Stress Markers, Executive Functioning, and Resilience Among Early Adolescents With Complex Congenital Heart Disease.

Importance: Infants with complex congenital heart disease (cCHD) may experience prolonged and severe stress when undergoing open heart surgery. However, little is known about long-term stress and its role in neurodevelopmental impairments in this population. Objective: To investigate potential differences between early adolescents aged 10 to 15 years with cCHD and healthy controls in physiological stress markers by hair analysis, executive function (EF) performance, and resilience. Design, Setting, and Participants: This single-center, population-based case-control study was conducted at the University Children's Hospital Zurich, Switzerland. Patients with different types of cCHD who underwent cardiopulmonary bypass surgery during the first year of life and who did not have a genetic disorder were included in a prospective cohort study between 2004 and 2012. A total of 178 patients were eligible for assessment at ages 10 to 15 years. A control group of healthy term-born individuals was cross-sectionally recruited. Data assessment was between 2019 and 2021. Statistical analysis was performed from January to April 2023. Exposure: Patients with cCHD who underwent infant open heart surgery. Main Outcomes and Measures: Physiological stress markers were quantified by summing cortisol and cortisone concentrations measured with liquid chromatography with tandem mass spectrometry in a 3-centimeter hair strand. EFs were assessed with a neuropsychological test battery to produce an age-adjusted EF summary score. Resilience was assessed with a standardized self-report questionnaire. Results: The study included 100 patients with cCHD and 104 controls between 10 and 15 years of age (mean [SD] age, 13.3 [1.3] years); 110 (53.9%) were male and 94 (46.1%) were female. When adjusting for age, sex, and parental education, patients had significantly higher sums of hair cortisol and cortisone concentrations (ß, 0.28 [95% CI, 0.12 to 0.43]; P < .001) and lower EF scores (ß, -0.36 [95% CI, -0.49 to -0.23]; P < .001) than controls. There was no group difference in self-reported resilience (ß, -0.04 [95% CI, -0.23 to 0.12]; P = .63). A significant interaction effect between stress markers and EFs was found, indicating a stronger negative association in patients than controls (ß, -0.65 [95% CI, -1.15 to -0.15]; P = .01). The contrast effects were not significant in patients (ß, -0.21 [95% CI, -0.43 to -0.00]; P = .06) and controls (ß, 0.09 [95% CI, -0.11 to 0.30]; P = .38). Conclusions and Relevance: This case-control study provides evidence for altered physiological stress levels in adolescents with cCHD and an association with poorer EF. These results suggest that future studies are needed to better understand the neurobiological mechanisms and timing of alterations in the stress system and its role in neurodevelopment.

Cerebral perfusion differences are linked to executive function performance in very preterm-born children and adolescents.

Children and adolescents born very preterm are at risk of cognitive impairment, particularly affecting executive functions. To date, the neural correlates of these cognitive differences are not yet fully understood, although converging evidence points to a pattern of structural and functional brain alterations, including reduced brain volumes, altered connectivity, and altered brain activation patterns. In very preterm neonates, alterations in brain perfusion have also been reported, but the extent to which these perfusion alterations persist into later childhood is not yet known. This study evaluated global and regional brain perfusion, measured with arterial spin labelling (ASL) MRI, in 26 very preterm children and adolescents and 34 term-born peers. Perfusion was compared between groups and relative to executive function (EF) scores, derived from an extensive EF battery assessing working memory, cognitive flexibility, and planning. Very preterm children and adolescents showed regions of altered perfusion, some of which were also related to EF scores. Most of these regions were located in the right hemisphere and included regions like the thalamus and hippocampus, which are known to play a role in executive functioning and can be affected by prematurity. In addition, perfusion decreased with age during adolescence and showed a significant interaction between birth status and sex, such that very preterm girls showed lower perfusion than term-born girls, but this trend was not seen in boys. Taken together, our results indicate a regionally altered perfusion in very preterm children and adolescents, with age and sex related changes during adolescence.

Occipital transcranial direct current stimulation in episodic migraine patients: effect on cerebral perfusion.

