Congenital hypotonia: systematic approach for prenatal detection.

OBJECTIVES: Congenital hypotonic conditions are rare and heterogeneous, and some are severely debilitating or lethal. Contrary to its prominent postnatal manifestation, the prenatal presentation of hypotonia is frequently subtle, inhibiting prenatal detection. We aimed to characterize the prenatal sonographic manifestation of congenital hypotonia throughout pregnancy, evaluate the yield of diagnostic tests and propose diagnostic models to increase its prenatal detection. METHODS: This was a retrospective observational study of singleton pregnancies with congenital hypotonia, diagnosed either prenatally or immediately after birth, at a single tertiary center between the years 2012 and 2020. Prenatally, hypotonia was diagnosed if a fetus showed sonographic or clinical signs suggestive of hypotonia and had a confirmed underlying genetic condition, or in the absence of a known genetic abnormality if the fetus exhibited multiple prominent signs suggestive of hypotonia. Postnatally, it was diagnosed in neonates displaying reduced muscle tone leading to reduced spontaneous movement, reduced swallowing or feeding difficulty. We reviewed the medical records of pregnant patients carrying fetuses subsequently diagnosed with congenital hypotonia and assessed the yield of ultrasound scans, fetal magnetic resonance imaging, computed tomography and genetic tests. The detection rate of sonographic signs suggesting fetal hypotonia was calculated. The prevalence of non-specific signs, including polyhydramnios, persistent breech presentation, intrauterine growth restriction and maternal perception of reduced fetal movement, were compared between the study group and the local liveborn singleton population. Potential detection rates of different theoretical semiotic diagnostic models, differing in the threshold for referral for a targeted scan, were assessed based on the cohort's data. RESULTS: The study group comprised 26 cases of congenital hypotonia, of which 10 (38.5%) were diagnosed prenatally, and the controls included 95 105 singleton live births, giving a prevalence of congenital hypotonia of 1:3658. Nuchal translucency thickness and the early anomaly scan at 13-17 weeks were normal in all 22 and 23 cases, respectively, in which this was performed. The mid-trimester scan performed at 19-25 weeks was abnormal in four of 24 (16.7%) cases. The overall prenatal detection rate of congenital hypotonic conditions in our cohort was 38.5%. Only cases which underwent a targeted scan were detected and, among the 16 cases which underwent this scan, the prenatal detection rate was 62.5% compared with 0% in pregnancies that did not undergo this scan (P = 0.003). An abnormal genetic diagnosis was obtained in 21 (80.8%) cases using the following modalities: chromosomal microarray analysis (CMA) in two (9.5%), whole-exome sequencing (WES) in 14 (66.7%) and methylation analysis in five (23.8%). CMA was abnormal in 8% (2/25) of the cases and WES detected a causative genetic mutation in 87.5% (14/16) of the cases in which these were performed. Comparison of non-specific signs in the study group with those in the local singleton population showed that hypotonic fetuses had significantly more polyhydramnios (64.0% vs 3.0%, P < 0.0001), persistent breech presentation (58.3% vs 4.2%, P < 0.0001), intrauterine growth restriction (30.8% vs 3.0%, P < 0.0001) and maternal perception of reduced fetal movement (32.0% vs 4.7%, P < 0.0001). Prenatally, the most commonly detected signs supporting a diagnosis of hypotonia were structural anomaly (62.5%, 10/16), reduced fetal movement (46.7%, 7/15), joint contractures (46.7%, 7/15) and undescended testes ≥ 30 weeks (42.9%, 3/7 males). Proposed diagnostic strategies that involved performing a targeted scan for a single non-specific ultrasound sign or two such signs, and then carrying out a comprehensive genetic evaluation for any additional sign, offered theoretical detection rates in our cohort of 88.5% and 57.7%, respectively. CONCLUSIONS: Congenital hypotonic conditions are rare and infrequently detected prenatally. Sonographic signs are visible from the late second trimester. A targeted scan increases prenatal detection significantly. Comprehensive genetic testing, especially WES, is the cornerstone of diagnosis in congenital hypotonia. Theoretical diagnostic models which may increase prenatal detection are provided. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Fetal Exposure to MR Imaging: Long-Term Neurodevelopmental Outcome.

