Association between prenatal glucocorticoid exposure and adolescent neurodevelopment: An observational follow-up study.

INTRODUCTION: Prenatal exposure to supraphysiological glucocorticoid (GC) levels may lead to long-lasting developmental changes in numerous biological systems. Our prior study identified an association between prenatal GC prophylaxis and reduced cognitive performance, electrocortical changes, and altered autonomic nervous system (ANS) activity in children aged 8-9 years. This follow-up study aimed to examine whether these findings persisted into adolescence. MATERIAL AND METHODS: Prospective observational follow-up study involving twenty-one 14- to 15-year-old adolescents born to mothers who received betamethasone for induction of fetal lung maturation in threatened preterm birth, but who were born with a normal weight appropriate for their gestational age (median 37+4 gestational weeks). Thirty-five children not exposed to betamethasone served as the reference group (median 37+6 gestational weeks). The primary endpoint was cognitive performance, measured by intelligence quotient (IQ). Key secondary endpoints included symptoms of attention-deficit/hyperactivity disorder (ADHD) and metabolic markers. Additionally, we determined electrocortical (electroencephalogram), hypothalamus-pituitary-adrenal axis (HPAA), and ANS activity in response to a standardized stress paradigm. RESULTS: No statistically significant group difference was observed in global IQ (adjusted mean: betamethasone 103.9 versus references 105.9, mean difference -2.0, 95% confidence interval [CI]: -7.12 to 3.12, p = 0.44). Similarly, ADHD symptoms, metabolic markers, the overall and stress-induced activity of the HPAA and the ANS did not differ significantly between groups. However, the betamethasone group exhibited reduced electrocortical activity in the frontal brain region (spectral edge frequency-adjusted means: 16.0 Hz versus 17.8 Hz, mean difference -1.83 Hz, 95% CI: -3.21 to -0.45, p = 0.01). CONCLUSIONS: In 14- to 15-year-old adolescents, prenatal GC exposure was not associated with differences in IQ scores or ANS activity compared to unexposed controls. However, decelerated electrocortical activity in the frontal region potentially reflects disturbances in the maturation of cortical and/or subcortical brain structures. The clinical significance of these changes remains unknown. Given the small sample size, selective participation/loss of follow-up and potential residual confounding, these findings should be interpreted cautiously. Further research is required to replicate these results in larger cohorts before drawing firm clinical conclusions.

[Beyond NICE: Updated Systematic Review on the Current Evidence of Using Puberty Blocking Pharmacological Agents and Cross-Sex-Hormones in Minors with Gender Dysphoria]. / Beyond NICE: Aktualisierte systematische Übersicht zur Evidenzlage der Pubertätsblockade und Hormongabe bei Minderjährigen mit Geschlechtsdysphorie.

Beyond NICE: Updated Systematic Review on the Current Evidence of Using Puberty Blocking Pharmacological Agents and Cross-Sex-Hormones in Minors with Gender Dysphoria Abstract: Objective: The suppression of physiological puberty using puberty-blocking pharmacological agents (PB) and prescribing cross-sex hormones (CSH) to minors with gender dysphoria (GD) is a current matter of discussion, and in some cases, PB and CSH are used in clinical practice for this particular population. Two systematic reviews (one on PB, one on CSH treatment) by the British National Institute for Clinical Excellence (NICE) from 2020 indicated no clear clinical benefit of such treatments regarding critical outcome variables. In particular, these two systematic NICE reviews on the use of PB and CSH in minors with GD detected no clear improvements of GD symptoms. Moreover, the overall scientific quality of the available evidence, as discussed within the above-mentioned two NICE reviews, was classified as "very low certainty" regarding modified GRADE criteria. Method: The present systematic review presents an updated literature search on this particular topic (use of PB and CSH in minors with GD) following NICE principles and PICO criteria for all relevant new original research studies published since the release of the two above-mentioned NICE reviews (updated literature search period was July 2020-August 2023). Results: The newly conducted literature search revealed no newly published original studies targeting NICE-defined critical and important outcomes and the related use of PB in minors with GD following PICO criteria. For CSH treatment, we found two new studies that met PICO criteria, but these particular two studies had low participant numbers, yielded no significant additional clear evidence for specific and clearly beneficial effects of CSH in minors with GD, and could be classified as "low certainty" tfollowing modified GRADE criteria. Conclusions: The currently available studies on the use of PB and CSH in minors with GD have significant conceptual and methodological flaws. The available evidence on the use of PB and CSH in minors with GD is very limited and based on only a few studies with small numbers, and these studies have problematic methodology and quality. There also is a lack of adequate and meaningful long-term studies. Current evidence doesn't suggest that GD symptoms and mental health significantly improve when PB or CSH are used in minors with GD. Psychotherapeutic interventions to address and reduce the experienced burden can become relevant in children and adolescents with GD. If the decision to use PB and/or CSH is made on an individual case-by-case basis and after a complete and thorough mental health assessment, potential treatment of possibly co-occurring mental health problems as well as after a thoroughly conducted and carefully executed individual risk-benefit evaluation, doing so as part of clinical studies or research projects, as currently done in England, can be of value in terms of generation of new research data. The electronic supplement (ESM) 1 is an adapted and abreviated English version of this work.

