Comprehensive analyses of RNA-seq and genome-wide data point to enrichment of neuronal cell type subsets in neuropsychiatric disorders.

Neurological and psychiatric disorders, including substance use disorders, share a range of symptoms, which could be the result of shared genetic background. Many genetic loci have been identified for these disorders using genome-wide association studies, but conclusive evidence about cell types wherein these loci are active is lacking. We aimed to uncover implicated brain cell types in neuropsychiatric traits and to assess consistency in results across RNA datasets and methods. We therefore comprehensively employed cell type enrichment methods by integrating single-cell transcriptomic data from mouse brain regions with an unprecedented dataset of 42 human genome-wide association study results of neuropsychiatric, substance use and behavioral/quantitative brain-related traits (n = 12,544,007 individuals). Single-cell transcriptomic datasets from the Karolinska Institute and 10x Genomics were used. Cell type enrichment was determined using Linkage Disequilibrium Score Regression, Multi-marker Analysis of GenoMic Annotation, and Data-driven Expression Prioritized Integration for Complex Traits. We found the largest degree of consistency across methods for implication of pyramidal cells in schizophrenia and cognitive performance. For other phenotypes, such as bipolar disorder, two methods implicated the same cell types, i.e., medium spiny neurons and pyramidal cells. For autism spectrum disorders and anorexia nervosa, no consistency in implicated cell types was observed across methods. We found no evidence for astrocytes being consistently implicated in neuropsychiatric traits. In conclusion, we provide comprehensive evidence for a subset of neuronal cell types being consistently implicated in several, but not all psychiatric disorders, while non-neuronal cell types seem less implicated.

High speed laser drilling of metals using a high repetition rate, high average power ultrafast fiber CPA system.

We present an experimental study on the drilling of metal targets with ultrashort laser pulses at high repetition rates (from 50 kHz up to 975 kHz) and high average powers (up to 68 Watts), using an ytterbium-doped fiber CPA system. The number of pulses to drill through steel and copper sheets with thicknesses up to 1 mm have been measured as a function of the repetition rate and the pulse energy. Two distinctive effects, influencing the drilling efficiency at high repetition rates, have been experimentally found and studied: particle shielding and heat accumulation. While the shielding of subsequent pulses due to the ejected particles leads to a reduced ablation efficiency, this effect is counteracted by heat accumulation. The experimental data are in good qualitative agreement with simulations of the heat accumulation effect and previous studies on the particle emission. However, for materials with a high thermal conductivity as copper, both effects are negligible for the investigated processing parameters. Therefore, the full power of the fiber CPA system can be exploited, which allows to trepan high-quality holes in 0.5mm-thick copper samples with breakthrough times as low as 75 ms.

Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up.

The benefits versus the risks of postnatal administration of steroids in preterm-born infants are still debatable. This review examines the literature on postnatal hydrocortisone treatment for chronic lung disease (CLD) in preterm-born infants with a particular focus on the effects of such treatment on long-term neurodevelopmental outcomes. Quantitative published evidence does not point to a clear advantage of treatment with hydrocortisone over dexamethasone with regard to the impact on long-term neurological outcomes. However, in the absence of a randomised comparison, a consensus may soon have to be reached on the basis of the best available evidence whether hydrocortisone should replace dexamethasone in the treatment of CLD.

90 W average power 100 microJ energy femtosecond fiber chirped-pulse amplification system.

We report on an ytterbium-doped fiber based chirped-pulse amplification system delivering 100 microJ pulse energy at a repetition rate of 900 kHz, corresponding to an average power of 90 W. The emitted pulses are as short as 500 fs. To the best of our knowledge, this is the highest average power ever reported for high-energy femtosecond solid-state laser systems.

Millijoule pulse energy Q-switched short-length fiber laser.

We report on a Q-switched short-length fiber laser producing 100 W of average output power at 100 kHz repetition rate and pulse durations as short as 17 ns. Up to 2 mJ of energy and sub-10-ns pulse duration are extracted at lower repetition rates. This performance is obtained by employing a rod-type ytterbium-doped photonic crystal fiber with a 70 microm core as gain medium, allowing for very short pulse durations, high energy storage, and emission of a single-transverse-mode beam.