BACKGROUND AND PURPOSE: Very few studies have investigated long-term neurodevelopment of children exposed to MR imaging antenatally. Thus, the purpose of our study was to evaluate long-term neurodevelopmental outcomes of children exposed to MR imaging during pregnancy. MATERIALS AND METHODS: We conducted a historical prospective cohort study in a single tertiary medical center. Women exposed to 1.5T noncontrast MR imaging for maternal or fetal indications were matched to unexposed controls. Long-term neurodevelopmental outcomes were evaluated of their children, 2.5 to 6 years of age, according to the Vineland-II Adaptive Behavior Scale. The Vineland-II Adaptive Behavior Scale assesses communication, daily living skills, socialization, and motor skills. A composite score summarizes these 4 domains. RESULTS: A total of 131 exposed women matched our inclusion criteria and were included in the study group, and 771 unexposed women, in the control group. No difference was identified in the Vineland-II Adaptive Behavior Scale composite score between the children of the study and control groups (mean, 110.79 versus 108.18; P = .098). Differences were also not observed between the children of the 2 groups in 3 of the 4 questionnaire domains: communication (108.84 versus 109.10; P = .888), daily living skills (109.51 versus 108.28; P = .437), and motor skills (105.09 versus 104.42; P = .642). However, the socialization score was favorable for the study group (112.98 versus 106.47; P < .001). CONCLUSIONS: Exposure to 1.5T noncontrast MR imaging during pregnancy had no harmful effects on long-term neurodevelopmental outcomes. This study contributes to understanding the safety of MR imaging during pregnancy.

The earliest human occupation of the high-altitude Tibetan Plateau 40 thousand to 30 thousand years ago.

The Tibetan Plateau is the highest and one of the most demanding environments ever inhabited by humans. We investigated the timing and mechanisms of its initial colonization at the Nwya Devu site, located nearly 4600 meters above sea level. This site, dating from 40,000 to 30,000 years ago, is the highest Paleolithic archaeological site yet identified globally. Nwya Devu has yielded an abundant blade tool assemblage, indicating hitherto-unknown capacities for the survival of modern humans who camped in this environment. This site deepens the history of the peopling of the "roof of the world" and the antiquity of human high-altitude occupations more generally.

Apparent Diffusion Coefficient Levels and Neurodevelopmental Outcome in Fetuses with Brain MR Imaging White Matter Hyperintense Signal.

BACKGROUND AND PURPOSE: One of the perplexing findings of fetal brain MR imaging is white matter T2 hyperintense signal. The aims of our study were initially to determine the main etiologies associated with white matter T2 hyperintense signal, then to examine whether the different etiologies have different ADC values, and, last, to assess the association of white matter T2 hyperintense signal with developmental outcome. MATERIALS AND METHODS: This was a prospective cohort study of 44 MR imaging scans of fetal brains obtained for suspected brain pathologies at a tertiary medical center during 2011-2015. Clinical data were collected from electronic medical charts. ADC values were measured and averaged in the frontal, parietal, occipital, and temporal lobes. Neurodevelopmental assessments were performed with the Vineland Adaptive Behavior Scales II. RESULTS: Half of the cases of MRI hyperintense T2 signal of the fetal brain were associated with congenital cytomegalovirus infection. The other half were mainly idiopathic. Thus, the study group was divided to subgroups positive and negative for cytomegalovirus. Both groups had hyperintense signal in the temporal lobe. The group positive for cytomegalovirus had involvement of the parietal lobe. Only this group had increased ADC values in the temporal and parietal lobes. There was no association between the neurodevelopment outcome and the etiologies or ADC values. CONCLUSIONS: T2 hyperintense signal in fetal brain MRI associated with positive cytomegalovirus infection has increased ADC values in the temporal and parietal lobes, suggestive of brain edema in these areas. However, the association between this finding and neurodevelopment outcome requires further evaluation.

