Multimodal personalised executive function intervention (E-Fit) for school-aged children with complex congenital heart disease: protocol for a randomised controlled feasibility study.

INTRODUCTION: Children with congenital heart disease (CHD) are at risk for executive functions (EF) impairments. To date, interventions have limited effects on EF in children and adolescents with complex CHD. Therefore, we developed a new multimodal and personalised EF intervention (E-Fit). This study aims to test the feasibility of this intervention called 'E-Fit' for children with complex CHD and EF impairments. METHODS AND ANALYSIS: This is a single-centre, single-blinded, randomised controlled feasibility study exploring the E-Fit intervention. We aim to enrol 40 children with CHD aged 10-12 years who underwent infant cardiopulmonary bypass surgery and show clinically relevant EF impairments (T-score ≥60 on any Behaviour Rating Inventory for Executive Function questionnaire summary scale). The multimodal intervention was developed with focus groups and the Delphi method involving children and adolescents with CHD, their parents and teachers, and health professionals. The intervention is composed of three elements: computer-based EF training using CogniFit Inc 2022, performed three times a week at home; weekly EF remote strategy coaching and analogue games. The content of the computer and strategy training is personalised to the child's EF difficulties. The control group follows their daily routines as before and completes a diary about their everyday activities four times a week. Participants will be randomised in a 1:1 ratio. Feasibility is measured by the participants' and providers' ratings of the participants' adherence and exposure to the intervention, recruitment rates and the evaluation of the intended effects of the programme. ETHICS AND DISSEMINATION: Local ethics committee approval was obtained for the study (BASEC-Nr: 2021-02413). Parents provide written informed consent. Key outputs from the trial will be disseminated through presentations at conferences, peer-reviewed publications and directly to participating families. Furthermore, these results will inform the decision whether to proceed to a randomised controlled trial to investigate effectiveness. TRIAL REGISTRATION NUMBER: NCT05198583.

Prefrontal Glutathione Levels in Major Depressive Disorder Are Linked to a Lack of Positive Affect.

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders, with symptoms including persistent sadness and loss of interest. MDD is associated with neurochemical alterations in GABA, glutamate, and glutamine levels but, to date, few studies have examined changes in glutathione (GSH) in MDD. This study investigated changes in GSH in an unmedicated group of young adults, including 46 participants with current (n = 12) or past MDD (n = 34) and 20 healthy controls. Glutathione levels were assessed from GSH-edited magnetic resonance (MR) spectra, acquired from a voxel in the left prefrontal cortex, and depressive symptoms were evaluated with validated questionnaires and clinical assessments. Cortisol levels were also assessed as a marker for acute stress. Participants with current MDD demonstrated elevated GSH in comparison to participants with past MDD and controls, although the results could be influenced by differences in tissue composition within the MRS voxel. In addition, participants with both current and past MDD showed elevated cortisol levels in comparison to controls. No significant association was observed between GSH and cortisol levels, but elevated GSH levels were associated with a decrease in positive affect. These results demonstrate for the first time that elevated GSH in current but not past depression may reflect a state rather than a trait neurobiological change, related to a loss of positive affect.

Feasibility of Non-Gated Dynamic Fetal Cardiac MRI for Identification of Fetal Cardiovascular Anatomy.

INTRODUCTION: The aim of this study was to evaluate the feasibility of identifying the fetal cardiac and thoracic vascular structures with non-gated dynamic balanced steady-state free precession (SSFP) MRI sequences. METHODS: We retrospectively assessed the visibility of cardiovascular anatomy in 60 fetuses without suspicion of congenital heart defect. Non-gated dynamic balanced SSFP sequences were acquired in three anatomic planes of the fetal thorax. The images were analyzed following a segmental approach in consensus reading by an experienced pediatric cardiologist and radiologist. An imaging score was defined by giving one point to each visualized structure, yielding a maximum score of 21 points. Image quality was rated from 0 (poor) to 2 (excellent). The influence of gestational age (GA), field strength, placenta position, and maternal panniculus on image quality and imaging score were tested. RESULTS: 30 scans were performed at 1.5T, 30 at 3T. Heart position, atria, and ventricles could be seen in all 60 fetuses. Basic diagnosis (>12 points) was achieved in 54 cases. The mean imaging score was 16.8+/-3.8. Maternal panniculus (r = -0.3; p = 0.015) and GA (r = 0.6; p < 0.001) correlated with imaging score. Field strength influenced image quality, with 1.5T being better than 3T images (p = 0.012). Imaging score or quality was independent of placenta position. CONCLUSION: Fetal cardiac MRI with non-gated SSFP sequences enables recognition of basic cardiovascular anatomy.