Multiple Case Studies in German Children with Dyslexia: Characterization of Phonological, Auditory, Visual, and Cerebellar Processing on the Group and Individual Levels.

BACKGROUND: The underlying mechanisms of dyslexia are still debated. The question remains as to whether there is evidence of a predominant type of deficit or whether it is a multideficit disorder with individual profiles. The assumptions of which mechanism causes the disorder influences the selection of the training approach. METHODS: A sample of German neurotypical reading children (NT) and children with dyslexia (DYSL) was investigated with a comprehensive behavioral test battery assessing phonological, auditory, visual, and cerebellar performance, thus addressing performance described in three major theories in dyslexia. RESULTS: In the present sample using the test battery of the present study, DYSL had the strongest impairment in phonological and auditory processing, accompanied by individual processing deficits in cerebellar performance, but only a few in the investigated visual domains. Phonological awareness and auditory performance were the only significant predictors for reading ability. CONCLUSION: These findings point out that those reading difficulties were associated with phonological as well as auditory processing deficits in the present sample. Future research should investigate individual deficit profiles longitudinally, with studies starting before literacy acquisition at as many processing domains as possible. These individual deficit profiles should then be used to select appropriate interventions to promote reading and spelling.

Association between antenatal glucocorticoid exposure and the activity of the stress system, cognition, and behavior in 8- to 9-year-old children: A prospective observational study.

INTRODUCTION: Glucocorticoid (GC) -induced fetal programming of the activity of the hypothalamus-pituitary-adrenal axis (HPAA) and its associated cognitive and behavioral consequences in later life have been well characterized in several animal species. However, information on humans is scarce. In this study, we examined HPAA activity markers and associated outcomes at 8 to 9 years of age among children prenatally exposed to GC for suspected preterm birth. Our hypothesis was that antenatal exposure to the betamethasone (BM) is associated with exacerbation of HPAA activity in childhood. MATERIAL AND METHODS: Prospective observational study in 31 children whose mothers received single (n = 19) or multiple (n = 12) courses of BM for threatened preterm birth but born with normal weight appropriate for the gestational age (median 37+6  weeks of gestation) compared with 38 non-exposed, age-matched children. Primary end point was the activity of the HPAA in response to the Trier Social Stress Test. Secondary end points were changes in autonomic nervous system (ANS) activity, cognitive performance (IQ), attention-deficit/hyperactivity disorder (ADHD) symptoms, and electrocortical activity (EEG). RESULTS: There was no statistically significant difference in HPAA activity markers between antenatal BM exposed and unexposed groups. ANS activity in BM-exposed children shifted towards a higher parasympathetic tone reflected by a higher overall high-frequency band power of heart rate variability. IQ scores were within normal limits for both groups; however, BM-exposed children had lower IQ scores than the unexposed group. BM-exposed group had marginally more ADHD core symptoms and increased electrocortical activity in the occipital brain region compared with controls. A monotonic dose-response relation between BM exposure and activity of the ANS and IQ was estimated in post-hoc analyses. CONCLUSIONS: Antenatal exposure to BM in the context of threatened preterm birth was not associated with changes in HPAA activity in childhood. However, BM exposure may be associated with changes in ANS activity. Antenatal GC prophylaxis is a valuable and often life-saving therapy, but its prescription may warrant a well-balanced risk-benefit assessment.

Cross-Sectional Investigation of Brain Volume in Dyslexia.