Incidence of infections of ventricular reservoirs in the treatment of post-haemorrhagic ventricular dilatation: a retrospective study (1992-2003).

BACKGROUND: Since 1992, infants with progressive posthaemorrhagic ventricular dilatation (PHVD) have been treated in the Neonatal Intensive Care Unit, Wilhelmina Children's Hospital, Utrecht, The Netherlands, with a ventricular reservoir. OBJECTIVE: To retrospectively study the incidence of infection using this invasive procedure. METHODS: Between January 1992 and December 2003, 76 preterm infants were treated with a ventricular reservoir. Infants admitted during two subsequent periods were analysed: group 1 included infants admitted during 1992-7 (n = 26) and group 2 those admitted during 1998-2003 (n = 50). Clinical characteristics and number of reservoir punctures were evaluated. The incidence of complications over time was assessed, with a focus on the occurrence of infection of the reservoir. RESULTS: The number of punctures did not change during both periods. Infection was significantly less common during the second period (4% (2/50) v 19.2% (5/26), p = 0.029). CONCLUSION: The use of a ventricular reservoir is a safe treatment to ensure adequate removal of cerebrospinal fluid in preterm infants with PHVD. In experienced hands, the incidence of infection of the ventricular reservoir or major complications remains within acceptable limits.

Neonatal cranial ultrasound versus MRI and neurodevelopmental outcome at school age in children born preterm.

AIM: To examine the correlation between neonatal cranial ultrasound and school age magnetic resonance imaging (MRI) and neurodevelopmental outcome. METHODS: In a prospective 2 year cohort study, 221 children (gestational age < or =32 weeks and/or birth weight < or =1500 g) participated at a median age of 8.1 years (inclusion percentage 78%). Conventional MRI, IQ (subtests of the WISC), and motor performance (Movement Assessment Battery for Children) at school age were primary outcome measurements. RESULTS: Overall, there was poor correspondence between ultrasound group classifications and MRI group classifications, except for the severe group (over 70% agreement). There was only a 1% chance of the children with a normal cranial ultrasound having a major lesion on MRI. Mean IQ (standard deviation) was significantly lower in children with major ultrasound or MRI lesions, but was also lower in children with minor lesions on MRI compared to children with a normal MRI (91+/-16, 100+/-13, 104+/-13 for major lesions, minor lesions, and normal MRI, respectively). Median total impairment score (TIS) was significantly higher in children with major lesions on ultrasound or MRI as well as in children with minor lesions on MRI (TIS 4.0 and 6.25 for normal and minor lesions on MRI, respectively; p<0.0001). CONCLUSIONS: A normal neonatal cranial ultrasound excluded a severe lesion on MRI in 99% of cases. MRI correlated more strongly with mean IQ and median TIS than ultrasound. Subtle white matter lesions are better detected with MRI which could explain the stronger correlation of MRI with IQ and motor performance.

Larger corpus callosum size with better motor performance in prematurely born children.

The objective of this study is to determine the relation between the size of the corpus callosum (CC) and motor performance in a population-based cohort of preterm children. Preterm born children (n = 221) with a gestational age less than or equal to 32 weeks and/or a birth weight below 1500 g were eligible for this study. At the age of 7 or 8 years, frontal, middle, posterior, and total areas (mm2) of the corpus callosum were measured on true midsagittal MRI. Due to anxiety of 10 children and motion artifacts in 7 other children, 204 MRIs could be assessed in the preterm group (mean GA 29.4 weeks, sd 2.0,mean BW 1200 g, sd 323). The preterm group consisted of 15 children with cerebral palsy (CP) and 189 children without CP. Motor function was established by using the Movement Assessment Battery for Children, and the Developmental Test of Visual Motor Integration was obtained. The same examinations were performed in 21 term born children. The mean total cross-sectional CC area was significantly smaller in preterm born infants compared with their term born controls (338 mm2 versus 422 mm2, P < 0.0001). The preterm children with CP had significantly smaller mean CC areas compared with the preterms who did not develop CP (P < 0.0001-P < 0.002). However, the preterms born without CP also had significantly smaller body, posterior, and total CC areas compared with term born controls (P < 0.0001-P < 0.002). Only the difference in frontal area measurements dilrc) -3.3 mm2/score point (95% CI -4.5, -2.1). The association existed in all parts of the CC but increased in the direction of the posterior part: frontal: lrc -0.8 mm2/score point (-1.2, -0.4), middle: lrc -1.1 mm2/score point (-1.7, -0.5) and posterior: lrc -1.4 mm2/score point (-1.8, -0.9). An association between CC area and its subareas and the standard scores of the VMI was also found. A larger CC was strongly related t o better scores onthe VMI test total area CC: lrc 0.05 score/mm2 (95% CI 0.03, 0.07), frontal: lrc 0.12 score/mm2 (0.05,0.19), middle: lrc 0.10 score/mm2 (0.05, 0.15) and posterior: lrc 0.12 score/mm2 (0.06, 0.18). After adjustment for gestational age, birth weight, and total cerebral area, these associations were still significant. There is a strong association between the size of the corpus callosum (total midsagittal cross area as well as frontal, middle, and posterior area) and motor function in preterm children, investigated at school age. A poorer score on the Movement ABC was related to a smaller CC. A larger CC was strongly associated with better VMI standard scores.