Sleep-related and diurnal effects on brain diffusivity and cerebrospinal fluid flow.

The question of how waste products are cleared from the brain, and the role which sleep plays in this process, is critical for our understanding of a range of physical and mental illnesses. In rodents, both circadian and sleep-related processes appear to facilitate clearance of waste products. The purpose of this study was to investigate whether overnight changes in diffusivity, brain volumes, and cerebrospinal fluid flow measured with MRI are associated with sleep parameters from overnight high-density sleep EEG, and circadian markers. In healthy adults investigated with MRI before and after sleep EEG, we observed an increase in water diffusivity overnight, which was positively related to the proportion of total sleep time spent in rapid eye movement (REM) sleep, and negatively associated with the fraction of sleep time spent in non rapid eye movement (NREM) sleep. Diffusivity was also associated with the sleep midpoint, a circadian marker. CSF flow increased overnight; this increase was unrelated to sleep or diffusivity measures but was associated with circadian markers. These results provide evidence for both sleep related and diurnal effects on water compartmentalisation within the brain.

Subacute Changes in N-Acetylaspartate (NAA) Following Ischemic Stroke: A Serial MR Spectroscopy Pilot Study.

Preservation of neuronal tissue is crucial for recovery after stroke, but studies suggest that prolonged neuronal loss occurs following acute ischaemia. This study assessed the temporal pattern of neuronal loss in subacute ischemic stroke patients using 1H magnetic resonance spectroscopy, in parallel with functional recovery at 2, 6 and 12 weeks after stroke. Specifically, we measured N-acetylaspartate (NAA), choline, myoinositol, creatine and lactate concentrations in the ipsilesional and contralesional thalamus of 15 first-ever acute ischaemic stroke patients and 15 control participants and correlated MRS concentrations with motor recovery, measured at 12 weeks using the Fugl-Meyer scale. NAA in the ipsilesional thalamus fell significantly between 2 and 12 weeks (10.0 to 7.97 mmol/L, p = 0.003), while choline, myoinositol and lactate concentrations increased (p = 0.025, p = 0.031, p = 0.001, respectively). Higher NAA concentrations in the ipsilesional thalamus at 2 and 12 weeks correlated with higher Fugl Meyer scores at 12 weeks (p = 0.004 and p = 0.006, respectively). While these results should be considered preliminary given the modest sample size, the progressive fall in NAA and late increases in choline, myoinositol and lactate may indicate progressive non-ischaemic neuronal loss, metabolically depressed neurons and/or diaschisis effects, which have a detrimental effect on motor recovery. Interventions that can potentially limit this ongoing subacute tissue damage may improve stroke recovery.

Magnetic resonance imaging markers reflect cognitive outcome after rehabilitation in children with acquired brain injury.