Cerebral blood flow differs between migraine patients and healthy controls during attack and the interictal period. This study compares the brain perfusion of episodic migraine patients and healthy controls and investigates the influence of anodal transcranial direct current stimulation (tDCS) over the occipital cortex. We included healthy adult controls and episodic migraineurs. After a 28-day baseline period and the baseline visit, migraine patients received daily active or sham anodal tDCS over the occipital lobe for 28 days. All participants underwent a MRI scan at baseline; migraineurs were also scanned shortly after the stimulation period and about five months later. At baseline, brain perfusion of migraine patients and controls differed in several areas; among the stimulated areas, perfusion was increased in the cuneus of healthy controls. At the first visit, the active tDCS group had an increased blood flow in regions processing visual stimuli and a decreased perfusion in other areas. Perfusion did not differ at the second follow-up visit. The lower perfusion level in migraineurs in the cuneus indicates a lower preactivation level. Anodal tDCS over the occipital cortex increases perfusion of several areas shortly after the stimulation period, but not 5 months later. An increase in the cortical preactivation level could mediate the transient reduction of the migraine frequency.Trial registration: NCT03237754 (registered at clincicaltrials.gov; full date of first trial registration: 03/08/2017).

Association of cerebellar volume with cognitive and motor function in adults with congenital heart disease.

INTRODUCTION: Patients with congenital heart disease (CHD) are at risk for cognitive and motor function impairments, brain injury, and smaller total brain volumes. The specific vulnerability of the cerebellum and its role in cognitive and motor functions in adults with congenital heart disease is not well defined. METHODS: Forty-three patients with CHD and 53 controls between 18 and 32 years underwent brain magnetic resonance imaging and cognitive, executive (EF), and motor function assessment. Cerebellar volumes were obtained using EasyMeasure and SUIT Toolbox. Associations between cerebellar volumes and cognitive and motor function were calculated using linear models. RESULTS: General cognitive and pure motor functions were lower in patients compared to controls (P < 0.05). Executive functions were within the normal range. While total cerebellar volumes and the anterior lobes were similar in patients and controls (P > 0.1), the posterior cerebellar lobe was smaller in patients with more complex CHD (P = 0.006). Smaller posterior cerebellar gray matter was not associated with cognitive functions. Smaller anterior cerebellar gray matter was not significantly related to motor functions (P > 0.1). CONCLUSION: In adults with CHD, cerebellar volume was largely unimpaired. Patients with more complex CHD may be vulnerable to changes in the posterior cerebellar gray matter. We found no significant contribution of cerebellar gray matter to cognitive and motor impairments. More advanced imaging techniques are necessary to clarify the contribution of the cerebellum to cognitive and motor functions.

Postnatal cerebral hemodynamics in infants with severe congenital heart disease: a scoping review.

Patients with severe congenital heart disease (CHD) are at risk for impaired neurodevelopment. Cerebral blood supply may be diminished by congenital anomalies of cardiovascular anatomy and myocardial function. The aim of this scoping review was to summarize the current knowledge on cerebral hemodynamics in infants with severe CHD. A scoping review was performed. Five databases were searched for articles published from 01/1990 to 02/2022 containing information on cerebral hemodynamics assessed by neuroimaging methods in patients with severe CHD within their first year of life. A total of 1488 publications were identified, of which 26 were included. Half of the studies used Doppler ultrasound, and half used magnetic resonance imaging techniques. Studies focused on preoperative findings of cerebral hemodynamics, effects of surgical and conservative interventions, as well as on associations between cerebral hemodynamics and brain morphology or neurodevelopment. Cerebral perfusion was most severely affected in patients with single ventricle and other cyanotic disease. Neuroimaging methods provide a large variety of information on cerebral hemodynamics. Nevertheless, small and heterogeneous cohorts complicate this field of research. Further studies are needed to improve our understanding of the link between CHD and altered cerebral hemodynamics to optimize neuroprotection strategies. IMPACT: Postnatal cerebral hemodynamics are altered in infants with congenital heart disease (CHD) as compared to healthy controls, especially in most severe types such as single ventricle or other cyanotic CHD. Associations of these alterations with brain volume and maturation reveal their clinical relevance. Research in this area is limited due to the rarity and heterogeneity of diagnoses. Furthermore, longitudinal studies have rarely been conducted. Further effort is needed to better understand the deviation from physiological cerebral perfusion and its consequences in patients with CHD to optimize neuroprotection strategies.