Early versus late treatment of posthaemorrhagic ventricular dilatation: results of a retrospective study from five neonatal intensive care units in The Netherlands.

UNLABELLED: Posthaemorrhagic ventricular dilatation (PHVD) in very preterm infants carries a poor prognosis. As earlier studies have failed to show a benefit of early intervention, it is recommended that PHVD be first treated when head circumference is rapidly increasing and/or when symptoms of raised intracranial pressure develop. Infants with PHVD, admitted to 5 of the 10 Dutch neonatal intensive care units were studied retrospectively, to investigate whether there was a difference in the time of onset of treatment of PHVD and, if so, whether this was associated with a difference in the requirement of a ventriculo-peritoneal (VP) shunt and/or neurodevelopmental outcome. The surviving infants with a gestational age <34 wk, born between 1992 and 1996, diagnosed as having a grade III haemorrhage according to Papile on cranial ultrasound and who developed PHVD were included in the study. PHVD was defined as a ventricular index (VI) exceeding the 97th percentile according to Levene (1981), and severe PHVD as a VI crossing the p 97 + 4 mm line. Ninety-five infants met the entry criteria. Intervention was not deemed necessary in 22 infants, because of lack of progression. In 31 infants lumbar punctures (LP) were done before the p 97 + 4 mm line was crossed (early intervention). In 20/31 infants, stabilization occurred. In 9 a subcutaneous reservoir was placed, with subsequent stabilization in 6. In 5/31 infants a VP shunt was eventually inserted. In 42 infants treatment was started once the p 97 + 4 mm line was crossed (late intervention). In 30 infants LPs were performed and in 17 of these a VP shunt was eventually inserted. In 11 infants a subcutaneous reservoir was immediately inserted and in 8 of these infants a VP shunt was needed. In one infant a VP shunt was immediately inserted, without any other form of treatment. Infants with late intervention crossed the p 97 + 4 mm earlier (p 0.03) and needed a shunt (26/42; 62%) more often than those with early intervention (5/31; 16%). Early LP was associated with a strongly reduced risk of VP-shunting (odds ratio = 0.22, 95% confidence interval: 0.08-0.62). The number of infants who developed a moderate or severe handicap was also higher (11/42; 26%) in the late intervention group, compared with those not requiring any intervention (3/22; 14%) or treated early (5/31; 16%). CONCLUSION: In this retrospective study, infants receiving late intervention required shunt insertion significantly more often than those treated early. A randomized prospective intervention study, comparing early and late drainage, is required to further assess the role of earlier intervention.

Unilateral parenchymal haemorrhagic infarction in the preterm infant.

A unilateral parenchymal haemorrhage associated with a germinal matrix-intraventricular haemorrhage (GMH-IVH) is still an important problem in the preterm infant and especially in those who are very immature. This type of lesion is now considered mainly to be caused by impaired drainage of the veins in the periventricular white matter and is often referred to as a venous infarction. The risk factors and neonatal imaging findings, as well as neurodevelopmental outcome and imaging data in infancy, of this type of lesion differ from those found in children with bilateral periventricular leukomalacia. An effort should, therefore, always be made to make a distinction between these two types of lesions. In our experience it is possible to make this distinction in most cases, when performing both sequential ultrasonography as well as selective magnetic resonance imaging during the neonatal period.