The goal of the study was to determine whether dyslexia is associated with differences in local brain volume, and whether these local brain volume differences show cross-sectional age-effects. We investigated the local volume of gray and white brain matter with voxel-based morphometry (VBM) as well as reading performance in three age groups of dyslexic and neurotypical normal reading subjects (children, teenagers and adults). Performance data demonstrate a steady improvement of reading skills in both neurotypical as well as dyslexic readers. However, the pattern of gray matter volumes tell a different story: the children are the only group with significant differences between neurotypical and dyslexic readers in local gray matter brain volume. These differences are localized in brain areas associated with the reading network (angular, middle temporal and inferior temporal gyrus as well as the cerebellum). Yet the comparison of neurotypical and normal readers over the age groups shows that the steady increase in performance in neurotypical readers is accompanied by a steady decrease of gray matter volume, whereas the brain volumes of dyslexic readers do not show this linear correlation between brain volume and performance. This is further evidence that dyslexia is a disorder with a neuroanatomical basis in the form of a lower volume of gray matter in parts of the reading network in early dyslexic readers. The present data point out that network shaping processes in gray matter volume in the reading network does take place over age in dyslexia. Yet this neural foundation does not seem to be sufficient to allow normal reading performances even in adults with dyslexia. Thus dyslexia is a disorder with lifelong consequences, which is why consistent support for affected individuals in their educational and professional careers is of great importance. Longitudinal studies are needed to verify whether this holds as a valid pattern or whether there is evidence of greater interindividual variance in the neuroanatomy of dyslexia.

Signal-Adaptive Denoising Of Event-Related Potentials.

In the present study we propose a data-driven, fully unsupervised denoising approach for multi-trial univariate signals. The proposed methodology is based on Empirical Mode Decomposition (EMD) and hence also applicable for transient or non-stationary signals. The rationale of the presented method is that different realizations (multiple trials) of the same underlying process have also similar intrinsic signal components. These components may be extracted by EMD for each single realization and finally, the entirety of all signal components forms clusters of corresponding components with similar spectral characteristics. A denoising is then tantamount to identifying the cluster(s) containing high-frequency noise components. The effectiveness of the proposed methodology is demonstrated on the basis of visual event-related potentials (ERPs) of dyslexic and normal control children. We could show that the novel method allows for a reliable ERP estimation and that it provides a tool for an objective extraction of ERPs on both a single-subject as well as on a single-trial basis.

Does independent component analysis influence EEG connectivity analyses?

Analysis of electroencephalographic (EEG) data requires cautious consideration of interfering artefacts such as ocular, muscular or cardiac noise. Independent component analysis (ICA) has proven to be a powerful tool for the detection and separation out of these contaminating components from brain activity. Yet thus far thorough investigation is lacking into how this pre-processing step might affect or even distort the information on brain connectivity inherent in the raw signals. The aim of this work is to address this question by systematically investigating and comparing three different strategies: first, analysis of all network nodes without eliminating contamination; second, removing the node which is contaminated by artefacts; third, using the ICA artefact removal method as an initial step prior to the analysis. Multivariate, time-variant autoregressive models are used to approximate the recorded data; the assessment of information flow within the modelled networks is carried out by means partial directed coherence, offering a frequency-selective estimation of connectivity.

Influence of imputation strategies on the identification of brain functional connectivity networks.

Whenever neurophysiological data, such as EEG data are recorded, occurring artifacts pose an essential problem. This study addresses this issue by using imputation methods whereby whole data sets of a trial, or distinct electrodes, are not removed from the analysis of the EEG data but are replaced. We present different imputation strategies but use only two which are optimal for this particular study; predictive mean matching and data augmentation. The study addresses the as of yet unresolved question if the quality of derived brain functional networks is improved by imputation methods compared to traditional exclusion techniques which drop data, and will finally assesses the differences between the two imputation methods themselves used here. In this study, EEG data from a study evaluating dyslexia-specific therapy on a neurophysiological level were used to investigate imputation strategies in research of cortical interaction. Several recorded values were artificially declared as 'missing'. This enables the comparison of networks based on the complete data set without any missing values (pseudo ground truth) and those derived from imputation approaches in a realistic situation of disturbed data. Functional connectivity was quantified by time-variant partial directed coherence, providing a directed, temporally varying and frequency-selective connectivity measure. Based on the comparison between pseudo ground truth and networks of data with excluded missing values and data with imputed values, we found that any imputation strategy is preferable to the entire exclusion of data. The study also showed that the choice of the applied imputation algorithm impacts the resulting networks only marginally.

Advanced Insights into Functional Brain Connectivity by Combining Tensor Decomposition and Partial Directed Coherence.

