cytokine, in the motor neurons of lumbar spinal cord of mnd mice, already in a presymptomatic stage (4 months of age). In the present study, using immunohistochemical analysis, we performed a time course in mnd mice (1, 4 and 9 months of age) evaluating the expression and the distribution of astroglial and microglial cells and the expression of both TNF receptors, TNFR-I and TNFR-II. We observed a marked increase in astroglial and microglial cells and in TNFR-I immunoreactivity already at the 4th month. Since motor neuron dysfunction occurs in mnd mice in the absence of evident loss of spinal motor neurons, the present results indicate that the activation of microglial cells and astrocytes is independent from neuronal degeneration. The role of TNF and TNFR-I on motor neurons is still to be demonstrated.     

Postnatal change in lipid composition and nerve conduction of peripheral nerves of young rhesus monkeys.

Body weight, motor and sensory nerve conduction velocities of fore and hind limbs, and lipid composition were measured sequentially in peripheral nerves of 15 rhesus monkeys. Initially measurements were made with monkeys six to eight months of age. There were significant increases in body weight, motor, and sensory nerve conduction and myelin marker lipids over a five months period, but no change was observed in free fatty acids, triglycerides, and esterified cholesterol. These results indicate that myelination continues at least for 11 to 13 months of postnatal age in rhesus monkeys.     

The stability of motor activity in rats

Individual differences in motor activity were investigated in two groups of male rats. One group contained non-homozygotic and the second homozygotic rats. In both groups the individual differences were similar and very pronounced. Starting from the age of about 3 months the level of motor activity in individual animals remained relatively stable until the age of at least 6 1/2 months. The results may be useful for certain behavioural investigations and for long-term pharmacological studies and bioassays.     

Effects of bone marrow mesenchymal stromal cells on gross motor function measure scores of children with cerebral palsy: a preliminary clinical study

Background aimsPre-clinical evidence indicates that autologous bone marrow-derived mesenchymal stromal cell (BM-MSC) transplantation improves motor function in patients with central nervous system disorders.MethodsAfter providing informed consent, 52 patients with cerebral palsy (CP) who met the study criteria received BM-MSC transplantation. Gross motor function was assessed using the Gross Motor Function Measure (GMFM)-88 and GMFM-66 scales at baseline (before transplantation) and at 1 month, 6 months and 18 months post-transplantation. The participants completed the trial without visible side effects. The GMFM-66 percentile (motor growth curves) was used as the control index of motor function to exclude the interference of improvement with age.ResultsThe score domains A, B, C and D and the total GMFM-88 and GMFM-66 scores in participants increased at 1 month, 6 months and 18 months post-transplantation compared with the baseline value (P < 0.01). The scores of domain E also increased at 6 months and 18 months post-transplantation, although they were not significantly increased at 1 month post-transplantation. There were significant increases in the GMFM-66 score and the GMFM-66 percentile corresponding to patient age and Gross Motor Function Classification System level after cell transplantation.ConclusionsAutologous BM-MSC transplantation appears to be a feasible, safe and effective therapy for patients with CP. The treatment improved the development of children with CP with regard to motor function.     

Aging of the dopaminergic system and motor behavior in mice intoxicated with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

J. Neurochem. (2012) 122, 1032-1046. ABSTRACT: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinson's disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5?months were followed up to a maximum age of 21?months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post-MPTP intoxication decrease in dopamine cell was no longer significant at 21?months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14?months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In bothgroups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process.     

Functional Analogs of the Motor and Premotor Areas of Neocortex in Developing White Rats

To study functional characteristics of the brain cortex motor areas in developing white rats and to determine their interlocation in rat pups at the different age and at critical terms of formation of motor representations in the process of postnatal development, mapping of neocortex frontal areas at the age up to 1.5 months was performed using intracortical microstimulation method. It has been shown that for first 10 days of postnatal development the microstimulation is not effective to evoke corticomotor reactions. An earlier appearance of functional activity of the non-primary motor cortex has been established, as compared with that of the primary motor cortex. It is suggested that there occurs a parallel, but heterochronous formation of primary and non-primary motor areas at the frontal neocortex territory.     

Accuracy of Two Motor Assessments during the First Year of Life in Preterm Infants for Predicting Motor Outcome at Preschool Age

Aim

The primary aim of this study was to investigate the accuracy of the Alberta Infant Motor Scale (AIMS) and Neuro-Sensory Motor Developmental Assessment (NSMDA) over the first year of life for predicting motor impairment at 4 years in preterm children. The secondary aims were to assess the predictive value of serial assessments over the first year and when using a combination of these two assessment tools in follow-up.

