[Effects of glial cell line-derived neurotrophic factor and memantine on long-term prognosis in neonatal rats with periventricular leukomalacia].

OBJECTIVE: To evaluate the effects of glial cell line-derived neurotrophic factor (GDNF) and memantine on the long-term prognosis in neonatal rats with ischemia-induced periventricular leukomalacia (PVL). METHODS: Thirty-two 5-day-old neonatal rats were randomly divided into 4 groups: sham-operated, PVL, GDNF-treated and memantine-treated. PVL was induced by right carotid artery ligation and hypoxia in the PVL, GDNF-treated and memantine-treated groups. GDNF (100 µg/kg) or memantine (20 mg/kg) was injected in the two treatment groups immediately after PVL inducement. The weight of the rats was measured immediately before and after hypoxia ischemia (HI). Both of Morris water maze test and Rivlin inclined plane test were performed at 26 days old (21 days after HI). The values of the escape latency (EL) and swimming distance, and the maximum inclined plane degree which the rats could stand at least 5 seconds were compared among the four groups. RESULTS: The lower weight, the prolonged mean values of EL and swimming distance and the reduced maximum inclined plane degree were observed in the PVL group compared to those in the sham-operated, GDNF-treated and memantine-treated groups. There were no significant differences in the weight, the values of EI and swimming distance and the maximum inclined plane degree between the two treatment groups and the sham-operated group. CONCLUSIONS: The administration of either GDNF or memantine can markedly increase the abilities of spatial discrimination,learning and memory, and motor coordination, promote weight gain, and improve long-term prognosis in rats with PVL.

[To what degree does the NICU environment influence neurodevelopment of preterm infants?]. / Intensivmedizinisches Reizumfeld und Stressoren--welchen Einfluss haben sie auf die Gehirnentwicklung frühgeborener Kinder?

What effect do the various stressing stimuli in a neonatal intensive care unit have on the very sensitive process of synaptogenesis and apoptosis, dendritic growth and neuronal differentiation? To what degree can even minimal changes in the neuronal network of the developing cortex lead to behavioural disorders? And is there any possibility to improve the long term outcome of preterm infants by offering special support within the framework of individualized developmental care? This article combines the results of several studies and discovers interactions to illustrate the complexity and vulnerability of the developing human brain and to discuss the potential benefit of individualized developmental care interventions.

Arithmetic and brain connectivity: mental calculation in adolescents with periventricular lesions.

The ability for mental calculation represents a fundamental prerequisite for development of intelligence, which is predictive for educational and professional success in life. Many individuals with calculation difficulties are survivors of premature birth. The brain mechanisms of these deficits are, however, largely unknown. In this work, we clarify whether and, if so, how calculation abilities in adolescents who were born premature are related to the extent and topography of periventricular lesions that affect brain connectivity. Performance on a set of mental calculation tasks is lower in adolescents with periventricular leukomalacia (PVL) than in former preterms and term-born peers without signs of brain abnormalities on a magnetic resonance imaging scan. No difference in the calculation ability was found between term-born and preterm adolescents without PVL. Calculation abilities in PVL patients were unrelated to volumetric extent and topography of lesions in both brain hemispheres. Whereas previous work clearly reveals the link between the extent and topography of lesions and severity of impairments in visual cognition ranging from body motion processing to visual navigation and social cognition, no such association occurs for mental calculation. We assume that the lack of relationship between calculation abilities and the extent and topography of periventricular lesions point to topographically restricted neural substrate that serves as the keystone for mental calculation. The findings suggest that periventricular brain damage does not substantially affect the connectivity of this region with other brain structures engaged in the mental calculation network.

The quality of preterm infants' spontaneous movements: an early indicator of intelligence and behaviour at school age.

BACKGROUND: The quality of very preterm infants' spontaneous movements at 11 to 16 weeks post-term age is a powerful predictor of their later neurological status. This study investigated whether early spontaneous movements also have predictive value for the intellectual and behavioural problems that children born very preterm often experience. METHODS: Spontaneous movement quality was assessed, using Prechtl's method, at 11 to 16 weeks post-term in 65 infants born at

[Periventricular leukomalacia and spastic diplegia: implications in the psycholinguistic abilities]. / Leucomalácia periventricular e diplegia espástica: implicações nas habilidades psicolingüísticas.