PURPOSE: To test markers from conventional and diffusion Magnetic Resonance Imaging (MRI) as possible predictors of cognitive outcome following rehabilitation therapy in children with acquired brain injury (ABI). METHODS: Twenty-one children (10 boys, mean age 11.6 years, range 7.1-19.4) with stroke or traumatic brain injury underwent MRI including Diffusion Tensor Imaging (DTI) before admission to the rehabilitation centre. The conventional images were scored according to a standardised injury scoring system, and mean Fractional Anisotropy (FA) was determined within the Corpus Callosum (CC), as this structure is hypothesised to play an important role in cognition. Both conventional MRI injury scores and mean FA of the CC and its sub-regions were compared with standard functional cognitive outcome scores. Relationships between MRI indices and cognitive outcome scores were assessed using multiple regression and receiver operating characteristic (ROC) analyses. RESULTS: A backwards regression analysis revealed that the mean FA of the CC body and genu and the supratentorial injury score appear to represent the best predictors of outcome, together with the age at rehabilitation and time in rehabilitation. In the ROC analysis, the mean FA values of the CC body and genu and the infratentorial injury score provided the highest sensitivity, while the mean FA of the CC splenium showed the highest specificity for outcome. CONCLUSIONS: The conventional MRI injury scores and DTI metrics from the CC reflect cognitive outcomes following rehabilitation. Neuroimaging methods such as MRI with DTI may therefore provide important markers for cognitive recovery after brain injury.

Executive function and brain development in adolescents with severe congenital heart disease (Teen Heart Study): protocol of a prospective cohort study.

INTRODUCTION: Congenital heart disease (CHD) is the most frequent congenital malformation. With recent advances in medical care, the majority of patients with CHD survive into adulthood. As a result, interest has shifted towards the neurodevelopmental outcome of these patients, and particularly towards the early detection and treatment of developmental problems. A variety of mild to moderate cognitive impairments as well as emotional and behavioural problems has been observed in this population. However, a more detailed assessment of the various domains of executive function and their association with structural and functional brain development is lacking. Therefore, the current study will examine all domains of executive function and brain development in detail in a large sample of children and adolescents with CHD and healthy control children. METHODS AND ANALYSIS: A total of 192 children and adolescents with CHD aged 10-15 years, who participated in prospective cohort studies at the University Children's Hospital Zurich, will be eligible for this study. As a control group, approximately 100 healthy children will be enrolled. Primary outcome measures will include executive function abilities, while secondary outcomes will consist of other neurodevelopmental measures, including intelligence, processing speed, attention, fine motor abilities and brain development. An MRI will be performed to assess structural and functional brain development. Linear regression analyses will be applied to investigate group differences and associations between executive function performance and neurodevelopmental measures. ETHICS AND DISSEMINATION: This study is supported by the Swiss National Science Foundation (SNF 32003B_172914) and approved by the ethical committee of the Canton Zurich (KEK 2019-00035). Written informed consent will be obtained from all the parents and from children aged 14 years or older. Findings from this study will be published in peer-reviewed journals and presented at national and international conferences for widespread dissemination of the results.

Postoperative brain volumes are associated with one-year neurodevelopmental outcome in children with severe congenital heart disease.

Children with congenital heart disease (CHD) remain at risk for neurodevelopmental impairment despite improved perioperative care. Our prospective cohort study aimed to determine the relationship between perioperative brain volumes and neurodevelopmental outcome in neonates with severe CHD. Pre- and postoperative cerebral MRI was acquired in term born neonates with CHD undergoing neonatal cardiopulmonary bypass surgery. Brain volumes were measured using an atlas prior-based automated method. One-year neurodevelopmental outcome was assessed with the Bayley-III. CHD infants (n = 77) had lower pre- and postoperative total and regional brain volumes compared to controls (n = 44, all p < 0.01). CHD infants had poorer cognitive and motor outcome (p ≤ 0.0001) and a trend towards lower language composite score compared to controls (p = 0.06). Larger total and selected regional postoperative brain volumes were found to be associated with better cognitive and language outcomes (all p < 0.04) at one year. This association was independent of length of intensive care unit stay for total, cortical, temporal, frontal and cerebellar volumes. Therefore, reduced cerebral volume in CHD neonates undergoing bypass surgery may serve as a biomarker for impaired outcome.

Smaller brain volumes at two years of age in patients with hypoplastic left heart syndrome - Impact of surgical approach.