Method

Children born <30 weeks’ gestation were prospectively recruited and assessed at 4, 8 and 12 months’ corrected age using the AIMS and NSMDA. At 4 years’ corrected age children were assessed for cerebral palsy (CP) and motor impairment using the Movement Assessment Battery for Children 2^nd-edition (MABC-2). We calculated accuracy of the AIMS and NSMDA for predicting CP and MABC-2 scores ≤15^th (at-risk of motor difficulty) and ≤5^th centile (significant motor difficulty) for each test (AIMS and NSMDA) at 4, 8 and 12 months, for delay on one, two or all three of the time points over the first year, and finally for delay on both tests at each time point.

Results

Accuracy for predicting motor impairment was good for each test at each age, although false positives were common. Motor impairment on the MABC-2 (scores ≤5^th and ≤15^th) was most accurately predicted by the AIMS at 4 months, whereas CP was most accurately predicted by the NSMDA at 12 months. In regards to serial assessments, the likelihood ratio for motor impairment increased with the number of delayed assessments. When combining both the NSMDA and AIMS the best accuracy was achieved at 4 months, although results were similar at 8 and 12 months.

Interpretation

Motor development during the first year of life in preterm infants assessed with the AIMS and NSMDA is predictive of later motor impairment at preschool age. However, false positives are common and therefore it is beneficial to follow-up children at high risk of motor impairment at more than one time point, or to use a combination of assessment tools.

Trial Registration

ACTR.org.au ACTRN12606000252516     

Effect of extirpation of the sensorimotor cortex on the formation of conditioned reflexes to a complex signal in the ontogeny of the cat

In kittens of the age from 39 days to 4 months the influence was studied of the sensorimotor cortex (SMC) ablation on formation and preservation of previously elaborated reflex to a simultaneous complex stimulus (light + sound) with extinction of reaction to nonreinforced components of the complex signal. It is shown that SMC ablation in the age up to 2.5 months does not affect the formation or preservation of the conditioned reflex. The SMC ablation in preliminarily trained kittens in the age of 3.5 months and older leads to disinhibition of components differentiation with preservation of the positive conditioned reflex to the complex signal. In untrained kittens of the same age the SMC ablation leads to disability of animals to inhibit the motor reaction to differentiation signal. The question is discussed of SMC significance in the ontogenesis at formation of adequate forms of behaviour requiring heterosensory interaction.     

American society of maxillofacial surgeons outcome study: preoperative and postoperative neurodevelopmental findings in single-suture craniosynostosis

The purpose of this study was to prospectively determine the neurodevelopmental effects associated with single-suture, nonsyndromic craniosynostosis before and after surgery. Children diagnosed with single-suture craniosynostosis were evaluated by a psychologist using the Bayley Scales of Infant Development-Second Edition (BSID-II) within 2 months before and again 1 year after surgical correction. The BSID-II is a widely used measure of infant cognitive and motor development. The scale consists of three parts, the Mental Developmental Index (MDI), the Psychomotor Developmental Index (PDI), and the Behavior Rating Scale. The MDI and PDI yield age-standard scores (mean, 100; SD, 16). The children ranged in age from 2.5 to 10 months at the time of the craniofacial reconstruction (average age, 5.9 months). Metopic synostosis was diagnosed in 23 percent, sagittal synostosis in 45 percent, and unilateral coronal synostosis in 32 percent of patients. Twenty-two patients were evaluated preoperatively, of whom 15 patients were evaluated postoperatively. Mean baseline BSID-II scores revealed a mild delay in mental and motor scores (MDI, 82.3; PDI, 79.5). Mean postoperative BSID-II scores still revealed a mild delay in mental scores but significantly improved motor scores (MDI, 79.3; PDI, 89.3). Of the 15 children, four (27 percent) had BSID-II evaluations that were in the average range for all scales and nine infants (60 percent) had at least one MDI or PDI score in the significantly delayed range (<70). Among children with single-suture nonsyndromic craniosynostosis, mean Bayley scores indicated mild baseline deficits in both mental and motor scores. After surgical treatment, improvement was seen in the motor scale. It appears from this sample that neurodevelopmental abnormalities may be present in children with single-suture synostosis, and some may persist at 1 year of follow-up.     

Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia.

There has been considerable debate over whether asymptomatic neonatal hypoglycaemia results in neurological damage. In a detailed multicentre study of 661 preterm infants hypoglycaemia was found to be common. Moderate hypoglycaemia (plasma glucose concentration less than 2.6 mmol/l) occurred in 433 of the infants and in 104 was found on three to 30 separate days. There was considerable variation among the centres, implying differences in decisions to intervene. The number of days on which moderate hypoglycaemia occurred was strongly related to reduced mental and motor development scores at 18 months (corrected age), even after adjustment for a wide range of factors known to influence development. When hypoglycaemia was recorded on five or more separate days adjusted mental and motor developmental scores at 18 months (corrected age) were significantly reduced by 14 and 13 points respectively, and the incidence of neurodevelopmental impairment (cerebral palsy or developmental delay) was increased by a factor of 3.5 (95% confidence interval 1.3 to 9.4). These data suggest that, contrary to general belief, moderate hypoglycaemia may have serious neurodevelopmental consequences, and reappraisal of current management is urgently required.     

