There is considerable concern over the widespread use of caffeine during and after pregnancy. We ... more 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 A, and A,, receptors, A, mRNA and A, , 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 rt 3.2% in controls to 29.8 ? 4.0% (p < 0.05) in low dose and 33.7 2 3.9% (NS) in the high dose group. The A, receptor density measured as [3~]-1,3-dipropyl-8-cyclopentyl xanthine ([?HI-DPCPX) bind-Caffeine is widely consumed by women during pregnancy and immediately thereafter (1) and it is used, together with its metabolite theophylline, in the treatment of premature apnea (2). Furthermore, the fetus and the newborn become exposed because caffeine crosses the placenta (3,4) and diffuses into the breast milk (5). Caffeine affects several systems in the body, e.g. the renal, respiratory, cardiovascular (6), gastrointestinal, and the C N S (7,8). Caffeine is metabolized in the liver (9), and the metabolites are then excreted in the urine. The metabolism is much slower in neonates than in adults: tl12 in infants is 50-103 h (7,10, 11) and tIl2 in adults is 2-6 h (7, 12). Several recent reports have raised concern about the safety of caffeine use during and after pregnancy (13).
The perinatal development of respiratory rhythm generation and its modulation by adenosinergic dr... more The perinatal development of respiratory rhythm generation and its modulation by adenosinergic drugs have been examined in rats from embryonic d 18 (E18) to postnatal d 3 using an in vitro brain stem-spinal cord preparation. Generation of rhythmic respiratory activity in the medulla oblongata and inhibition of this activity by pontine structures were evident on E18. The adenosine A 1 -receptor agonist, N 6 -(2-phenylisopropyl) adenosine, R (Ϫ) isomer (R-PIA) (1 M), induced an age-dependent reduction of respiratory frequency that could be reversed by the adenosine antagonist theophylline (55 M). The effect of R-PIA was reduced 24 h after birth compared with E21 and 2 h postnatal age. In preparations from pups that had been exposed to a low dose of caffeine (0.3 g/L in drinking water to dams), pontine inhibition of respiratory rhythm generation in the medulla was more pronounced. When the pons was removed, the respiratory frequency was higher than in the control group. Adenosine A 1 -mRNA and A 1 -receptor development in pons and medulla were studied, and by E18, mRNA, receptor protein, and functional coupling to G-proteins were confirmed using guanylyl-5'-O-(␥-[ 35 S]thio)-triphosphate binding. There were no major changes in receptor numbers or distribution of A 1 receptors or mRNA in rat pups subjected to caffeine exposure. We conclude that respiration is already modulated by adenosine A 1 receptors at the level of the medulla oblongata in the fetal period in an age-dependent manner. Furthermore, long-term maternal caffeine intake during gestation seems to increase the pontine inhibition of, and the activity of, respiratory rhythm-generating neuronal networks in medulla oblongata without detectable changes in expression of A 1 -receptor number or A 1 -receptor mRNA. (Pediatr Res 51: 4-12, 2002) Abbreviations CPA, N 6 -cyclopentyladenosine CPG, Central Pattern Generator DPCPX, 8-cyclopentyl-1,3-dipropylxanthine f R , frequency of respiratory activity (bursts/min) T i , inspiratory time R-PIA, N 6 -(2-phenylisopropyl) adenosine, R (Ϫ) isomer aCSF, artificial cerebrospinal fluid E, embryonic day P, postnatal day GTP␥[ 35 S], guanylyl-5'-O-(␥-[ 35 S]thio)-triphosphate CV, coefficient of variation ABSTRACT 4
Background and Purpose—Severe perinatal asphyxia is an important cause of brain injury in the new... more Background and Purpose—Severe perinatal asphyxia is an important cause of brain injury in the newborn infant. We examined early events after hypoxic ischemia (HI) in the 7-day-old mouse brain by MRI and related them to long-term functional effects and histopathology in the same animals at 4 to 5 weeks of age. Methods—HI was induced in 7-day-old CD1 mice by exposure
Caffeine has biphasic effects on locomotion, and blockade of the adenosine A2A receptor (A2AR) is... more Caffeine has biphasic effects on locomotion, and blockade of the adenosine A2A receptor (A2AR) is necessary for the stimulatory effect of low doses of caffeine, but not for the locomotor depressant effect observed at high doses. We wanted to elucidate the role of the adenosine A1 receptor (A1R) in mediating the locomotor effects of increasing doses of caffeine using wild-type
Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, wit... more Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd to 33rd wk postconception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory, and vascular pathways and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH, suggesting an as yet unknown environmental trigger. The methylenetetrahydrofolate reductase (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The prese...
