Hippocampal volumes and cognitive performance in children born extremely preterm with and without low-grade intraventricular haemorrhage.

Children born extremely preterm, especially those with intraventricular haemorrhage (IVH), are at increased risk of adverse cognitive outcomes during childhood. The present study aimed to explore the effects of IVH (grades I-II) on hippocampal volumes, and their correlates with cognitive performance. The sample consisted of 94 participants, including 54 children born extremely preterm (19 with IVH, grades I-II), and 40 children born at term. All participants underwent a magnetic resonance imaging study at the age of 10 (Mage = 10.20 years; SDage = 0.78), and 74 of them (45 extremely preterm and 29 full-term) carried out a cognitive assessment at 12 years old. Children born extremely preterm had lower scores in cognitive performance compared to their full-term peers. Significant positive partial correlations were observed between global bilateral hippocampus, left CA-field, and left subiculum volumes with processing speed in the full-term group, while no significant correlations were found in the extremely preterm group. Moderation analyses in the extremely preterm sample revealed that low-grade IVH moderated the relationship between right hippocampal volume and full-IQ (F(4,40) = 5.42, p = 0.001, R2 = 0.35). Having greater right hippocampal volume had a protective effect on full-IQ in those children born extremely preterm with low-grade IVH.

A lateral-to-mesial organization of human ventral visual cortex at birth.

In human adults, ventral extra-striate visual cortex contains a mosaic of functionally specialized areas, some responding preferentially to natural visual categories such as faces (fusiform face area) or places (parahippocampal place area) and others to cultural inventions such as written words and numbers (visual word form and number form areas). It has been hypothesized that this mosaic arises from innate biases in cortico-cortical connectivity. We tested this hypothesis by examining functional resting-state correlation at birth using fMRI data from full-term human newborns. The results revealed that ventral visual regions are functionally connected with their contra-lateral homologous regions and also exhibit distinct patterns of long-distance functional correlation with anterior associative regions. A mesial-to-lateral organization was observed, with the signal of the more lateral regions, including the sites of visual word and number form areas, exhibiting higher correlations with voxels of the prefrontal, inferior parietal and temporal cortices, including language areas. Finally, we observed hemispheric asymmetries in the functional correlation of key areas of the language network that may influence later adult hemispheric lateralization. We suggest that long-distance circuits present at birth constrain the subsequent functional differentiation of the ventral visual cortex.

Functional maturation of neocortex: a base of viability.

The term "viability" is not simply a synonymous with being "born alive," but is closely related to the capability of having a "meaningful life" and having a reasonable period of survival. The definition of "viability" is generally based on two major criteria: the biological, which takes into consideration the maturity of the foetus, and the epidemiological, which is based on the survival rates reported in literature. The neuromaturation of the cerebral cortex is a dynamic process promoted by the subplate, a transient population of neurons that guides the development of cortical and thalamocortical connections. These connections are for example fundamental for cortical processing of sensory information and mental processes. The first thalamocortical and cortico-cortical connections grows at 23-24 postconceptional weeks, which coincides with the age limit for premature baby survival.

Cranial ultrasound and MRI at term age in extremely preterm infants.

OBJECTIVES: Conventional MRI at term age has been reported to be superior to cranial ultrasound (cUS) in detecting white matter (WM) abnormalities and predicting outcome in preterm infants. However, in a previous study cUS was performed during the first 6 weeks only and not in parallel to MRI at term age. Therefore, the aim of the present work was to study brain injuries in preterm infants performing concomitant cUS and MRI at full-term age. METHODS: In a population-based cohort of 72 extremely low gestational age infants paired cUS and conventional MRI were performed at term age. Abnormalities on MRI were graded according to a previously published scoring system. On cUS images the lateral ventricles, the corpus callosum, the interhemispheric fissure and the subarachnoidal spaces were measured and the presence of cysts, grey matter abnormalities and gyral folding were scored. RESULTS: Moderate or severe WM abnormalities were detected on MRI in 17% of infants and abnormalities of the grey matter in 11% of infants. Among infants with normal ultrasound (n=28, 39%) none had moderate or severe WM abnormalities or abnormal grey matter on MRI. All infants with severe abnormalities (n=3, 4%) were identified as severe on MRI and cUS. CONCLUSIONS: All severe WM abnormalities identified on MRI at term age were also detected by cUS at term, providing the examinations were performed on the same day. Infants with normal cUS at term age were found to have a normal MRI or only mild WM abnormalities on MRI at term age.