Quantification of functional connectivity in physiological networks is frequently performed by means of time-variant partial directed coherence (tvPDC), based on time-variant multivariate autoregressive models. The principle advantage of tvPDC lies in the combination of directionality, time variance and frequency selectivity simultaneously, offering a more differentiated view into complex brain networks. Yet the advantages specific to tvPDC also cause a large number of results, leading to serious problems in interpretability. To counter this issue, we propose the decomposition of multi-dimensional tvPDC results into a sum of rank-1 outer products. This leads to a data condensation which enables an advanced interpretation of results. Furthermore it is thereby possible to uncover inherent interaction patterns of induced neuronal subsystems by limiting the decomposition to several relevant channels, while retaining the global influence determined by the preceding multivariate AR estimation and tvPDC calculation of the entire scalp. Finally a comparison between several subjects is considerably easier, as individual tvPDC results are summarized within a comprehensive model equipped with subject-specific loading coefficients. A proof-of-principle of the approach is provided by means of simulated data; EEG data of an experiment concerning visual evoked potentials are used to demonstrate the applicability to real data.

Topographic analysis of engagement and disengagement of neural oscillators in photic driving: a combined electroencephalogram/magnetoencephalogram study.

OBJECTIVE: A coupled system of nonlinear neural oscillators with an individual resonance frequency is assumed to form the neuronal substrate for the photic driving phenomenon. The aim was to investigate the spatiotemporal stability of these oscillators and quantify the spatiotemporal process of engagement and disengagement of the neuronal oscillators in both multitrial and single-trial data. METHODS: White light-emitting diode flicker stimulation was used at 15 frequencies, which were set relative to the individual α frequency of each of the 10 healthy participants. Simultaneously, the electroencephalogram (EEG) and the magnetoencephalogram (MEG) were recorded. Subsequently, spatiotemporal matching pursuit (MP) algorithms were used to analyze the EEG and MEG topographies. RESULTS: Intraindividually similar topographies were found at stimulation frequencies close to (1) the individual α frequency and (2) half the individual α frequency in the multitrial and the single-trial cases. In both stimulation frequency ranges, the authors observed stable topographies 5 to 10 stimuli after the beginning of the stimulation and lasting three nonexisting periods after the end of the stimulation. This was interpreted as the engaging/disengaging effect of the observed oscillations, because especially the frequency parameter adopted before and after stable topographies were observed. Topographic entrainment was slightly more pronounced in MEG as compared with that in EEG. CONCLUSIONS: The results support the hypothesis of nonlinear information processing in human visual system, which can be described by nonlinear neural oscillators.

Imaging genetics of FOXP2 in dyslexia.

Dyslexia is a developmental disorder characterised by extensive difficulties in the acquisition of reading or spelling. Genetic influence is estimated at 50-70%. However, the link between genetic variants and phenotypic deficits is largely unknown. Our aim was to investigate a role of genetic variants of FOXP2, a prominent speech and language gene, in dyslexia using imaging genetics. This technique combines functional magnetic resonance imaging (fMRI) and genetics to investigate relevance of genetic variants on brain activation. To our knowledge, this represents the first usage of fMRI-based imaging genetics in dyslexia. In an initial case/control study (n = 245) for prioritisation of FOXP2 polymorphisms for later use in imaging genetics, nine SNPs were selected. A non-synonymously coding mutation involved in verbal dyspraxia was also investigated. SNP rs12533005 showed nominally significant association with dyslexia (genotype GG odds ratio recessive model = 2.1 (95% confidence interval 1.1-3.9), P = 0.016). A correlated SNP was associated with altered expression of FOXP2 in vivo in human hippocampal tissue. Therefore, influence of the rs12533005-G risk variant on brain activity was studied. fMRI revealed a significant main effect for the factor 'genetic risk' in a temporo-parietal area involved in phonological processing as well as a significant interaction effect between the factors 'disorder' and 'genetic risk' in activation of inferior frontal brain areas. Hence, our data may hint at a role of FOXP2 genetic variants in dyslexia-specific brain activation and demonstrate use of imaging genetics in dyslexia research.

A time-variant processing approach for the analysis of alpha and gamma MEG oscillations during flicker stimulus generated entrainment.