midbody were consistently good. The highest correlation was achieved by combining the coronal fro... more midbody were consistently good. The highest correlation was achieved by combining the coronal frontal horn measurements to a frontal horn product (r 2 ؍ right 0.94, left 0.95). Our study underlines the value of cranial ultrasound measurements in neonatal care and follow-up. (E-mail: [email protected])
Background and Purpose-Cerebral hypoxic ischemia (HI) is an important cause of brain injury in th... more Background and Purpose-Cerebral hypoxic ischemia (HI) is an important cause of brain injury in the newborn infant.
Proceedings of the National Academy of Sciences, 2007
In the absence of any overt task performance, it has been shown that spontaneous, intrinsic brain... more In the absence of any overt task performance, it has been shown that spontaneous, intrinsic brain activity is expressed as systemwide, resting-state networks in the adult brain. However, the route to adult patterns of resting-state activity through neuronal development in the human brain is currently unknown. Therefore, we used functional MRI to map patterns of resting-state activity in infants during sleep. We found five unique resting-states networks in the infant brain that encompassed the primary visual cortex, bilateral sensorimotor areas, bilateral auditory cortex, a network including the precuneus area, lateral parietal cortex, and the cerebellum as well as an anterior network that incorporated the medial and dorsolateral prefrontal cortex. These results suggest that resting-state networks driven by spontaneous signal fluctuations are present already in the infant brain. The potential link between the emergence of behavior and patterns of resting-state activity in the infant brain is discussed. development ͉ functional MRI ͉ spontaneous activity R ecent research on functional connectivity in the brain, in particular during resting-state conditions, has come to focus on low-frequency (Ͻ0.1 Hz), spontaneous fluctuations in the functional MRI (fMRI) signal. Discovered by Biswal et al. , it has been shown that systemwide networks in the resting brain are synchronized in time through intrinsic low-frequency signal fluctuations. Whereas early fMRI studies demonstrated synchronicity of intrinsic brain activity across hemispheres in primary sensory cortices (2, 3), succeeding studies have shown temporal synchronization in a resting-state network encompassing higher-order cortices (4). A systematic investigation of resting-state activity in the adult human brain was recently presented by Damoiseaux et al. (5). Using independentcomponent analysis (ICA), a data-driven explorative data analysis approach, they showed that there are numerous networks in the brain that are driven by spontaneous activity. Besides networks that are in part or fully described by the previously reported default mode (6) and task-positive network (7, 8), they found consistent patterns of resting-state activity in the visual cortex, sensorimotor areas, auditory areas, as well as extrastriate brain regions. These findings together with previous investigations on spontaneous activity suggest that the assumption that the brain during rest is idle and waiting to be triggered and respond to changes in the environment is not strictly valid. Rather, in addition to responding to changes in external stimuli or tasks, the brain is characterized by intrinsic dynamics in the form of coherent and spontaneous fluctuations, clustered together in networks that are credible from an anatomical and functional perspective.
WHAT'S KNOWN ON THIS SUBJECT: Among preterm infants, hyperglycemia during the first week of life ... more WHAT'S KNOWN ON THIS SUBJECT: Among preterm infants, hyperglycemia during the first week of life is recognized as a common condition. An association between hyperglycemia and increased morbidity/mortality rates has been shown in some studies, but results are conflicting.