Neurodevelopmental outcome of fetal isolated ventricular asymmetry without dilation: a cohort study.

OBJECTIVE: Fetal isolated ventricular asymmetry (IVA) is a relatively common finding in pregnancy, but data regarding its effect on neurodevelopmental outcome are scarce and founded principally on ultrasound-based studies. The purpose of this study was to assess the neurodevelopmental outcome of IVA cases in a magnetic resonance imaging (MRI)-based study. METHODS: Cases referred for fetal brain MRI as part of the assessment of IVA without ventriculomegaly (lateral ventricular atrial diameter ≤ 10 mm), identified during routine ultrasound examination, were assessed for possible inclusion. Asymmetry was defined as a difference in width of ≥ 2 mm between the two lateral ventricles. Forty-three cases were included in the study group and compared with a control group of 94 normal cases without IVA. Children were assessed at ages 13-74 months using the Vineland-II Adaptive Behavior Scales (VABS-II). RESULTS: VABS-II scores were within normal range. There was no significant difference in composite VABS-II score between the study and control groups (106.5 vs 108.0; P = 0.454). VABS-II scores did not differ between the groups when matched for gender and age at VABS-II interview (109.6 in study group vs 107.8 in control group; P = 0.690). CONCLUSION: In cases of IVA without ventriculomegaly on MRI, neurodevelopmental test scores were normal and did not differ from cases without IVA. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Neurological deficit is predicted by S100B in children after cardiac surgery.

INTRODUCTION: Children undergoing cardiac surgery may suffer from brain injuries after surgery and develop neurological deficit. Early diagnosis of brain injury after surgery would enable early therapeutic interventions. The aim of the study is to test whether S100B can serve as a biomarker for brain injury after cardiac surgery. METHODS: Seventy-five patients were enrolled in the study. Serum S100B was collected at the beginning of the surgery, and 6, 12, 24 h after surgery. S100B z-scores were calculated based on norms for age. Neurological evolutions were done before surgery and at discharge by the Pediatric Stroke Outcome Measure (PSOM). New neurological deficit (NND) was defined as a 1 point increase on the PSOM scale. RESULTS: Twenty patients had an NND after cardiac surgery. Medical background was similar between the groups with and without NND. S100B z-scores were significantly higher in the NND group at all time points after surgery. Using a cut-off of 3 z-score at 6 h after surgery, the positive predictive value was 79% and the negative predictive value was 90%. CONCLUSIONS: S100B is a potent early biomarker for brain injury after cardiac surgery. Hopefully, S100B could be used to prevent progression of brain injuries after cardiac surgery.

Fetal Brain Anomalies Associated with Ventriculomegaly or Asymmetry: An MRI-Based Study.

BACKGROUND AND PURPOSE: Fetal lateral ventriculomegaly is a relatively common finding with much debate over its clinical significance. The purpose of this study was to examine the association between ventriculomegaly and asymmetry and concomitant CNS findings as seen in fetal brain MR imaging. MATERIALS AND METHODS: Fetal brain MR imaging performed for various indications, including ventriculomegaly, with or without additional ultrasound findings, was assessed for possible inclusion. Two hundred seventy-eight cases found to have at least 1 lateral ventricle with a width of ≥10 mm were included in the study. Ventriculomegaly was considered mild if the measurement was 10-11.9 mm; moderate if, 12-14.9 mm; and severe if, ≥15 mm. Asymmetry was defined as a difference of ≥2 mm between the 2 lateral ventricles. Fetal brain MR imaging findings were classified according to severity by predefined categories. RESULTS: The risk of CNS findings appears to be strongly related to the width of the ventricle (OR, 1.38; 95% CI, 1.08-1.76; P = .009). The prevalence of associated CNS abnormalities was significantly higher (P = .005) in symmetric ventriculomegaly compared with asymmetric ventriculomegaly (38.8% versus 24.2%, respectively, for all CNS abnormalities and 20% versus 7.1%, respectively, for major CNS abnormalities). CONCLUSIONS: In this study, we demonstrate that the rate of minor and major findings increased with each millimeter increase in ventricle width and that the presence of symmetric ventricles in mild and moderate ventriculomegaly was a prognostic indicator for CNS abnormalities.

Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone-mediated tubulinopathy.

Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/ß-tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families. TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re-polymerization. Morpholino-mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development. Our findings confirm the link between inactivating TBCD variants and this newly described chaperone-associated tubulinopathy, and provide insights into the phenotype of this disorder.

Prenatal Evaluation, Imaging Features, and Neurodevelopmental Outcome of Prenatally Diagnosed Periventricular Pseudocysts.

BACKGROUND AND PURPOSE: Periventricular pseudocysts are cystic cavities that lack the ependymal cell lining found in true cysts. The aim of this study was to characterize periventricular pseudocysts and related findings and their neurodevelopmental outcome. MATERIALS AND METHODS: This was a retrospective study of periventricular pseudocysts detected prenatally on fetal MR imaging in 26 fetuses. The fetuses were divided into group A (n = 8), which included cases with isolated periventricular pseudocysts, and group B (n = 18), which included cases of periventricular pseudocysts with additional findings. Cases were further subdivided into connatal cysts and subependymal pseudocysts. Data collected included prenatal history, MR imaging features, sonographic follow-up, and neurodevelopmental outcome. RESULTS: All cases in group A (n = 8) had a normal outcome. In group B (n = 18), 6 pregnancies were terminated and 2 had an abnormal outcome. Both cases with an abnormal outcome involved patients with subependymal pseudocysts. No significant association was found between the morphologic features on MR imaging and the neurodevelopmental outcome. CONCLUSIONS: Neurodevelopmental outcome in cases of isolated periventricular pseudocysts detected prenatally appears to be normal. A detailed evaluation should be performed to rule out additional brain findings, chromosomal aberration, and fetal malformation. This evaluation should include the following: maternal TORCH status, detailed fetal sonographic anatomic evaluation, fetal echocardiogram, fetal brain MR imaging, amniocentesis and karyotyping/comparative genomic hybridization, and genetic counseling. Additional findings on MR imaging, including mild-to-moderate dilated ventricles, asymmetric ventricles, or T2 hyperintense signal in the white matter without other findings or major fetal abnormality, appear to be benign. Connatal cysts appear to be benign.

Prenatal Brain Imaging in Isolated vs. Complicated Club Foot: A Cohort Study.

Purpose: Talipes equinovarus (TEV) is a common birth defect. Differentiation between isolated and complex TEV is fundamental due to its effect on prognosis. Association between TEV and poor neurological outcome is more prominent in complex cases and highlights the significance of brain evaluation. The aim of the current study was to evaluate the contribution of fetal brain MRI to sonographic evaluation. Materials and Methods: In this retrospective study we evaluated charts of all pregnant patients referred for fetal brain MRI due to fetal TEV between 1/1/2011 and 12/31/14 in a single tertiary referral center. Isolated and complex TEV were differentiated according to associated anomalies. Brain US and MRI results were compared. Results: 28 pregnant patients were included with an average gestation and parity of 2.5 and 1.5, respectively. Both isolated and complicated TEV groups included 14 fetuses after initial TEV diagnosis on anatomical survey. Brain sonography and MRI were normal among 12/14 patients with isolated TEV while two patients were later diagnosed with mild ventriculomegaly. US brain evaluation has revealed pathologic findings in 4 (28.6 %) cases in the complicated TEV group, while MRI demonstrated abnormal findings in 8 (57.1 %) fetuses with notable severity diversity. In 6 cases, MRI diagnosed additional pathologies which were not demonstrated by US. Conclusion: Brain fetal MRI is an efficient tool during antenatal evaluation of complicated TEV with a high percentage of additional findings not demonstrated songraphically while its efficacy in isolated cases is in doubt. The current study expands the relevance of fetal brain MRI in cases of non-CNS anomalies.