Adenosine A(1) receptor agonism in the immature rat brain and heart.

We examined if the adenosine A(1) receptor agonist adenosine amine congener (ADAC, 100 microg/kg i.p.) is neuroprotective in 7-day-old rats subjected to hypoxic ischemia. Brain damage, evaluated as weight deficit and gross morphology, was not affected by ADAC treatment. Nonetheless, ADAC (100 microg/kg i.p.) reduced heart rate by 44% (p<0.0001), indicating that the dose given was pharmacologically active. Adenosine A(1) receptors were determined by [(3)H] 1,3-dipropyl-8-cyclopentylxanthine (DPCPX)-binding and levels were 23% of the adult levels. GTP did not affect [(3)H] DPCPX-binding in the cerebral cortex at postnatal day 7 whereas there was strong enhancement of [(3)H] DPCPX-binding in the heart. This suggested a poor G-protein coupling at postnatal day 7 in the brain, which also was confirmed using GTP [gamma-(35)S]-binding in the presence of an adenosine A(1) receptor agonist. Thus, the lack of a neuroprotective effect of ADAC may be explained by the fact that adenosine A(1) receptors are not part of a functional unit in the 7-day-old rat brain.

Evidence for increased dorsal hippocampal adenosine release and metabolism during pharmacologically induced seizures in rats.

There is growing pharmacological evidence from several animal models of seizure disorder that adenosine possesses endogenous anticonvulsant activity. In order to further evaluate the role of adenosine in seizure activity, we monitored adenosine and its major biochemical metabolites inosine, xanthine, and hypoxanthine in the dorsal hippocampus by in vivo microdialysis before and during the induction of generalized seizures. Seizures were induced pharmacologically in groups of urethane-anesthetized rats by the administration of bicuculline (0.5 mg/kg, i.v.), kainic acid (12.0 mg/kg, i.v.) or pentylenetetrazol (100-250 mg/kg, i.p). Seizure activity was monitored electrophysiologically from the dorsal hippocampus. Dialysate hippocampal purine levels increased during all three seizure types. The largest increases were for the adenosine metabolites hypoxanthine and inosine, with smaller increases observed for adenosine and xanthine. Intra-hippocampal perfusion with the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl-adenine, (EHNA, 300 microM), only slightly increased basal hippocampal adenosine. Guanosine levels in the hippocampus, a purine not directly related to adenosine metabolism, were unaffected by all treatments. These findings demonstrate that an increase in hippocampal adenosine release and metabolism is associated with seizure activity and support the hypothesis that the increased adenosine levels may attenuate hippocampal seizure activity, possibly by terminating ongoing seizures and altering the pattern of subsequent seizures.

Maternal caffeine intake has minor effects on adenosine receptor ontogeny in the rat brain.

Maternal caffeine intake has been suggested to influence the offspring. We have studied the effects of maternal caffeine intake on adenosine and GABA receptors, targets for caffeine, during development of the rat brain. Caffeine (0.3 g/L) was added to the drinking water of rat dams during pregnancy and early postnatal life. Adenosine A1 and A2A and GABAA receptor development was studied using receptor autoradiography and in situ hybridization. Pups were examined on embryonic d 14 (E14), E18, E21, 2 h after birth (P2h), P24h, postnatal d 3 (P3), P7, P14, and P21. Adenosine A, receptor mRNA was detected at E14 and receptors at E18. A1 mRNA levels increased from the level reached at E18 between P3 and P14 (maximally a doubling), whereas A, receptors, studied by [3H]-1,3-dipropyl-8-cyclopentyl xanthine binding, increased later and to a much larger extent (about 10-fold) postnatally. Caffeine treatment had no significant effect on adenosine A1 receptors or on A1 receptor mRNA. A2A mRNA had reached adult levels by E18, whereas receptor levels were low or undetectable before birth and increased dramatically until P14. Caffeine did not influence A2A receptors or A2A receptor mRNA at any stage during development. [3H]-flunitrazepam binding, representing GABAA receptors, showed large regional variations during ontogeny, but there were no clear differences between the caffeine-exposed and the nonexposed pups. Thus, exposure to a low dose of caffeine during gestation and postnatal life had only minor effects on development of adenosine A, and A2A receptors and GABAA receptors in the rat brain.