Asymmetrical myelination of the posterior limb of the internal capsule in infants with periventricular haemorrhagic infarction: an early predictor of hemiplegia.

AIM: To prospectively assess the predictive value of asymmetrical myelination on MRI of the posterior limb of the internal capsule (PLIC) in newborn infants with an intraventricular haemorrhage (IVH) associated with unilateral haemorrhagic parenchymal involvement (PI), for subsequent development of a hemiplegia. METHODS: 12 preterm infants (GA 25-36 wks) and 4 full-term infants were studied. Using cranial ultrasound (US), the pre-term infants were diagnosed to have an IVH with unilateral PI. The term infants presented with a porencephalic cyst (PC) on the first postnatal US, following an antenatal IVH with PI. MRI was performed at 40 wks postmenstrual age in the pre-term infants and during the first 2 weeks of life in the full-term infants, using a 1.5T magnet. Using an inversion recovery sequence, the myelination of the internal capsule was recorded as normal, abnormal or equivocal. Neurological assessment > or = 12 months disclosed the presence of a hemiplegia or asymmetry in tone pattern. RESULTS: All 4 cases with a normal internal capsule had a normal outcome in spite of the development of a PC. All 9 cases with an abnormal PLIC developed a hemiplegia, while 1 of the 3 cases with an equivocal PLIC is normal on neurological assessment, one developed a mild asymmetry in tone and 1 a mild hemiplegia. CONCLUSION: While a symmetrical signal intensity within the internal capsule on MRI, performed at 40 weeks PMA, in infants with an IVH and unilateral PI appears to be strongly related to a normal outcome, an asymmetrical PLIC is an early predictor of future hemiplegia.

Correlation between neonatal cranial ultrasound, MRI in infancy and neurodevelopmental outcome in infants with a large intraventricular haemorrhage with or without unilateral parenchymal involvement.

UNLABELLED: During a 7-year-period, 1625 infants of 34 weeks gestation or less were enrolled in a prospective ultrasound (US) study. One hundred and eleven (6.8%) infants developed a large intraventricular haemorrhage (IVH) with or without unilateral parenchymal involvement (PI). Fifty-six of these 111 infants survived (50.4%) and in 23 (41%) of them a magnetic resonance imaging (MRI) study was performed beyond 12 months corrected age. There appeared to be a good agreement between neonatal ultrasound findings and MRI changes noted in infancy. Of the 10 cases with a large IVH without PI (group A), seven had a VP shunt with complete decompression of previously enlarged ventricles. Six of these seven infants had periventricular hyperintensity (PVHI) but none developed cerebral palsy (CP). Two of the ten cases without a VP shunt had irregular ventricular enlargement (VE) with PVHI in one. Both developed CP. Seven cases showed thinning of the corpus callosum. Of the 13 cases with a large IVH associated with PI (group B), the site of the PI could still be recognised on MRI and the degree of communication of the porencephalic cyst (PC) with the lateral ventricles correlated well with neonatal US findings. On MRI, VE was present in only 6 cases. Wallerian degeneration was present in 9/13 infants and all but one developed a hemiplegia. In 12/13 cases there was thinning of the corpus callosum, either focal or diffuse. PVHI was present in all infants. In 6/13 PVHI was only present around the PC. Neurodevelopmental outcome differed for both groups. CP was only present in 2/10 infants in group A, compared to 11/ 13 in group B. Global delay, in the absence of CP, was more common in infants with a large IVH than in those with associated PI. CONCLUSION: Combining neonatal US with MRI in infancy enhances our understanding of the long-term effects of severe haemorrhagic brain lesions, occurring in preterm infants.

Antenatal onset of haemorrhagic and/or ischaemic lesions in preterm infants: prevalence and associated obstetric variables.