BACKGROUND: spastic diplegic cerebral palsy (D-CP) is frequently related to periventricular leukomalacia (PVL), which usually affects the descending motor fibers of the association cortex and association fibers of the visual, auditory and somesthesic functions. AIM: to verify the performance of children with D-CP regarding their psycholinguistic skills. METHOD: participants were eight individuals of both genders and with chronological ages varying from four to six years, diagnosed with D-CP, having PVL confirmed through magnetic resonance. These children were evaluated through the Illinois Test of Psycholinguistic Abilities (ITPA) and the Peabody Picture Vocabulary Test (PPVT), considering the cognitive performance, the level of motor impairment and the performance in the auditory and visual subtests of the ITPA. RESULTS: the results pointed to a significant correlation between the cognitive performance and the PPVT. The same correlation was confirmed between the PPVT and the subtest of auditory reception of the ITPA, when considering the psycholinguistic age. In the comparison between the auditory and visual abilities, the participants demonstrated a better performance in the activities that involved visual abilities, indicating a significant correlation in the association subtest. There was a statistically significant correlation between the level of motor impairment and the psycholinguistic performance, confirming the influence of the motor impairment in these activities. CONCLUSION: the children with D-CP and with suggestive signs of PVL presented deficits in the psycholinguistics abilities, justifying the need of additional studies in this area in order to investigate the development of these abilities.

Spastic diplegia in preterm-born children: Executive function impairment and neuroanatomical correlates.

BACKGROUND: The neuropsychological literature on preterm-born children with spastic diplegia due to periventricular leukomalacia is convergent in reporting deficits in non-verbal intelligence and in visuo-spatial abilities. Nevertheless, other cognitive functions have found to be impaired, but data are scant and not correlated with neuroimaging findings. AIMS: This study analyzes the neuropsychological strengths and weaknesses in preterm-born children with spastic diplegia (pSD) and their relationships with neuroanatomical findings, investigated by a novel scale for MRI classification. METHODS AND PROCEDURES: Nineteen children with pSD, mild to moderate upper limb impairment and Verbal IQ>80, and 38 normal controls were evaluated with a comprehensive neuropsychological battery (NEPSY-II), assessing Attention/Executive Functioning, Language, Memory, Sensorimotor, Social Perception and Visuospatial Processing domains. The MRIs were quantitatively scored for lesion severity. OUTCOMES AND RESULTS: The results showed that, beyond core visuo-spatial and sensory-motor deficits, impairments in attention and executive functions were present in more than half of the sample, particularly in children with damage to the anterior corpus callosum. CONCLUSIONS AND IMPLICATIONS: The findings are discussed in terms of clinical and rehabilitative implications tailored for pSD subgroups diversified for neuropsychological and neuroanatomical characteristics.

Biological motion processing in adolescents with early periventricular brain damage.

The developing brain is traditionally viewed to possess a great compensatory potential. Here we ask whether visual processing of point-light displays depicting human walking is compromised in adolescents who were born premature (between 27 and 33 gestation weeks) and suffer early bilateral damage to periventricular brain regions. Combining psychophysics with volumetric analysis of structural magnetic resonance imaging (MRI), we found that even relatively small periventricular parieto-occipital lesions may result in long-lasting breakdown of visual processing of point-light displays. Analysis of receiver operating characteristic (ROC) curves revealed higher susceptibility of the patients' perceptual system to camouflage of a point-light figure. The lack of difference in sensitivity between former preterms with normal MRI scan and term-born controls indicates that perceptual deficiencies in patients with periventricular leukomalacia (PVL) are not simply due to premature birth. Most importantly, sensitivity in patients even with mild PVL was lower than in both control groups. Display 180 degrees inversion in the image plane, which is known to impair processing of point-light displays, resulted in a substantial reduction of sensitivity so that it no longer differed between the groups. Despite the social and ecological significance of human locomotion, the capacity of the brain to detect biological motion is substantially modulated by periventricular lesions even if they occur very early in life. The findings point to specific restrictions on the brain's spontaneous compensatory plasticity in perceptual development.