The longitudinal influence of tDCS on occipital GABA and glutamate/glutamine levels in episodic migraineurs.

This study investigated differences in the concentration of gamma-aminobutyric acid (GABA) and the combination of glutamine and glutamate (as GLX) in the early visual cortex of patients with episodic migraine and the influence of transcranial direct current stimulation (tDCS) on GABA and GLX. In this single-blind, sham-controlled trial, we randomly assigned patients with episodic migraine to receive daily anodal tDCS or sham stimulation. In addition, we included healthy controls. We acquired proton MR spectroscopy data of the visual cortex with 3 Tesla MRI at baseline and from migraine patients directly after the stimulation period and 4 months later. In 22 migraineurs and 25 controls, the GABA and the GLX concentrations did not differ at baseline between the groups. tDCS resulted in reduced concentrations of GABA but not GLX or the migraine frequency directly after the stimulation period, but not 4 months later. The changes in the levels of GABA in the early visual cortex of patients with episodic migraine in the interictal period suggest an effect of tDCS that allowed for subsequent changes in the migraine frequency. However, we might have missed relevant variations in the concentrations of these neurotransmitters during the follow-up period, as changes in migraine frequency appeared after the first MRI and disappeared before the second.

Functional networks of working memory abilities in children with complex congenital heart disease: a sleep EEG study.

Working memory is frequently impaired in children with complex congenital heart disease (CHD), but little is known about the functional neuronal correlates. Sleep slow wave activity (SWA; 1-4.5 Hz EEG power) has previously been shown to reliably map neurofunctional networks of cognitive abilities in children with and without neurodevelopmental impairments. This study investigated whether functional networks of working memory abilities are altered in children with complex CHD using EEG recordings during sleep. Twenty-one children with complex CHD (aged 10.9 [SD: 0.3] years) and 17 typically-developing peers (10.5 [0.7] years) completed different working memory tasks and an overnight high-density sleep EEG recording (128 electrodes). The combined working memory score tended to be lower in children with complex CHD (CHD group: -0.44 [1.12], typically-developing group: 0.55 [1.24], d = 0.59, p = .06). The working memory score and sleep SWA of the first hour of deep sleep were correlated over similar brain regions in both groups: Strong positive associations were found over prefrontal and fronto-parietal brain regions - known to be part of the working memory network - and strong negative associations were found over central brain regions. Within these working memory networks, the associations between working memory abilities and sleep SWA (r between -.36 and .58, all p < .03) were not different between the two groups (no interactions, all p > .05). The current findings suggest that sleep SWA reliably maps working memory networks in children with complex CHD and that these functional networks are generally preserved in these patients.

White matter microstructure and executive functions in congenital heart disease from childhood to adulthood: A pooled case-control study.

Congenital heart disease (CHD) patients are at risk for alterations in the cerebral white matter microstructure (WMM) throughout development. It is unclear whether the extent of WMM alterations changes with age, especially during adolescence when the WMM undergoes rapid maturation. We investigated differences in WMM between patients with CHD and healthy controls from childhood until early adulthood in a pooled sample of children, adolescents, and young adults. The association between WMM and EF was assessed. Patients with CHD (N=78) and controls (N=137) between 9 and 32 years of age underwent diffusion tensor imaging and an executive function test-battery. Mean fractional anisotropy (FA) was calculated for each white matter tract. Linear regression tested age and group effects (CHD vs control) and their interaction on FA. Relative Variable Importance (RI) estimated the independent contribution of tract FA, presence of CHD, CHD complexity, and parental education to the variability in EF. Mean FA was lower in patients compared to controls in almost all tracts (p between 0.057 and <0.001). WMM alterations in patients were not different depending on age (all interaction effects p>0.074). Predictors of EF were CHD group (RI=43%), parental education (RI=23%), CHD complexity (RI=10%), FA of the hippocampal cingulum (RI=6%) and FA of the corticospinal tract (RI=6%). The lack of group-FA-interactions indicates that the extent of altered FA remains similar across age. Altered FA is associated with EF impairments. CHD is a chronic disease with cerebral and neurocognitive impairments persisting into adulthood and, thus, long-term follow-up programs may improve overall outcome for this population.