AIM: To assess the prevalence of an antenatal onset of haemorrhagic and/or ischaemic lesions in preterm infants; to identify possibly related obstetric risk factors. METHODS: A prospective cohort study was made of 1332 infants born at less than 34 completed weeks, using cranial ultrasound, for the presence of antenatal brain lesions (group A) involving the periventricular white matter (PVWM) or central grey matter. Entry criteria were presence of (i) cysts in the PVWM < 7 days; (ii) increased PVWM echogenicity < 6 hours, confirmed to be white matter necrosis at post mortem examination; (iii) a unilateral porencephalic cyst < 3 days; (iv) an intraventricular haemorrhage with unilateral parenchymal involvement < 6 hours; and (v) symmetrical areas of increased echogenicity in the thalami, confirmed to be areas of calcification on post mortem examination. Group B consisted of infants with a normal early neonatal ultrasound scan with subsequent development of the lesions mentioned above. RESULTS: Twenty four cases met the entry criteria for group A: 17 died and five of the seven survivors developed cerebral palsy at follow up. Of the whole cohort, 156 (11.7%) infants died and in 63 (40.3%) of these a large ultrasound lesion was present. In 17 (26.9%) cases this lesion was considered to be of antenatal onset. Sixty eight of the 1176 (5.8%) survivors developed cerebral palsy and this was attributed to antenatal onset in five (7.3%). A comparison of the obstetric risk factors between the infants in group A and B, who either died or developed cerebral palsy, showed a significant difference in gestational age between the two groups (30.9 vs 28.9 weeks; p < 0.001). Prolonged rupture of membranes was significantly more common in group B (p = 0.03), while an ominous cardiotachogram was significantly more common in group A (p = 0.01), and this remained significant following logistic regression analysis. CONCLUSIONS: Although these data suggest that most preterm infants did not develop their brain lesions in utero, an antenatal onset was not uncommon, especially in those with PVWM lesions, who did not survive the neonatal period.

Early cerebral proton MRS and neurodevelopmental outcome in infants with cystic leukomalacia.

The present study tested the hypothesis that proton magnetic resonance spectroscopy (1H-MRS) predicted neurodevelopmental outcome in infants with cystic leukomalacia (CL). Nineteen infants with CL (grade 2, N = 7; grade 3, N = 7; grade 4, N = 5), graded according to the authors' classification, were examined at corrected ages of mean 1.5 +/- 2.1 SD weeks. 1H-MRS of the basal ganglia and the periventricular white matter was performed. Two infants died, 16 had an adverse neurodevelopmental outcome and one was normal at follow-up. N-acetylaspartate (NAA):choline (Cho) ratios were mean 1.12 +/- 0.19 (SD) (grade 2), mean 0.95 +/- 0.11 (SD) (grade 3), and mean 0.71 +/- 0.13 (SD) (grade 4). These differences are significant (P < 0.01, ANOVA). NAA:Cho ratios showed a positive correlation with developmental quotient (DQ) at the age of > or = 1 year (P < 0.05). In 13 infants lactate (Lac) was found. Lac:NAA ratios showed a negative correlation with NAA:Cho ratios, but not with DQ. We conclude that a low NAA:Cho ratio predicted a poor outcome, whereas some infants developed unfavourably despite a normal NAA:Cho ratio. We speculate that partial volume effects might explain this observation.

Infarcts in the vascular distribution of the middle cerebral artery in preterm and fullterm infants.

Twenty-three infants with an infarct in the territory of the middle cerebral artery are reported. The diagnosis was made using cranial ultrasound in all, confirmed on postmortem in two cases and on MRI, performed during the neonatal period or in infancy, in 18 of the 20 survivors. Involvement of the main branch was present in 7 cases and three of these had a gestational age of less than 35 weeks. In the other 16 infants, involvement of a cortical branch or one or more of the lenticulostriate branches was present and all but three of these had a gestational age of 34 weeks or less. While involvement of the main branch was usually diagnosed on postnatal day 1 or 2 using ultrasound, involvement of the lenticulostriate branches was noted as a wedgeshaped echogenic lesion in the caudate nucleus, thalamus or putamen, between day 4 up till day 24, and at term age in one of the cases. Neurodevelopmental outcome of those with involvement of the main branch was disappointing as all survivors developed a hemiplegia, associated with epilepsy in two; while so far only three of the other 16 infants developed cerebral palsy, one a hemiplegia and one athetoid cerebral palsy. Global delay was present in a further three cases. Infarcts in the region of the middle cerebral artery can occur in both preterm as well as fullterm infants. Involvement of the main branch also occurred in infants with a gestational age below 35 weeks and resulted in the development of a hemiplegia in all survivors. Involvement of one of the other branches was especially common in preterm infants, who had a more favourable outcome. As the lesion in the latter group was usually not present before the end of the first week, serial ultrasound up till term age is needed in order to identify these lesions.