Object working memory deficits predicted by early brain injury and development in the preterm infant.

Children born preterm and of very low birth weight are at increased risk of learning difficulties and educational under-achievement. However, little is known about the specific neuropsychological problems facing these children or their neurological basis. Using prospective longitudinal data from a regional cohort of 92 preterm and 103 full-term children, this study examined relations between term MRI measures of cerebral injury and structural brain development and children's subsequent performance on an object working memory task at the age of 2 years. Results revealed clear between-group differences, with preterm children having greater difficulty encoding new information in working memory than term control children. Within the preterm group, task performance at the age of 2 years was related to both qualitative MRI measures of white matter (WM) injury and quantitative measures of total and regional brain volumes assessed at term equivalent. Bilateral reductions in total tissue volumes (%region) of the following cerebral regions were specifically related to subsequent working memory performance: dorsolateral prefrontal cortex, sensorimotor, parietooccipital and premotor. Associations between total cerebral tissue volumes at term (adjusted and unadjusted for intracranial volume) persisted even after the effects of WM injury were taken into account. This suggests that early disturbance in cerebral development may have an independent adverse impact on later working memory function in the preterm infant. These findings add to our understanding of the neuropathological pathways associated with later executive dysfunction in the very preterm infant.

Periventricular echodensities detected by cranial ultrasonography: usefulness in predicting neurodevelopmental outcome in low-birth-weight, preterm infants.

Forty-eight low-birth-weight, preterm graduates of the University of Washington's neonatal intensive care unit who had received periodic, serial scanning by means of cranial ultrasonography during the first 4 to 6 weeks of life were longitudinally observed in an interdisciplinary neurodevelopmental follow-up program to a mean corrected age of 18 months. Mean birth weight for the sample was 1286 g; mean gestational age was 29 weeks. Periventricular echodensities were graded from 0 to 3, with 0 indicating no densities and 3 indicating cystic formation. Intracranial hemorrhage was graded in the conventional manner from 0 to IV. Neurodevelopmental outcome was assessed by means of a neurologic examination and the Bayley Scales of Infant Development. To synthesize the results, neurodevelopmental outcome for each subject was classified as normal, demonstrating minor abnormalities, or demonstrating major abnormalities. Multiple statistical analyses with various subgroupings of subjects consistently indicated severe intracranial hemorrhage (grades III and/or IV) to be a better predictor of overall neurodevelopmental outcome than grade of periventricular echodensity, including small cysts. These results suggest a wide range of outcomes after detection of periventricular echodensities and caution against communicating overly pessimistic prognoses in many cases.

Psychological findings in preterm children related to neurologic status and magnetic resonance imaging.

OBJECTIVE: Preterm children experience learning disabilities more often than full-term children, but detailed information on their neuropsychological and neurologic determinants is lacking. We therefore examined these problems more closely and also studied if clinical neurologic examination and/or magnetic resonance imaging (MRI) can be used as tools to screen the preterm children at risk for these problems. METHODS: In a population-based study, the psychological performance of 42 preterm children with a birth weight <1750 g and of their matched controls was assessed at 8 years of age and the findings were then related to clinical neurologic examination and MRI. Learning disabilities of these children, reported by the teachers, were also studied. RESULTS: The cognitive ability of the preterm children, although in the normal range, was significantly lower than that of the control children. They performed particularly poorly in tasks requiring spatial and visuoperceptual abilities, which were associated with the finding of periventricular leukomalacia in MRI, especially with posterior ventricular enlargement. The preterm children with minor neurodevelopmental dysfunction (MND) had the most problems in neuropsychological tests, whereas the clinically healthy preterm children and those with cerebral palsy had fewer problems. The problems of MND children emerged in the domain of attention. They also experienced the most problems at school. CONCLUSIONS: Visuospatial problems were associated with periventricular leukomalacia in MRI, but learning disabilities were most frequent among the preterm children with minor neurologic abnormalities. We recommend closer follow-up of preterm children with MND.

Spontaneous leg movements in infants with and without periventricular leukomalacia: effects of unilateral weighting.