Microstructural alterations of the corticospinal tract are associated with poor motor function in patients with severe congenital heart disease.

Congenital heart disease (CHD) patients are at risk for neurodevelopmental impairments, including altered motor function. However, little is known about the neuroanatomical correlates of persistent motor deficits in CHD. Thus, we examined the link between corticospinal tract (CST) microstructure and motor function in adolescent and adult CHD patients compared to healthy controls. This study investigated 89 CHD patients (N(adolescents) = 47, N(adults) = 42, mean age = 19.9 years) and 97 age-matched healthy controls (N(adolescents) = 44, N(adults) = 53, mean age = 20.6 years). Diffusion tensor imaging was conducted and fractional anisotropy (FA) of the left and right CST was extracted for each participant. Fine (pegboard) and pure motor (repeated finger, hand and foot movements) performance was evaluated with a standardized test battery. FA and motor performance were correlated and the effect of CHD complexity was tested using multivariate linear regression. Clinically relevant motor impairments (>2SD below normative mean) were evident in 24% of patients and 9% of controls. On average, motor performance was lower in CHD patients compared to controls, particularly in those with more complex CHD (fine motor: p = 0.023; pure motor: p < 0.001). FA CST was lower in patients compared to controls, particularly in those with more complex CHD (left: p < 0.001, right: p = 0.003). There was a significant interaction between CHD complexity and FA CST (left: p = 0.025, right: p = 0.025), indicating that FA correlates significantly with pure motor in patients with severe CHD, while there is only a weak association in moderate CHD and no association in patients with simple CHD and controls. Microstructure of the CST is altered in CHD patients, and is associated with pure motor impairments in patients with severe CHD. This indicates that persistent motor impairments may arise from atypical development of the primary motor pathway in the presence of a complex CHD. Early interventions promoting brain maturation in infancy may prevent persisting impairments across the lifetime.

EEG-fMRI Signal Coupling Is Modulated in Subjects With Mild Cognitive Impairment and Amyloid Deposition.

Cognitive impairment indicates disturbed brain physiology which can be due to various mechanisms including Alzheimer's pathology. Combined functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) recordings (EEG-fMRI) can assess the interplay between complementary measures of brain activity and EEG changes to be localized to specific brain regions. We used a two-step approach, where we first examined changes related to a syndrome of mild cognitive impairment irrespective of pathology and then studied the specific impact of amyloid pathology. After detailed clinical and neuropsychological characterization as well as a positron emission tomography (PET) scans with the tracer 11-[C]-Pittsburgh Compound B to estimate cerebral amyloid deposition, 14 subjects with mild cognitive impairment (MCI) (mean age 75.6 SD: 8.9) according to standard criteria and 21 cognitively healthy controls (HCS) (mean age 71.8 SD: 4.2) were assessed with EEG-fMRI. Thalamo-cortical alpha-fMRI signal coupling was only observed in HCS. Additional EEG-fMRI signal coupling differences between HCS and MCI were observed in parts of the default mode network, salience network, fronto-parietal network, and thalamus. Individuals with significant cerebral amyloid deposition (amyloid-positive MCI and HCS combined compared to amyloid-negative HCS) displayed abnormal EEG-fMRI signal coupling in visual, fronto-parietal regions but also in the parahippocampus, brain stem, and cerebellum. This finding was paralleled by stronger absolute fMRI signal in the parahippocampus and weaker absolute fMRI signal in the inferior frontal gyrus in amyloid-positive subjects. We conclude that the thalamocortical coupling in the alpha band in HCS more closely reflects previous findings observed in younger adults, while in MCI there is a clearly aberrant coupling in several networks dominated by an anticorrelation in the posterior cingulate cortex. While these findings may broadly indicate physiological changes in MCI, amyloid pathology was specifically associated with abnormal fMRI signal responses and disrupted coupling between brain oscillations and fMRI signal responses, which especially involve core regions of memory: the hippocampus, para-hippocampus, and lateral prefrontal cortex.