Repetitive flicker stimulation (photic driving) offers the possibility to study the properties and coupling characteristics of stimulation-sensitive neuronal oscillators by means of the MEG/EEG analysis. With flicker frequencies in the region of the individual alpha band frequency, the dynamics of the entrainment process of the alpha oscillation, as well as the dynamics of the accompanying gamma oscillations and the coupling between the oscillations, are investigated by means of an appropriate combination of time-variant analysis methods. The Hilbert and the Gabor transformation reveal time-variant properties (frequency entrainment, phase locking, and n:m synchronization) of the entrainment process in the whole frequency range. Additionally, time-variant partial directed coherence is applied to identify ocular saccadic interferences and to study the directed information transfer between the recording sites of the simultaneously derived MEG/EEG data during the entrainment. The MEG data is the focus of this methodological study as the entrainment effects of the alpha oscillation are stronger in MEG than in the EEG. The occipital brain region (visual cortex) was mainly investigated and the dynamics of the alpha entrainment quantified. It can be shown that at the beginning of this entrainment, a transient, strongly phase-locked "40-Hz" gamma oscillation occurs.

Understanding the time variant connectivity of the language network in developmental dyslexia: new insights using Granger causality.

The reading process takes place in a neuronal network comprising the inferior frontal, posterior dorsal and posterior ventral brain areas. It is suggested that developmental dyslexia is caused by a disruption of the two posterior network areas. What remains debatable is whether these areas are affected in their functionality or whether the neuronal networking (connectivity) of these areas suffer from a disturbed information transfer. Thus, it is of major interest to investigate the time flow of the directed information transfer (time variant connectivity) within the neuronal reading network of dyslexic subjects. We investigated adolescents with dyslexia and normal-reading controls with functional magnetic resonance imaging and electroencephalography (EEG) with a paradigm addressing basic visual, orthographic and phonological processing. EEG data were analyzed with the time variant Granger causality index (tvGCI) to investigate the temporal order of the directed information transfer (time variant causal connectivity: which network node passes when information to which network node) during reading in dyslexic readers. Results show that the reading network of dyslexic readers comprises the same brain areas as identified in normal-reading subjects. The tvGCI analysis of the network profiles of dyslexic readers indicates that dyslexics show a difference in timing and localization of connectivity within this reading network compared to normal readers. Dyslexic readers use right hemisphere language areas to counterbalance posterior left hemisphere processing deficits. The compensatory involvement of homologue right hemisphere brain areas for the reading process may be the neurobiological background for the significantly longer reading times by dyslexics.

[Survey of fMRI results regarding a phonological deficit in children and adults with dyslexia: fundamental deficit or indication of compensation?]. / Ubersicht über Bildgebungs-befunde zum phonologischen Defizit der Lese-Rechtschreibstörung bei Kindern und Erwachsenen: Grundlegende Defizite oder Anzeichen von Kompensation?

Early neuroimaging studies exploring the neurobiological correlates of the phonological deficit in dyslexia were restricted to adult probands with dyslexia due to the exposure to radioactivity in the course of PET measurements. The differences in activation between normal adult readers and adults with dyslexia recorded in these studies left open the issue of whether or not these are indeed fundamental activation deficits or only a reflection of lifelong experience with poor reading and writing skills and thus should be interpreted as a sign of compensation. Development of fMRI in recent years has enabled the investigation of children with dyslexia in order to explore the neurobiological activation patterns that underlie dyslexia. On the whole, the imaging findings in children and adults with dyslexia indicate that the left-hemisphere inferior frontal differences in activation, as well as the dorsal and ventral temporal differences in activation observed in all age groups during the processing of phonological language tasks are to be regarded as a fundamental biological deficit in dyslexia. Right-hemisphere differences in activation, which in German-speaking areas are observable in adults but only rarely in children with dyslexia, might, on the other hand, be regarded as a sign of developmental compensation.

Alpha entrainment in human electroencephalogram and magnetoencephalogram recordings.

Visual stimulation by repetitive flashes of light can lead to an entrainment of the alpha rhythm in electroencephalogram recordings (also called photic driving). We report a comparison of simultaneously recorded electric and magnetic data in a photic driving experiment, adapted to the individual alpha rhythm of 10 healthy volunteers. We show that there is a stronger frequency entrainment in magnetoencephalogram than in electroencephalogram recordings in all volunteers, which indicates a possible tangential brain activity underlying the dominant entrainment effect. The entrainment in the magnetoencephalogram lasts over significantly more frequencies and is most effective in the region around the individual alpha and a half alpha. For different channels, we found different degrees of entrainment showing topological and time-varying properties.