Normal fetal posterior fossa in MR imaging: new biometric data and possible clinical significance.

BACKGROUND AND PURPOSE: Posterior fossa malformations are a common finding in prenatal diagnosis. The objectives of this study are to re-evaluate existing normal MR imaging biometric data of the fetal posterior fossa, suggest and evaluate new parameters, and demonstrate the possible clinical applications of these data. MATERIALS AND METHODS: This was a retrospective review of 215 fetal MR imaging examinations with normal findings and 5 examinations of fetuses with a suspected pathologic posterior fossa. Six previously reported parameters and 8 new parameters were measured. Three new parameter ratios were calculated. Interobserver agreement was calculated by using the intraclass correlation coefficient. RESULTS: For measuring each structure, 151-211 MR imaging examinations were selected, resulting in a normal biometry curve according to gestational age for each parameter. Analysis of the ratio parameters showed that vermian lobe ratio and cerebellar hemisphere ratio remain constant with gestational age and that the vermis-to-cisterna magna ratio varies with gestational age. Measurements of the 5 pathologic fetuses are presented on the normal curves. Interobserver agreement was excellent, with the intraclass correlation coefficients of most parameters above 0.9 and only 2 parameters below 0.8. CONCLUSIONS: The biometry curves derived from new and existing biometric data and presented in this study may expand and deepen the biometry we use today, while keeping it simple and repeatable. By applying these extensive biometric data on suspected abnormal cases, diagnoses may be confirmed, better classified, or completely altered.

Early detection by diffusion-weighted sequence magnetic resonance imaging of severe brain lesions after fetoscopic laser coagulation for twin-twin transfusion syndrome.

OBJECTIVE: Monochorionic twins treated by fetoscopic laser coagulation (FLC) for twin-twin transfusion syndrome (TTTS) are at increased risk of neurodevelopmental impairment. Our aim was to evaluate the additional value of diffusion-weighted imaging (DWI) over fetal sonography and T2 magnetic resonance imaging (MRI) in the detection of acute ischemic cerebral lesions shortly following FLC. METHODS: This was a prospective cohort study of fetuses with TTTS treated by FLC. All fetuses underwent brain DWI and T2-MRI within 24-96 h after the procedure and a follow-up MRI at 30-32 weeks' gestation. All fetuses also had frequent ultrasound evaluation until delivery. RESULTS: Thirty pregnancies with TTTS were included in the study. Eight resulted in survival of only one twin after the procedure (Group A), while the other 22 pregnancies resulted in the survival of both twins (Group B), as assessed at the time of initial MRI. Two fetuses in Group A and four in Group B had evidence of transient bleeding in the germinal matrix. Three fetuses in Group B and none in Group A had diffuse ischemic changes in the white matter. One fetus died in utero 24 h after MRI. The other two fetuses in Group B demonstrated an acute infarct 24-48 h after the procedure. Subsequent scans at 28-29 and 32 weeks showed brain atrophy compatible with an old infarct. CONCLUSIONS: DWI can demonstrate cerebral damage immediately after FLC. Larger cohorts are needed to determine the role of fetal MRI in the prenatal assessment and follow-up of patients with TTTS.

Site formation processes at Zhoukoudian, China.