The present study was designed to investigate the contribution of the corticospinal tracts in the regulation and coordination of interlimb couplings and the spatio-temporal organization of kicking movements in young infants. Both healthy infants and those with differing degrees of periventricular leukomalacia (PVL) were subjected to a unilateral weight manipulation at the (corrected) age of 26 weeks. Infants with PVL were grouped according to the amount of damage in the area in which the corticospinal tracts are located as shown by neonatal MRI and confirmed with MRI recordings at 18 months. The main question asked was whether unilateral weighting would reveal different adjustment in infants with and without PVL and whether these differences were related to the severity of the lesions, if present. The major finding was that no differences were evident between groups in adjusting to the weight manipulation with regard to the tightness of interlimb couplings. This finding corroborates the suggestion that corticospinal influences are not directly involved in the regulation of these parameters. Although the same conclusion could be drawn concerning the kinematic details of kicks on the basis of group data, individual analyses revealed that kinematics in a few infants with PVL were markedly affected by the weighting. Thus, combining group with individual analyses may have additional value in the clinical interpretation of the effects of PVL on the neural functions of young infants.

Cranial magnetic resonance imaging and school performance in very low birth weight infants in adolescence.

AIM: To determine whether neurological deficits are associated with structural anomalies of the brain in very low birthweight (VLBW) infants with subsequent learning disorders but without cerebral palsy, or whether other factors, such as poor early growth, are responsible. METHODS: Eighty seven VLBW infants and eight term controls who had been examined at school between the ages of 12 and 13 years, had cranial magnetic resonance imaging (MRI) scans at 15-17 years of age. RESULTS: Thirty seven (42.5%) of the VLBW children had abnormalities reported on their scans (two porencephaly, 28 periventricular leucomalacia, 24 ventricular dilatation, and 15 thinning of the corpus callosum). No significant differences in intelligence quotient, motor clumsiness, or frequency of attention deficit / hyperactivity disorder were observed between those children with MRI lesions and those with normal scans. Quantitative measurements showed the VLBW infants had smaller brains, and a relatively smaller corpus callosum compared with controls. No association between brain measurements and school performance was observed among the VLBW infants. CONCLUSIONS: The difficulties experienced by VLBW children at school are unlikely to be the result of perinatal brain injury, but they might to be attributable to the effects of poor postnatal growth.

Neurodevelopmental outcome of children with evidence of periventricular leukomalacia on late MRI.

Fifteen children, 8 months of age or older, from a neonatal follow-up program underwent magnetic resonance imaging and neurologic, cognitive, and language evaluations. Magnetic resonance imaging findings in all children included increased white matter signal on T2-weighted images and ventricular enlargement adjacent to regions of abnormal white matter. The extent of degree of abnormal white matter signal and the degree of sulcal prominence were variable. Twelve children had cerebral palsy; 5 children, 4 of whom had cerebral palsy, manifested significant sensory impairments. The median score on cognitive testing was 89; only 2 children exhibited severe-to-profound cognitive disability. Cognitive scores were stable on retesting. The degree of motor disability was correlated with the extent of white matter signal abnormality; however, cognitive outcome was not related to the extent and degree of white matter signal abnormality or to the degree of sulcal prominence. Despite the association of a major handicapping condition and periventricular leukomalacia, cognitive and language functioning may be relatively spared.

Periventricular leukomalacia (PVL): an identical twin case study illustration of white matter dysfunction and nonverbal learning disability (NLD).

This paper discusses the implications of Periventricular Leukomalacia (PVL) lesions for the development of Nonverbal Learning Disabilities (NLD) as illustrated through an identical twin case study. PVL lesions were identified in an 8-year-old child, but were not detected in his identical twin brother who served as a matched comparison. While the nonclinical twin displayed a largely unremarkable neuropsychological profile, the clinical twin evidenced a distinct pattern of social, intellectual, academic, and neuropsychological test results often identified among children with PVL and those with the NLD syndrome. The clinical and theoretical implications for this case study are discussed.

Early language and communicative abilities of children with periventricular leukomalacia.