Brain volumes in adults with congenital heart disease correlate with executive function abilities.

Congenital heart disease is the most common birth defect, and patients are at risk for neurodevelopmental impairment and brain abnormalities. Yet, little is known about the link between brain volumes and cognitive function in adults with congenital heart disease. Forty-four patients and 53 controls between 18 and 32 years underwent brain magnetic resonance imaging and cognitive testing, assessed with an intelligence quotient and executive function global score. Associations between brain volumes and cognitive function were calculated using linear models. Cognitive function in patients was within the normal range (intelligence quotient: 97.74 (10.76)). Total brain volume was significantly smaller in patients compared to controls (1067.26 (113.53) vs 1113.04 (97.88) cm3, P < 0.01), irrespective of cardiac factors (heart defect complexity, cyanosis, cardiopulmonary bypass: all P > 0.4). After adjusting for total brain volume, only corpus callosum volume remained significantly smaller (P = 0.03). Smaller total brain volume was associated with poorer overall executive functioning (P = 0.02) and inhibition (P < 0.01), in both patients and controls. The association between total brain volume and overall executive functioning was moderated by parental socioeconomic status (lower socioeconomic status was associated with a stronger association between brain volume and EF; interaction P = 0.03). In adults with congenital heart disease, despite normal intelligence quotient, brain volume alterations persist into adulthood and are related to executive functioning, in particular inhibitory control. Adults coming from low socioeconomic background and with altered brain volumes are especially vulnerable and should thus be followed-up during adulthood to ensure optimal social and educational support.

Persistent Differences in Brain Structure in Developmental Dyscalculia: A Longitudinal Morphometry Study.

Developmental dyscalculia (DD) is a learning disability affecting the acquisition of numerical-arithmetical skills. Affected people show persistent deficits in number processing, which are associated with aberrant brain activation and structure. Reduced gray matter has been reported in DD for the parietal cortex including the intraparietal sulcus (IPS), but also the frontal and occipito-temporal cortex. Furthermore, dyscalculics show white matter differences for instance in the inferior (ILF) and superior longitudinal fasciculus (SLF). However, the longitudinal development of these structural differences is unknown. Therefore, our goal was to investigate the developmental trajectory of gray and white matter in children with and without DD. In this longitudinal study, neuropsychological measures and T1-weighted structural images were collected twice with an interval of 4 years from 13 children with DD (8.2-10.4 years) and 10 typically developing (TD) children (8.0-10.4 years). Voxel-wise estimation of gray and white matter volumes was assessed using voxel-based morphometry for longitudinal data. The present findings reveal for the first time that DD children show persistently reduced gray and white matter volumes over development. Reduced gray matter was found in the bilateral inferior parietal lobes including the IPS, supramarginal gyri, left precuneus, cuneus, right superior occipital gyrus, bilateral inferior and middle temporal gyri, and insula. White matter volumes were reduced in the bilateral ILF and SLF, inferior fronto-occipital fasciculus (IFOF), corticospinal tracts, and right anterior thalamic radiation (ATR). Behaviorally, children with DD performed significantly worse in various numerical tasks at baseline and follow-up, corroborating persistent deficits in number processing. The present results are in line with the literature showing that children with DD have reduced gray and white matter volumes in the numerical network. Our study further sheds light on the trajectory of brain development, revealing that these known structural differences in the long association fibers and the adjacent regions of the temporal- and frontoparietal cortex persist in dyscalculic children from childhood into adolescence. In conclusion, our results underscore that DD is a persistent learning disorder accompanied by deficits in number processing and reduced gray and white matter volumes in number related brain areas.

Multimodal assessment shows misalignment of structural and functional thalamocortical connectivity in children and adolescents born very preterm.