Zhoukoudian is often cited for its human remains and the early evidence of fire. Yet, since its first excavations over 70 years ago, detailed studies of processes responsible for the accumulation of anthropogenic and geogenic sediments in the site have been sparse. This paper provides some details of site formation processes mainly through field observations of the extant section at Locality 1, and the use of soil micromorphology and Fourier Transform Infrared Spectrometry (FTIR) analyses of the sediments. Samples from Layers 10 through 3 show extensive water deposition of fine silt-sized material (reworked loess), including fine-grained organic matter. The dark organic-rich unit in Layer 10--often cited as one of the earliest evidence of fire--is a water-laid accumulation. Much of the fine-grained sediment was derived from outside Locality 1, implying that the site was open to varying extents throughout most of its depositional history. The 4-6 m accumulation of "ashes" in Layer 4 represents subaerial water-laid silt deposits derived from the loess-covered hillslopes surrounding the site. They presumably accumulated in an open depression that formed after the collapse of the brecciated roof deposits represented by Layer 6. Diagenesis is present in many of the Layers, and is exemplified by calcite precipitation and dissolution, and localized apatite (dahllite) replacement of calcite. In Layer 4 diagenesis is more advanced, including calcite/dahllite precipitation, subaerial weathering of the loess and associated precipitation of hematite, alteration of clay and the neoformation of quartz. Many of our conclusions concur with those of Teilhard de Chardin & Young published over 70 years ago.

Relating cluster and population responses to natural sounds and tonal stimuli in cat primary auditory cortex.

Most information about neuronal properties in primary auditory cortex (AI) has been gathered using simple artificial sounds such as pure tones and broad-band noise. These sounds are very different from the natural sounds that are processed by the auditory system in real world situations. In an attempt to bridge this gap, simple tonal stimuli and a standard set of six natural sounds were used to create models relating the responses of neuronal clusters in AI of barbiturate-anesthetized cats to the two classes of stimuli. A significant correlation was often found between the response to the separate frequency components of the natural sounds and the response to the natural sound itself. At the population level, this correlation resulted in a rate profile that represented robustly the spectral profiles of the natural sounds. There was however a significant scatter in the responses to the natural sound around the predictions based on the responses to tonal stimuli. Going the other way, in order to understand better the non-linearities in the responses to natural sounds, responses of neuronal clusters were characterized using second order Volterra kernel analysis of their responses to natural sounds. This characterization predicted reasonably well the amplitude of the response to other natural sounds, but could not reproduce the responses to tonal stimuli. Thus, second order non-linear characterizations, at least those using the Volterra kernel model, do not interpolate well between responses to tones and to natural sounds in auditory cortex.

Paleolithic population growth pulses evidenced by small animal exploitation

Variations in small game hunting along the northern and eastern rims of the Mediterranean Sea and results from predator-prey simulation modeling indicate that human population densities increased abruptly during the late Middle Paleolithic and again during the Upper and Epi-Paleolithic periods. The demographic pulses are evidenced by increasing reliance on agile, fast-reproducing partridges, hares, and rabbits at the expense of slow-reproducing but easily caught tortoises and marine shellfish and, concurrently, climate-independent size diminution in tortoises and shellfish. The results indicate that human populations of the early Middle Paleolithic were exceptionally small and highly dispersed.

Responses of auditory-cortex neurons to structural features of natural sounds.

Sound-processing strategies that use the highly non-random structure of natural sounds may confer evolutionary advantage to many species. Auditory processing of natural sounds has been studied almost exclusively in the context of species-specific vocalizations, although these form only a small part of the acoustic biotope. To study the relationships between properties of natural soundscapes and neuronal processing mechanisms in the auditory system, we analysed sound from a range of different environments. Here we show that for many non-animal sounds and background mixtures of animal sounds, energy in different frequency bands is coherently modulated. Co-modulation of different frequency bands in background noise facilitates the detection of tones in noise by humans, a phenomenon known as co-modulation masking release (CMR). We show that co-modulation also improves the ability of auditory-cortex neurons to detect tones in noise, and we propose that this property of auditory neurons may underlie behavioural CMR. This correspondence may represent an adaptation of the auditory system for the use of an attribute of natural sounds to facilitate real-world processing tasks.

Evidence for the use of fire at zhoukoudian, china

Zhoukoudian is widely regarded as having the oldest reliable evidence for the controlled use of fire by humans. A reexamination of the evidence in Layer 10, the earliest archaeological horizon in the site, shows that burned and unburned bones are present in the same layer with stone tools. However, no ash or charcoal remnants could be detected. Hence, although indirect evidence for burning is present, there is no direct evidence for in situ burning.