Ten 2-year-old children with periventricular leukomalacia (PVL), a brain injury associated with prematurity, were evaluated using language samples. Five children scored less than 80 on cognitive testing (delayed). Five children with this disorder and normal cognitive scores were assessed at two ages, matched with the delayed group on CA and developmental level. The delayed group produced significantly fewer lexical tokens and spontaneous verbal utterances than did the CA-matched group. No significant differences were observed between the delayed group and either comparison group on other measures of lexicon, grammar, or communication. The data demonstrate a relation between cognitive abilities and measures of verbal productivity in children with PVL.

Neurologic and psycho-intellectual outcome related to structural brain imaging in adolescents and young adults after neonatal arterial switch operation for transposition of the great arteries.

OBJECTIVE: We studied brain structure abnormalities in adolescents and young adults who had undergone the neonatal arterial switch operation for transposition of the great arteries and related them to the neurologic and psycho-intellectual outcomes. METHODS: In a prospective longitudinal study, 60 unselected adolescents and young adults who had undergone surgery with combined deep hypothermic circulatory arrest and low flow cardiopulmonary bypass were re-evaluated at a mean age of 16.9±1.7 years to determine their clinical neurologic status, intellectual development, and psychological condition. The results were related to population norms and anatomic structural abnormalities assessed by brain magnetic resonance imaging, with consideration of the risk factors in the preoperative and perioperative periods. RESULTS: Neurologic impairment was more frequent (10%) than in the normal population. Although the average full-scale, verbal, and performance intelligence quotients were not reduced, scores>2 standard deviations less than the expected mean were increased. Above average scores were found for analytical thinking, but the orthography testing results were reduced. The self-rated psychological condition was better than expected. Magnetic resonance imaging demonstrated moderate or severe structural brain abnormalities in 32% of the patients. Periventricular leukomalacia was detected in >50%; its severity correlated with the grade of neurologic impairment, which correlated significantly with reduced intelligence, analytical thinking, and orthography. Preoperative acidosis and hypoxia were the only independent patient-related risk factors for neurologic dysfunction, reduced intelligence, periventricular leukomalacia, and reduced brain volume. CONCLUSIONS: Despite encouraging overall neurodevelopmental outcomes, a significant minority had performances below the expected level, emphasizing the need for ongoing surveillance. Considering the high frequency of structural brain abnormalities, prospective long-term studies are needed to define their prognostic value with respect to the neuropsychological outcomes in childhood and adolescence.

[Visuospatial functions and prematurity]. / Funciones visuoespaciales y prematuridad.

Visuospatial functions are very important in learning process and development of abstract thought during childhood. Several studies show that preterm and low birth weight infants obtain lower scores in test that assess cognitive functions, specially in the first year of life. These differences are attenuated over time, but a developmental delay that affects working memory and visuospatial process still persists. It is unclear what factors are involved in development of these functions, and pre- or perinatal factors may interfere with the proper conduct of the same, but have been described anatomical and physiological differences between the preterm and term brain that could explain somewhere in these alterations. The different selective vulnerability to hypoxia between immature brain in which preoligodendrocytes and subplate neurons predominate, and mature brain, determine differences in the pattern of injury from hypoxia with greater involvement of the periventricular white matter in preterm children. This lesional pattern leaves to a dysfunction in attentional and visuospatial process, due to the increased vulnerability of the regions involved in the dorsal pathway of visual processing.

TITLE: Funciones visuoespaciales y prematuridad.Durante la infancia, las funciones visuoespaciales son importantes en los procesos de aprendizaje y en el desarrollo del pensamiento abstracto. Diferentes estudios muestran que los niños prematuros o con bajo peso al nacer obtienen menores puntuaciones en los tests que valoran las funciones cognitivas, siendo estas diferencias mas pronunciadas durante el primer año de vida. Con el tiempo, estas diferencias se van atenuando, pero persiste un retraso madurativo que afecta a la memoria de trabajo y a los procesos visuoespaciales. No esta claro cuales son los factores implicados en el desarrollo de estas funciones y que factores pre o perinatales pueden interferir en su buen desarrollo, pero se han descrito diferencias anatomicas y fisiologicas entre el cerebro del niño pretermino y el termino que podrian explicar, en parte, alguna de estas alteraciones. La diferente vulnerabilidad selectiva a la hipoxia entre el cerebro inmaduro, en el que predominan las neuronas de la subplaca y los preoligodendrocitos, y el cerebro maduro del niño nacido a termino determinan diferencias en el patron de lesion por hipoxia con mayor afectacion de la sustancia blanca periventricular en el niño pretermino. Este patron lesional conlleva una disfuncion en los procesos atencionales y visuoespaciales debido a la mayor vulnerabilidad de las regiones que intervienen en la ruta dorsal del procesamiento visual.