Recent progress in functional neuroimaging research has provided the opportunity to probe at the ... more Recent progress in functional neuroimaging research has provided the opportunity to probe at the brain's intrinsic functional architecture. Synchronized spontaneous neuronal activity is present in the form of resting-state networks in the brain even in the absence of external stimuli. The objective of this study was to investigate the presence of resting-state networks in the unsedated infant brain born at full term. Using functional MRI, we investigated spontaneous low-frequency signal fluctuations in 19 healthy full-term infants. Resting-state functional MRI data acquired during natural sleep was analyzed using independent component analysis. We found five resting-state networks in the unsedated infant brain born at full term, encompassing sensory cortices, parietal and temporal areas, and the prefrontal cortex. In addition, we found evidence for a restingstate network that enclosed the bilateral basal ganglia. (Pediatr Res 66: 301-305, 2009) Abbreviations: BOLD, blood oxygenation level dependent; CS, caesarean section; EPI, echo planar imaging; fMRI, functional MRI; PICA, probabilistic independent component analysis 0031-3998/09/6603-0301 PEDIATRIC RESEARCH
We used quantitative in situ hybridization to study changes in the expression of c-fos following ... more 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% 02 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.
Caffeine has biphasic effects on locomotion, and blockade of the adenosine A(2A) receptor (A2AR) ... more Caffeine has biphasic effects on locomotion, and blockade of the adenosine A(2A) receptor (A2AR) is necessary for the stimulatory effect of low doses of caffeine, but not for the locomotor depressant effect observed at high doses. We wanted to elucidate the role of the adenosine A(1) receptor (A1R) in mediating the locomotor effects of increasing doses of caffeine using wild-type mice (A1R(WT)), mice heterozygous for (A1R(HET)), and mice lacking the adenosine A(1) receptor (A1R(KO)). Caffeine had the typical biphasic dose-effect relationship in all three genotypes, but the stimulatory action of caffeine was facilitated in the A1R(KO) mice. In order to investigate the interaction between blockade of A1Rs and A2ARs, mice lacking both receptors (A1R(KO)/A2AR(KO)) were tested. Regardless of A1R genotype, animals lacking A2AR were not stimulated by caffeine, whereas animals heterozygous for A2AR were. As expected, the A1R is not crucial for the stimulatory effect of caffeine, but seems to modulate the effect of caffeine exerted via A2AR blockade. Furthermore, these results suggest that the inhibitory effect of high doses of caffeine is due neither to blockade of the A1R, nor of the A2AR, and an effect independent of these adenosine receptors is likely.
The: effects of nonselective (theophylline), Al-(DPCPX) or A2A-selective (SCH 58261) adenosine re... more The: effects of nonselective (theophylline), Al-(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 < O.OOl), 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 Al 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 mgkg) had no effect on the development of brain injury. In conclusion, nonselective and AZA adenosine receptor antagonists reduced brain injury in a. model of HI in immature animals. 0 1997 Elsevier Science Ltd.
on behalf of the Gene Targets for Intraventricular Hemorrhage Study Group* Intraventricular hemor... more on behalf of the Gene Targets for Intraventricular Hemorrhage Study Group* Intraventricular hemorrhage (IVH) is a disorder of complex etiology. We analyzed genotypes for 7 genes from 224 inborn preterm neonates treated with antenatal steroids and grade 3-4 IVH and 389 matched controls. Only methylenetetrahydrofolate reductase was more prevalent in cases of IVH, emphasizing the need for more comprehensive genetic strategies. (
To investigate sex differences in neurologic and developmental outcomes in extremely preterm (EPT... more To investigate sex differences in neurologic and developmental outcomes in extremely preterm (EPT) children and explore associations with neonatal brain morphology. A population-based cohort of infants born at &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;27 weeks gestation underwent magnetic resonance imaging (MRI) at term equivalent age (n = 107). Voxel-based morphometry (n = 27) and tract-based spatial statistics (n = 29) were performed in infants with normal MRI findings. Neurologic and developmental assessment (using the Bayley Scales of Infant and Toddler Development-Third Edition [BSITD-III]) was performed at 30 months corrected age (n = 91). EPT boys had lower mean cognitive composite scores (P = .03) and lower mean language composite scores (P = .04) compared with EPT girls. Rates of cerebral palsy were similar in the 2 sexes. No perinatal factor explained the variance in outcomes. Visual inspection of T1- and T2-weighted MRI images found that delayed myelination was found more frequently in boys, whereas cerebellar abnormalities were more common in girls. In the subgroup of children with normal MRI findings (n = 27), boys had poorer cognitive function (P = .015) and language function (P = .008), despite larger volumes of cerebellar tissue (P = .029). In boys, cerebellar volume was positively correlated with BSITD-III cognitive and motor scores (P = .04 for both). In girls, white matter volume (P = .02) and cortical gray matter volume (P = .03) were positively correlated with BSITD-III language score. At the regional level, significant correlations with outcomes were found only in girls. Cognitive and language outcomes at age 30 months were poorer in boys. Sex-related differences were observed on neonatal structural MRI, including differences in the patterns of correlations between brain volumes and developmental scores at both global and regional levels.