A randomized cross-over study on various hormonal parameters of two triphasic oral contraceptives.

The effect of two triphasic oral contraceptives (Triquilar [TRQ] and Trisiston [TRS]) containing ethinyl estradiol (EE) and levonorgestrel (LNG) on various hormonal parameters was investigated in 26 women during a cross-over study. TRS consisted of 0.03 mg EE + 0.05 mg LNG (six tablets), 0.04 mg EE + 0.075 mg LNG (six tablets), and 0.03 mg EE + 0.15 mg LNG (nine tablets), whereas TRQ was different in the second phase (five tablets) and third phase (10 tablets). Blood samples were taken on days 6, 11, 21, and 28 of the control and washout cycles and the third treatment cycle. Both formulations inhibited ovulation reliably and decreased the serum levels of gonadotropins, free testosterone, and dehydroepiandosterone sulfate in a time-dependent manner, whereas estradiol and testosterone were already suppressed on day 6, indicating a direct suppressive effect on ovarian steroid synthesis. Prolactin, which rose sporadically in some women, was not significantly changed. In contrast, the levels of sex hormone binding globulin, corticosteroid binding globulin, and cortisol were significantly elevated by 100%. During the hormone-free interval of 7 days, all parameters returned at least partly to baseline. There was no significant difference between the effects of both formulations. The results suggest the possibility of a direct inhibitory effect of contraceptive steroids on ovarian steroid synthesis.

PIP: A randomized crossover study involving 26 women in Germany investigated the effect of two triphasic oral contraceptives (OCs) on selected hormonal parameters. The first triphasic, Trisiston, contained 0.03 mg of ethinyl estradiol (EE) and 0.05 mg of levonorgestrel (LNG) (6 tablets), 0.04 mg EE and 0.075 mg LNG (6 tablets), and 0.03 mg EE and 0.15 mg LNG (9 tablets). The second, Triquilar, differed from the first in the second (5 tablets) and third (10 tablets) phases. Serum samples were collected on days 6, 11, 21, and 28 of the control and washout cycles and the third treatment cycle. There were no significant differences in the hormonal effects of the two formulations. Both triphasics inhibited ovulation reliably and decreased serum levels of gonadotropins, free testosterone, and dehydroepiandrosterone sulfate in a time-dependent manner. Estradiol and testosterone were already suppressed on day 6. Prolactin rose sporadically in some women, but was not significantly changed. In contrast, levels of sex hormone binding globulin, corticosteroid binding globulin, and cortisol were significantly elevated by 100%. During the 7-day hormone-free interval, all parameters returned at least partly to baseline. These findings suggest a direct inhibitory effect of OC steroids on ovarian steroid synthesis.

Neonatal cerebral hypoxia-ischemia: the effect of adenosine receptor antagonists.

The effects of nonselective (theophylline), A1-(DPCPX) or A2A-selective (SCH 58261) adenosine receptor antagonists administered before or after neonatal hypoxia-ischemia (HI) were studied on the extent of brain injury in 7-day-old rats evaluated after 14 days. A possible effect of theophylline (20 mg/kg) on expression of immediate early genes was studied with in situ hybridization. Theophylline (20, 30 or 60 mg/kg) given prior to HI reduced brain damage by 48% (P < 0.001), 36% (P < 0.01) and 34% (P < 0.05), respectively, compared to control rats. This effect was not explained by changes in temperature, cerebral blood flow, blood gas/acid base status or blood glucose during the insult. Theophylline enhanced the upregulation of c-fos and NFGI-A during reperfusion but did not prevent the decrease in adenosine A1 receptor mRNA. Posttreatment with SCH 58261 (0.2 or 2 mg/kg) reduced brain damage by 19% (P < 0.05) and 14% (NS), respectively, compared to control rats which was unrelated to the core temperature. DPCPX (2 or 10 mg/kg) had no effect on the development of brain injury. In conclusion, nonselective and A2A adenosine receptor antagonists reduced brain injury in a model of HI in immature animals.