Interleukin-6 G(--174)C polymorphism is associated with mental retardation in cystic periventricular leucomalacia in preterm infants.

OBJECTIVE: The fetal inflammatory response syndrome involving proinflammatory cytokines such as interleukin-6 (IL-6) has been associated with cystic periventricular leukomalacia (cPVL). We evaluated whether the development of cPVL is associated with the IL-6 G(-174)C polymorphism. METHODS: 52 children with cPVL were compared to 46 preterm and 395 term controls using retrospective cohort analysis. IL-6 genotyping was performed using an allele specific polymerase chain reaction technique. RESULTS: IL-6 G(-174)C polymorphisms did not differ between groups, but an association between mental retardation and the IL-6 C/C (78%) and G/C (43%) genotypes compared to the G/G (25%) genotype was found (p = 0.003 and 0.043, respectively; RR 3.11 (95% CI 1.54 to 6.29) and 1.79 (95% CI 1.10 to 2.92), respectively). CONCLUSIONS: The IL-6 (-174) C/C and G/C genotypes were associated with mental retardation in cPVL and seem to modify the severity of perinatal brain injury.

Insults to the developing brain and impact on neurodevelopmental outcome.

UNLABELLED: Premature infants have a disproportionately increased risk for brain injury based on several mechanisms including intraventricular hemorrhage, ischemia and the vulnerability of developing neuronal progenitor cells. Injury to the developing brain often results in neurologic abnormalities that can be correlated with a structural lesion; however more subtle injury may result in disruption of critical neural pathways. There also appears to be an important relationship between brain injury in the cortex and the growth and developing cerebellum. Although the survival rate for premature has improved over the past decade, researchers remain concerned about the risk for adverse neurocognitive functioning in these early childhood, including an increased risk for cerebral palsy, cognitive impairment, speech and language delay and sensory dysfunction. LEARNING OUTCOMES: After this activity, the learner will be able to (1) identify potential causes of brain injury in the premature infant, (2) understand that the maturational process for the human brain continues throughout gestation, (3) identify risk factors for adverse neurocognitive functioning in premature infants, and (4) identify abnormalities on central nervous system neuroimaging studies that correlate with an increased risk for adverse neurodevelopmental outcome in premature infants.

Inversion of perceived direction of motion caused by spatial undersampling in two children with periventricular leukomalacia.

We report here two cases of two young diplegic patients with cystic periventricular leukomalacia who systematically, and with high sensitivity, perceive translational motion of a random-dot display in the opposite direction. The apparent inversion was specific for translation motion: Rotation and expansion motion were perceived correctly, with normal sensitivity. It was also specific for random-dot patterns, not occurring with gratings. For the one patient that we were able to test extensively, contrast sensitivity for static stimuli was normal, but was very low for direction discrimination at high spatial frequencies and all temporal frequencies. His optokinetic nystagmus movements were normal but he was unable to track a single translating target, indicating a perceptual origin of the tracking deficit. The severe deficit for motion perception was also evident in the seminatural situation of a driving simulation video game. The perceptual deficit for translational motion was reinforced by functional magnetic resonance imaging studies. Translational motion elicited no response in the MT complex, although it did produce a strong response in many visual areas when contrasted with blank stimuli. However, radial and rotational motion produced a normal pattern of activation in a subregion of the MT complex. These data reinforce the existent evidence for independent cortical processing for translational, and circular or radial flow motion, and further suggest that the two systems have different vulnerability and plasticity to prenatal damage. They also highlight the complexity of visual motion perception, and how the delicate balance of neural activity can lead to paradoxical effects such as consistent misperception of the direction of motion. We advance a possible explanation of a reduced spatial sampling of the motion stimuli and report a simple model that simulates well the experimental results.