Thalamocortical connections are altered following very preterm birth but it is unknown whether structural and functional alterations are linked and how they contribute to neurodevelopmental deficits. We used a multimodal approach in 27 very preterm and 35 term-born children and adolescents aged 10-16 years: Structural thalamocortical connectivity was quantified with two measures derived from probabilistic tractography of diffusion tensor data, namely the volume of thalamic segments with cortical connections and mean fractional anisotropy (FA) within the respective segments. High-density sleep EEG was recorded and sleep spindles were identified at each electrode. Sleep spindle density and integrated spindle activity (ISA) were calculated to quantify functional thalamocortical connectivity. In term-born participants, the volume of the global thalamic segment with cortical connections was strongly related to sleep spindles across the entire head (mean r â€‹= â€‹.53 â€‹± .10; range â€‹= â€‹0.35 to 0.78). Regionally, the volume of the thalamic segment connecting to frontal brain regions correlated with sleep spindle density in two clusters of electrodes over fronto-temporal brain regions (.42 â€‹± .06; 0.35 to 0.51 and 0.43 â€‹± .08; 0.35 to 0.62) and the volume of the thalamic segment connecting to parietal brain regions correlated with sleep spindle density over parietal brain regions (mean r â€‹= â€‹.43 â€‹± .07; 0.35 to 0.61). In very preterm participants, the volume of the thalamic segments was not associated with sleep spindles. In the very preterm group, mean FA within the global thalamic segment was negatively correlated with ISA over a cluster of frontal and temporo-occipital brain regions (mean r â€‹= â€‹-.53 â€‹± .07; -.41 to -.72). No association between mean FA and ISA was found in the term-born group. With this multimodal study protocol, we identified a potential misalignment between structural and functional thalamocortical connectivity in children and adolescents born very preterm. Eventually, this may shed further light on the neuronal mechanisms underlying neurodevelopmental sequelae of preterm birth.

Test-Retest Reliability of the Brain Metabolites GABA and Glx With JPRESS, PRESS, and MEGA-PRESS MRS Sequences in vivo at 3T.

BACKGROUND: The optimization of magnetic resonance spectroscopy (MRS) sequences allows improved diagnosis and prognosis of neurological and psychological disorders. Thus, to assess the test-retest and intersequence reliability of such MRS sequences in quantifying metabolite concentrations is of clinical relevance. PURPOSE: To evaluate the test-retest and intersequence reliability of three MRS sequences to estimate GABA and Glx = Glutamine+Glutamate concentrations in the human brain. STUDY TYPE: Prospective. SUBJECTS: Eighteen healthy participants were scanned twice (range: 1 day to 1 week between the two sessions) with identical protocols. FIELD STRENGTH/SEQUENCE: 3T using a 32-channel SENSE head coil in the PCC region; PRESS, JPRESS, and MEGA-PRESS sequences. ASSESSMENT: Metabolite concentrations were estimated using LCModel (for PRESS and MEGA-PRESS) and ProFit2 (for JPRESS). STATISTICAL TESTS: The test-retest reliability was evaluated by Wilcoxon signed-rank tests, Pearson's r correlation coefficients, intraclass-correlation coefficients (ICC), coefficients of variation (CV), and by Bland-Altman (BA) plots. The intersequence reliability was assessed with Wilcoxon signed-rank tests, Pearson's r correlation coefficients, and BA plots. RESULTS: For GABA, only the MEGA-PRESS sequence showed a moderate test-retest correlation (r = 0.54, ICC = 0.5, CV = 8.8%) and the BA plots indicated good agreement (P > 0.05) for all sequences. JPRESS provided less precise results and PRESS was insensitive to GABA. For Glx, the r and ICC values for PRESS (r = 0.87, ICC = 0.9, CV = 2.9%) and MEGA-PRESS (r = 0.70, ICC = 0.7, CV = 5.3%) reflect higher correlations, compared with JPRESS (r = 0.39, ICC = 0.4, CV = 20.1%). DATA CONCLUSION: MEGA-PRESS and JPRESS are suitable for the reliable detection of GABA, the first being more precise. The three sequences included in the study can measure Glx concentrations. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:1181-1191.