To examine associations between brain white matter abnormalities, including diffuse excessive hig... more To examine associations between brain white matter abnormalities, including diffuse excessive high signal intensities, detected on neonatal magnetic resonance imaging (MRI) with neurodevelopmental outcome at age 30 months. This was a prospective, population-based study of infants born at &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;27 weeks gestation (n=117) undergoing conventional MRI at term equivalent age (n=107). At age 30 months corrected, 91 of the preterm infants (78%) and 85 term-born controls were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Cerebral palsy (CP) was present in 7% of the preterm group. On the BSID-III, mean composite scores were 96±9.5 for the cognitive scale, 97±14 for language scales, and 103±15 for motor scales, all within the normal range for age. Compared with the term-born controls, however, the preterm infants did not perform as well on all 3 scales, also when MRI was normal. Significant associations were seen between moderate to severe white matter abnormalities and CP (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.001). The presence of diffuse excessive high signal intensities was not associated with performance on the BSID-III or with CP. This 3-year cohort of extremely preterm infants had low rates of major brain injury and impaired outcome. Neonatal MRI provides useful information, but this information needs to be treated with caution when predicting outcome.
There is considerable concern over the widespread use of caffeine during and after pregnancy. We ... more 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 A, and A,, receptors, A, mRNA and A, , 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 rt 3.2% in controls to 29.8 ? 4.0% (p < 0.05) in low dose and 33.7 2 3.9% (NS) in the high dose group. The A, receptor density measured as [3~]-1,3-dipropyl-8-cyclopentyl xanthine ([?HI-DPCPX) bind-Caffeine is widely consumed by women during pregnancy and immediately thereafter (1) and it is used, together with its metabolite theophylline, in the treatment of premature apnea (2). Furthermore, the fetus and the newborn become exposed because caffeine crosses the placenta (3,4) and diffuses into the breast milk (5). Caffeine affects several systems in the body, e.g. the renal, respiratory, cardiovascular (6), gastrointestinal, and the C N S (7,8). Caffeine is metabolized in the liver (9), and the metabolites are then excreted in the urine. The metabolism is much slower in neonates than in adults: tl12 in infants is 50-103 h (7,10, 11) and tIl2 in adults is 2-6 h (7, 12). Several recent reports have raised concern about the safety of caffeine use during and after pregnancy (13).