Expression of NR2B in cerebellar granule cells specifically facilitates effect of motor training on motor learning

It is believed that gene/environment interaction (GEI) plays a pivotal role in the development of motor skills, which are acquired via practicing or motor training. However, the underlying molecular/neuronal mechanisms are still unclear. Here, we reported that the expression of NR2B, a subunit of NMDA receptors, in cerebellar granule cells specifically enhanced the effect of voluntary motor training on motor learning in the mouse. Moreover, this effect was characterized as motor learning-specific and developmental stage-dependent, because neither emotional/spatial memory was affected nor was the enhanced motor learning observed when the motor training was conducted starting at the age of 3 months old in these transgenic mice. These results indicate that changes in the expression of gene(s) that are involved in regulating synaptic plasticity in cerebellar granule cells may constitute a molecular basis for the cerebellum to be involved in the GEI by facilitating motor skill learning.     

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf ^im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf ^im on motor function, suggesting that Dysf ^im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.     

The outcome of Erb's palsy when the decision to operate is made at 4 months of age

Since the establishment of the obstetrical brachial plexus clinic in Saudi Arabia, the author has designed a prospective study in which the indication for brachial plexus surgery in infants with Erb's palsy was the lack of active elbow flexion against gravity at 4 months of age. Forty-three infants were included in the study and were distributed among four groups: group A (n = 20) included infants who had active elbow flexion at the initial assessment or at 2 months of age; group B (n = 9) included infants who had active elbow flexion at 3 months of age; group C (n = 11) included infants who had active elbow flexion at 4 months of age; and group D (n = 3) included infants who did not have active elbow flexion at 4 months of age. At the final follow-up, all children in group A demonstrated complete spontaneous recovery of the motor power of the limb. All children in group B also had satisfactory spontaneous recoveries, and none required secondary corrective procedures. Five of the 11 patients in group C had satisfactory spontaneous recoveries. The remaining six children in group C had good recovery of elbow flexion but a poor recovers of shoulder function. Finally, all three patients who did not have elbow flexion at 4 months of age (group D) underwent surgical exploration and reconstruction of the brachial plexus, using nerve grafts. The results of this prospective study are discussed, along with the controversial issue regarding the timing of primary plexus surgery in Erb's palsy.     

Transient and permanent effects of androgen during synapse elimination in the levator ani muscle of the rat

Young male rats were castrated at 7 days of age, and treated with testosterone propionate daily from 7 to 34 days of age. At 13 months of age, motor axons and terminals innervating the levator ani (LA) muscle were stained with tetranitroblue tetrazolium (TNBT). The number of separate axons innervating individual muscle fibers was counted, and muscle fiber diameter was measured. Previous studies have shown that this androgen treatment increases muscle fiber diameter and delays synapse elimination, measured as (1) a greater percentage of muscle fibers innervated by multiple axons and (2) larger motor units. The present results indicate that the androgenic effect on synapse elimination is permanent, in that high levels of multiple innervation persisted for 12 months after the end of androgen treatment. In contrast, the effect on muscle fiber diameter was not maintained for this period. This dissociation of androgenic effects on the pattern of innervation from androgenic effects on muscle fiber diameter offers further evidence that the androgenic maintenance of multiple innervation is not dependent on muscle fiber size. In addition, circulating testosterone levels were measured at 50 and 60 days of age in animals similarly treated with androgen or oil from 7 to 34 days of age. By 60 days of age, testosterone levels in hormone-treated animals had dropped below detectability, comparable to levels in oil-treated controls. This provides additional evidence that androgen treatment during juvenile development can have permanent effects on the adult pattern of innervation in the LA muscle.     

The effect of amniotic fluid taken from women in labor on the morphofunctional development of fetal and newborn rats]

Amniotic fluid from women was injected intra-amniotically to rats at the 14th day of pregnancy in a dose 0.3 ml. Morphological and functional parameters of embryonic development of rats and EMG activity of rat puppies at the age of 30-34 days differed from control ones with respect to the degree of maturity and motor disturbances of newborn babies. The data obtained reveal not only evident but also masked forms of motor pathology which was observed in children later, namely to 6-9 months. Chronic motor pathology in rat puppies was unilateral with central motor disturbances in babies being directly related to the degree of these disturbances.