The effect of long term caffeine treatment on hypoxic-ischemic brain damage in the neonate.

There is considerable concern over the widespread use of caffeine during and after pregnancy. We have therefore examined the effect of perinatal caffeine use on the vulnerability of the immature brain to hypoxic ischemia (HI). Rat pups were exposed to caffeine during the first 7 d after birth by addition of a low or a high dose (0.3 or 0.8 g/L) of caffeine to the drinking water of their dams. At 7 d the pups were exposed to unilateral carotid occlusion+exposure to 7.70% oxygen for 100 min. The extent of HI brain damage was evaluated 2 wk after the insult. The effects of caffeine on A1 and A2a receptors, A1 mRNA and A2a mRNA, were examined by receptor autoradiography and in situ hybridization. Caffeine, theobromine, theophylline, and paraxanthine were analyzed in plasma of separate animals. Exposure to caffeine reduced HI brain damage from 40.3 +/- 3.2% in controls to 29.8 +/- 4.0% (p < 0.05) in low dose and 33.7 +/- 3.9% (NS) in the high dose group. The A1 receptor density measured as [3H]-1,3-dipropyl-8-cyclopentyl xanthine ([3H]-DPCPX) binding was not significantly affected after low dose caffeine but increased in the brain of rat pups in the high dose group. The A2a receptor density measured as [3H]-2[p-(2-carbonylethyl)-phenethylamino]-5'-N- ethylcarboxamidoadenosine ([3H]-CGS 21680) binding and the expression of A1 mRNA and A2a mRNA were not altered by caffeine treatment. In conclusion, low dose caffeine exposure (plasma levels corresponding to umbilical cord plasma in newborns of coffee-consuming mothers) reduced HI brain damage by 30% in 7-d-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in c-fos mRNA in the neonatal rat brain following hypoxic ischemia.

We used quantitative in situ hybridization to study changes in the expression of c-fos following hypoxic-ischemia (H-I) in the neonatal rat brain. 7-day-old rat pups were subjected to a unilateral ligation of the common carotid artery followed by a 2 h 15 min hypoxic period (7.7% O2 in N2). This resulted in the expected ipsilateral infarction of cortex, lateral hippocampus, lateral-superior aspects of the striatum and the white matter of the corpus callosum. Brain damage was not seen in the contralateral hemisphere subjected only to hypoxia. c-fos mRNA levels increased in the contralateral hemisphere immediately after the hypoxia and had returned towards normal levels 2 h thereafter. In the ipsilateral hemisphere, the expression of c-fos was delayed but very marked at 2 h. Animals subjected only to hypoxia showed little or no increase in c-fos mRNA. Thus the earliest recorded increase in c-fos after hypoxic ischemia, which occurred on the non-ischemic, contralateral side, may represent a generalized response to a more localized insult.

Changes in adenosine receptors in the neonatal rat brain following hypoxic ischemia.

We used quantitative in situ hybridization and receptor autoradiography to study changes in adenosine receptors following hypoxia-ischemia (H-I) in the neonatal rat brain. Seven-day-old rat pups were subjected to a unilateral ligation of the common carotid artery followed by a 2 h 15 min hypoxic period (7.7% O2 in N2). Adenosine A1 receptor mRNA in cortex and several parts of hippocampus, and A2a mRNA was decreased in the ligated hemisphere 0 h, 1 h and 2 h following hypoxia. The binding of the A1 receptor selective antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine (DPCPX) in the presence or in the absence of GTP decreased immediately after the hypoxic period in both hemispheres and returned thereafter gradually towards control. These results show that there are rapid changes in A1 receptor number on both sides of the brain, and of adenosine A1 and A2a receptor mRNA in the hemisphere that would later develop infarction. Decreases in adenosine receptors may worsen H-I brain damage and have consequences for the use of adenosine directed therapy.