The perinatal development of respiratory rhythm generation and its modulation by adenosinergic dr... more The perinatal development of respiratory rhythm generation and its modulation by adenosinergic drugs have been examined in rats from embryonic d 18 (E18) to postnatal d 3 using an in vitro brain stem-spinal cord preparation. Generation of rhythmic respiratory activity in the medulla oblongata and inhibition of this activity by pontine structures were evident on E18. The adenosine A 1 -receptor agonist, N 6 -(2-phenylisopropyl) adenosine, R (Ϫ) isomer (R-PIA) (1 M), induced an age-dependent reduction of respiratory frequency that could be reversed by the adenosine antagonist theophylline (55 M). The effect of R-PIA was reduced 24 h after birth compared with E21 and 2 h postnatal age. In preparations from pups that had been exposed to a low dose of caffeine (0.3 g/L in drinking water to dams), pontine inhibition of respiratory rhythm generation in the medulla was more pronounced. When the pons was removed, the respiratory frequency was higher than in the control group. Adenosine A 1 -mRNA and A 1 -receptor development in pons and medulla were studied, and by E18, mRNA, receptor protein, and functional coupling to G-proteins were confirmed using guanylyl-5'-O-(␥-[ 35 S]thio)-triphosphate binding. There were no major changes in receptor numbers or distribution of A 1 receptors or mRNA in rat pups subjected to caffeine exposure. We conclude that respiration is already modulated by adenosine A 1 receptors at the level of the medulla oblongata in the fetal period in an age-dependent manner. Furthermore, long-term maternal caffeine intake during gestation seems to increase the pontine inhibition of, and the activity of, respiratory rhythm-generating neuronal networks in medulla oblongata without detectable changes in expression of A 1 -receptor number or A 1 -receptor mRNA. (Pediatr Res 51: 4-12, 2002) Abbreviations CPA, N 6 -cyclopentyladenosine CPG, Central Pattern Generator DPCPX, 8-cyclopentyl-1,3-dipropylxanthine f R , frequency of respiratory activity (bursts/min) T i , inspiratory time R-PIA, N 6 -(2-phenylisopropyl) adenosine, R (Ϫ) isomer aCSF, artificial cerebrospinal fluid E, embryonic day P, postnatal day GTP␥[ 35 S], guanylyl-5'-O-(␥-[ 35 S]thio)-triphosphate CV, coefficient of variation ABSTRACT 4
Background and Purpose—Severe perinatal asphyxia is an important cause of brain injury in the new... more Background and Purpose—Severe perinatal asphyxia is an important cause of brain injury in the newborn infant. We examined early events after hypoxic ischemia (HI) in the 7-day-old mouse brain by MRI and related them to long-term functional effects and histopathology in the same animals at 4 to 5 weeks of age. Methods—HI was induced in 7-day-old CD1 mice by exposure
Caffeine has biphasic effects on locomotion, and blockade of the adenosine A2A receptor (A2AR) is... more Caffeine has biphasic effects on locomotion, and blockade of the adenosine A2A receptor (A2AR) is necessary for the stimulatory effect of low doses of caffeine, but not for the locomotor depressant effect observed at high doses. We wanted to elucidate the role of the adenosine A1 receptor (A1R) in mediating the locomotor effects of increasing doses of caffeine using wild-type
Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, wit... more Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd to 33rd wk postconception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory, and vascular pathways and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH, suggesting an as yet unknown environmental trigger. The methylenetetrahydrofolate reductase (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The prese...
midbody were consistently good. The highest correlation was achieved by combining the coronal fro... more midbody were consistently good. The highest correlation was achieved by combining the coronal frontal horn measurements to a frontal horn product (r 2 ؍ right 0.94, left 0.95). Our study underlines the value of cranial ultrasound measurements in neonatal care and follow-up. (E-mail: [email protected])
Background and Purpose-Cerebral hypoxic ischemia (HI) is an important cause of brain injury in th... more Background and Purpose-Cerebral hypoxic ischemia (HI) is an important cause of brain injury in the newborn infant.