Rapidly progressive enlargement of the fourth ventricle in the preterm infant with post-haemorrhagic ventricular dilatation.

Six preterm infants who developed disproportionate enlargement of the 4th ventricle during the neonatal period, associated with post-haemorrhagic ventricular dilatation (PHVD), before shunt placement are reported. Five of the six preterm infants developed cyanotic spells and/or bradycardias at the time of rapid enlargement of the 4th ventricle, suggestive of raised posterior fossa pressure, which resolved following insertion of and drainage from a subcutaneous reservoir. In one of the three survivors an isolated 4th ventricle was subsequently diagnosed later in infancy, requiring drainage. These data suggest that a combination of an enlarged 4th ventricle on ultrasound and cyanotic spells and/or bradycardias should lead to rapid release of raised pressure in the posterior fossa. Long-term follow-up of these children is necessary, as isolation of the 4th ventricle can subsequently develop.

Intracranial lesions in the fullterm infant with hypoxic ischaemic encephalopathy: ultrasound and autopsy correlation.

To test the hypothesis that cranial ultrasound correlated with post-mortem findings in neonates with hypoxic ischaemic encephalopathy (HIE), the brains of 20 infants who died after at least two real time ultrasound scans were examined. The ultrasound abnormalities detected in the periventricular/subcortical white matter, cortex or thalami were compared with the macroscopic and histological appearances. Comparing the last ultrasound scan which was performed no longer than 12 hours before the infant died, with histological data, the sensitivity and specificity for lesions in the thalamus was 100% and 83.3% respectively; for cortical lesions 76.9 and 100% respectively and for lesions in the periventricular white matter 80% and 75% respectively. The value of cranial ultrasound for detecting intracranial abnormalities in infants with HIE was considerably better than reported previously. This could mainly be attributed to the use of a 10 MHz transducer which was of critical importance to identify lesions in the superficial cortical layer.

Unilateral haemorrhagic parenchymal lesions in the preterm infant: shape, site and prognosis.

In a prospective cranial ultrasound study of 544 infants with a gestational age of 32 weeks or less, 20 (3.6%) infants were diagnosed as having a unilateral parenchymal lesion (PL). Based on the shape of the PL and the evolution on ultrasound, the infants were divided into three groups: group I consisted of 11 infants, in whom the PL was triangular/fan-shaped and separate from the ventricle. The PL evolved into small cystic lesions; group II comprised 3 infants who had a PL with a similar shape, but partially communicating with the ventricle; group III consisted of 6 infants who had a globular-shaped lesion in communication with the ventricle. In groups II and III, the PL evolved into one porencephalic cyst. The PL was considered to be due to venous infarction in all cases with intraventricular haemorrhage preceding the PL in 7 cases. Sixteen infants survived. A postmortem was performed in 2 of the 4 infants who died, confirming the diagnosis of venous infarction. Neurological sequelae were present in only 2 cases in the first group, while all 6 survivors of the other two groups developed mild to severe hemiplegia. Long-term follow-up was not always available and 4 of the 18 survivors were still less than 18 months when last seen. In 9 of the 11 infants in group I, the PL was localized in the frontoparietal region, while in 8 of the 9 infants in group II or III, the PL was beyond the trigone in the occipital region. The outcome of the unilateral PL is not always unfavourable.(ABSTRACT TRUNCATED AT 250 WORDS)

Subependymal pseudocysts: ultrasound diagnosis and findings at follow-up.

During a two-year period, subependymal pseudocysts were diagnosed in 24 infants using cranial ultrasound: 8 were located at the external angle of the lateral ventricle and 16 at the caudothalamic notch. Associated congenital anomalies were present in six infants and CMV was isolated in one case. Four of the eight infants with pseudocysts at the external angle were one half of twins. As all but one of the surviving infants with pseudocysts were normal at follow-up (at 3-24 months of age), it is important to make a distinction between pseudocysts and extensive cystic periventricular leukomalacia, as the latter condition invariably leads to cerebral palsy and/or visual impairment.