BACKGROUND: Brain growth in hypoplastic left heart syndrome (HLHS) is reduced before and after birth. Little is known about further brain growth until two years of age before Fontan procedure and the potential impact of type of surgery. METHODS: In a prospective, two-center study 29 patients with HLHS and variants were treated by Norwood (n = 5) or Hybrid procedure (n = 24). At two years of age a cerebral MRI was performed and brain volumes (total gray, deep gray, white matter) and cerebrospinal fluid volume were calculated using FreeSurfer image analysis suite and compared to a healthy control group (n = 8). RESULTS: The total brain volumes in patients with HLHS were smaller compared to controls (HLHS: 893 ±â€¯76 ml vs. controls: 1015 ±â€¯148 ml, p = 0.005). This difference was found in all three brain compartments after Norwood procedure, whereas patients after Hybrid procedure had total and deep gray volumes comparable to controls. When comparing Norwood to Hybrid patients, deep gray matter volume reduction was more pronounced (Norwood: 38.4 ±â€¯4.1 ml vs. Hybrid: 44.4 ±â€¯3.9 ml, p = 0.005) than white matter reduction (Norwood: 255 ±â€¯19 ml vs. Hybrid: 285 ±â€¯31 ml, p = 0.032). CONCLUSIONS: Smaller total and regional brain volumes were found two years after Norwood or Hybrid procedure in children with HLHS. The brain volume reduction was more distinct after Norwood than after Hybrid procedure. Longitudinal studies are needed to identify impact of early staged-surgeries on brain development and may become part of the decision-making process in individual patients.

In human non-REM sleep, more slow-wave activity leads to less blood flow in the prefrontal cortex.

Cerebral blood flow (CBF) is related to integrated neuronal activity of the brain whereas EEG provides a more direct measurement of transient neuronal activity. Therefore, we addressed what happens in the brain during sleep, combining CBF and EEG recordings. The dynamic relationship of CBF with slow-wave activity (SWA; EEG sleep intensity marker) corroborated vigilance state specific (i.e., wake, non-rapid eye movement (NREM) sleep stages N1-N3, wake after sleep) differences of CBF e.g. in the posterior cingulate, basal ganglia, and thalamus, indicating their role in sleep-wake regulation and/or sleep processes. These newly observed dynamic correlations of CBF with SWA - namely a temporal relationship during continuous NREM sleep in individuals - additionally implicate an impact of sleep intensity on the brain's metabolism. Furthermore, we propose that some of the aforementioned brain areas that also have been shown to be affected in disorders of consciousness might therefore contribute to the emergence of consciousness.

Comparison of automated brain volumetry methods with stereology in children aged 2 to 3 years.

INTRODUCTION: The accurate and precise measurement of brain volumes in young children is important for early identification of children with reduced brain volumes and an increased risk for neurodevelopmental impairment. Brain volumes can be measured from cerebral MRI (cMRI), but most neuroimaging tools used for cerebral segmentation and volumetry were developed for use in adults and have not been validated in infants or young children. Here, we investigate the feasibility and accuracy of three automated software methods (i.e., SPM, FSL, and FreeSurfer) for brain volumetry in young children and compare the measures with corresponding volumes obtained using the Cavalieri method of modern design stereology. METHODS: Cerebral MRI data were collected from 21 children with a complex congenital heart disease (CHD) before Fontan procedure, at a median age of 27 months (range 20.9-42.4 months). Data were segmented with SPM, FSL, and FreeSurfer, and total intracranial volume (ICV) and total brain volume (TBV) were compared with corresponding measures obtained using the Cavalieri method. RESULTS: Agreement between the estimated brain volumes (ICV and TBV) relative to the gold standard stereological volumes was strongest for FreeSurfer (p < 0.001) and moderate for SPM segment (ICV p = 0.05; TBV p = 0.006). No significant association was evident between ICV and TBV obtained using SPM NewSegment and FSL FAST and the corresponding stereological volumes. CONCLUSIONS: FreeSurfer provides an accurate method for measuring brain volumes in young children, even in the presence of structural brain abnormalities.