Proceedings of the National Academy of Sciences, 2007
In the absence of any overt task performance, it has been shown that spontaneous, intrinsic brain... more In the absence of any overt task performance, it has been shown that spontaneous, intrinsic brain activity is expressed as systemwide, resting-state networks in the adult brain. However, the route to adult patterns of resting-state activity through neuronal development in the human brain is currently unknown. Therefore, we used functional MRI to map patterns of resting-state activity in infants during sleep. We found five unique resting-states networks in the infant brain that encompassed the primary visual cortex, bilateral sensorimotor areas, bilateral auditory cortex, a network including the precuneus area, lateral parietal cortex, and the cerebellum as well as an anterior network that incorporated the medial and dorsolateral prefrontal cortex. These results suggest that resting-state networks driven by spontaneous signal fluctuations are present already in the infant brain. The potential link between the emergence of behavior and patterns of resting-state activity in the infant brain is discussed. development ͉ functional MRI ͉ spontaneous activity R ecent research on functional connectivity in the brain, in particular during resting-state conditions, has come to focus on low-frequency (Ͻ0.1 Hz), spontaneous fluctuations in the functional MRI (fMRI) signal. Discovered by Biswal et al. , it has been shown that systemwide networks in the resting brain are synchronized in time through intrinsic low-frequency signal fluctuations. Whereas early fMRI studies demonstrated synchronicity of intrinsic brain activity across hemispheres in primary sensory cortices (2, 3), succeeding studies have shown temporal synchronization in a resting-state network encompassing higher-order cortices (4). A systematic investigation of resting-state activity in the adult human brain was recently presented by Damoiseaux et al. (5). Using independentcomponent analysis (ICA), a data-driven explorative data analysis approach, they showed that there are numerous networks in the brain that are driven by spontaneous activity. Besides networks that are in part or fully described by the previously reported default mode (6) and task-positive network (7, 8), they found consistent patterns of resting-state activity in the visual cortex, sensorimotor areas, auditory areas, as well as extrastriate brain regions. These findings together with previous investigations on spontaneous activity suggest that the assumption that the brain during rest is idle and waiting to be triggered and respond to changes in the environment is not strictly valid. Rather, in addition to responding to changes in external stimuli or tasks, the brain is characterized by intrinsic dynamics in the form of coherent and spontaneous fluctuations, clustered together in networks that are credible from an anatomical and functional perspective.
WHAT'S KNOWN ON THIS SUBJECT: Among preterm infants, hyperglycemia during the first week of life ... more WHAT'S KNOWN ON THIS SUBJECT: Among preterm infants, hyperglycemia during the first week of life is recognized as a common condition. An association between hyperglycemia and increased morbidity/mortality rates has been shown in some studies, but results are conflicting.
Recent progress in functional neuroimaging research has provided the opportunity to probe at the ... more Recent progress in functional neuroimaging research has provided the opportunity to probe at the brain's intrinsic functional architecture. Synchronized spontaneous neuronal activity is present in the form of resting-state networks in the brain even in the absence of external stimuli. The objective of this study was to investigate the presence of resting-state networks in the unsedated infant brain born at full term. Using functional MRI, we investigated spontaneous low-frequency signal fluctuations in 19 healthy full-term infants. Resting-state functional MRI data acquired during natural sleep was analyzed using independent component analysis. We found five resting-state networks in the unsedated infant brain born at full term, encompassing sensory cortices, parietal and temporal areas, and the prefrontal cortex. In addition, we found evidence for a restingstate network that enclosed the bilateral basal ganglia. (Pediatr Res 66: 301-305, 2009) Abbreviations: BOLD, blood oxygenation level dependent; CS, caesarean section; EPI, echo planar imaging; fMRI, functional MRI; PICA, probabilistic independent component analysis 0031-3998/09/6603-0301 PEDIATRIC RESEARCH
We used quantitative in situ hybridization to study changes in the expression of c-fos following ... more 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% 02 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.
Caffeine has biphasic effects on locomotion, and blockade of the adenosine A(2A) receptor (A2AR) ... more Caffeine has biphasic effects on locomotion, and blockade of the adenosine A(2A) receptor (A2AR) is necessary for the stimulatory effect of low doses of caffeine, but not for the locomotor depressant effect observed at high doses. We wanted to elucidate the role of the adenosine A(1) receptor (A1R) in mediating the locomotor effects of increasing doses of caffeine using wild-type mice (A1R(WT)), mice heterozygous for (A1R(HET)), and mice lacking the adenosine A(1) receptor (A1R(KO)). Caffeine had the typical biphasic dose-effect relationship in all three genotypes, but the stimulatory action of caffeine was facilitated in the A1R(KO) mice. In order to investigate the interaction between blockade of A1Rs and A2ARs, mice lacking both receptors (A1R(KO)/A2AR(KO)) were tested. Regardless of A1R genotype, animals lacking A2AR were not stimulated by caffeine, whereas animals heterozygous for A2AR were. As expected, the A1R is not crucial for the stimulatory effect of caffeine, but seems to modulate the effect of caffeine exerted via A2AR blockade. Furthermore, these results suggest that the inhibitory effect of high doses of caffeine is due neither to blockade of the A1R, nor of the A2AR, and an effect independent of these adenosine receptors is likely.
The: effects of nonselective (theophylline), Al-(DPCPX) or A2A-selective (SCH 58261) adenosine re... more The: effects of nonselective (theophylline), Al-(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 < O.OOl), 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 Al 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 mgkg) had no effect on the development of brain injury. In conclusion, nonselective and AZA adenosine receptor antagonists reduced brain injury in a. model of HI in immature animals. 0 1997 Elsevier Science Ltd.
on behalf of the Gene Targets for Intraventricular Hemorrhage Study Group* Intraventricular hemor... more on behalf of the Gene Targets for Intraventricular Hemorrhage Study Group* Intraventricular hemorrhage (IVH) is a disorder of complex etiology. We analyzed genotypes for 7 genes from 224 inborn preterm neonates treated with antenatal steroids and grade 3-4 IVH and 389 matched controls. Only methylenetetrahydrofolate reductase was more prevalent in cases of IVH, emphasizing the need for more comprehensive genetic strategies. (
To investigate sex differences in neurologic and developmental outcomes in extremely preterm (EPT... more To investigate sex differences in neurologic and developmental outcomes in extremely preterm (EPT) children and explore associations with neonatal brain morphology. A population-based cohort of infants born at &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;27 weeks gestation underwent magnetic resonance imaging (MRI) at term equivalent age (n = 107). Voxel-based morphometry (n = 27) and tract-based spatial statistics (n = 29) were performed in infants with normal MRI findings. Neurologic and developmental assessment (using the Bayley Scales of Infant and Toddler Development-Third Edition [BSITD-III]) was performed at 30 months corrected age (n = 91). EPT boys had lower mean cognitive composite scores (P = .03) and lower mean language composite scores (P = .04) compared with EPT girls. Rates of cerebral palsy were similar in the 2 sexes. No perinatal factor explained the variance in outcomes. Visual inspection of T1- and T2-weighted MRI images found that delayed myelination was found more frequently in boys, whereas cerebellar abnormalities were more common in girls. In the subgroup of children with normal MRI findings (n = 27), boys had poorer cognitive function (P = .015) and language function (P = .008), despite larger volumes of cerebellar tissue (P = .029). In boys, cerebellar volume was positively correlated with BSITD-III cognitive and motor scores (P = .04 for both). In girls, white matter volume (P = .02) and cortical gray matter volume (P = .03) were positively correlated with BSITD-III language score. At the regional level, significant correlations with outcomes were found only in girls. Cognitive and language outcomes at age 30 months were poorer in boys. Sex-related differences were observed on neonatal structural MRI, including differences in the patterns of correlations between brain volumes and developmental scores at both global and regional levels.
To examine associations between brain white matter abnormalities, including diffuse excessive hig... more To examine associations between brain white matter abnormalities, including diffuse excessive high signal intensities, detected on neonatal magnetic resonance imaging (MRI) with neurodevelopmental outcome at age 30 months. This was a prospective, population-based study of infants born at &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;27 weeks gestation (n=117) undergoing conventional MRI at term equivalent age (n=107). At age 30 months corrected, 91 of the preterm infants (78%) and 85 term-born controls were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Cerebral palsy (CP) was present in 7% of the preterm group. On the BSID-III, mean composite scores were 96±9.5 for the cognitive scale, 97±14 for language scales, and 103±15 for motor scales, all within the normal range for age. Compared with the term-born controls, however, the preterm infants did not perform as well on all 3 scales, also when MRI was normal. Significant associations were seen between moderate to severe white matter abnormalities and CP (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.001). The presence of diffuse excessive high signal intensities was not associated with performance on the BSID-III or with CP. This 3-year cohort of extremely preterm infants had low rates of major brain injury and impaired outcome. Neonatal MRI provides useful information, but this information needs to be treated with caution when predicting outcome.
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