Interictal Hyperperfusion in the Higher Visual Cortex in Patients With Episodic Migraine.

BACKGROUND: Migraine pathophysiology is complex and probably involves cortical and subcortical alterations. Structural and functional brain imaging studies indicate alterations in the higher order visual cortex in patients with migraine. Arterial spin labeling magnetic resonance imaging (ASL-MRI) is a non-invasive imaging method for assessing changes in cerebral blood flow (CBF) in vivo. OBJECTIVE: To examine if interictal CBF differs between patients with episodic migraine (EM) with or without aura and healthy controls (HC). METHODS: We assessed interictal CBF using 2D pseudo-continuous ASL-MRI on a 3 Tesla Philips scanner (University Hospital Zurich, Switzerland) in EM (N = 17, mean age 32.7 ± 9.9, 13 females) and HC (N = 19, mean age 31.0 ± 9.3, 11 females). RESULTS: Compared to HC, EM showed exclusively hyperperfusion in the right MT+ and Cohen's d effect size was 0.99 (HC mean CBF ± SD: 33.1 ± 5.9 mL/100 g/minutes; EM mean CBF: 40.9 ± 9.4 mL/100 g/minutes). EM with aura (N = 13, MwA) revealed hyperperfusion compared to HC in the right MT+ and superior temporal gyrus. For MT, Cohen's d effect size was 1.34 (HC mean CBF ± SD: 33.1 ± 5.9 mL/100 g/minutes; MwA mean CBF: 43.3 ± 8.6 mL/100 g/minutes). For the superior temporal gyrus, Cohen's d effect size was 1.28 (HC mean CBF ± SD: 40.1 ± 4.9 mL/100 g/minutes; MwA mean CBF: 47.4 ± 6.4 mL/100 g/minutes). In EM, anxiety was positively associated with CBF in the parietal operculum and angular gyrus. CONCLUSIONS: Our results suggest that extrastriate brain regions probably involved in cortical spreading depression are associated with CBF changes in the interictal state. We conclude that ASL-MRI is a sensitive method to identify local neuro-functional abnormalities in CBF in patients with EM in the interictal state.

Total cerebrovascular blood flow and whole brain perfusion in children sedated using propofol with or without ketamine at induction: An investigation with 2D-Cine PC and ASL.

BACKGROUND: Multiple sedation regimes may be used to facilitate pediatric MRI scans. These regimes might affect cerebral blood flow and hemodynamics to varying degrees, particularly in children who may be vulnerable to anesthetic side effects. PURPOSE: To compare the effects of propofol monosedation solely (Pm group) vs. a combination of propofol and ketamine (KP group) on brain hemodynamics and perfusion. STUDY TYPE: Prospective double-blind randomized trial. FIELD STRENGTH/SEQUENCES: 1.5T and 3T. 2D-Cine phase contrast (2D-Cine PC) and pseudocontinuous arterial spin labeling (ASL). POPULATION: Children aged from 3 months to 10 years referred for MRI with deep sedation were randomized into either the KP or the Pm group. Perfusion images were acquired with ASL followed by single-slice 2D-Cine PC acquired between the cervical vertebra C2 and C3. ASSESSMENT: Average whole-brain perfusion (WBP ml.min-1 .100 ml-1 ) was extracted from the ASL perfusion maps and total cerebrovascular blood flow (CVF) was quantified by bilaterally summing the flow in the vertebral and the internal carotid arteries. The CVF values were converted to units of ml.min-1 .100 g-1 to calculate the tissue CVF100g (ml.min-1 .100 g-1 ). Images were assessed by a neuroradiologist and data from n = 81 (ASL) and n = 55 (PC) cases with no apparent pathology were entered into the analysis. STATISTICAL TESTS: Multivariate analysis of covariance was performed to compare drug sedation effects on WBP, CVF, and CVF100g . RESULTS: No significant difference in arterial flow was observed (P = 0.57), but the KP group showed significantly higher WBP than the Pm group, covarying for scanner and age (P = 0.003). A correlation analysis showed a significant positive correlation between mean WBP (ml.min-1 .100 g-1 ) and mean CVF100g . DATA CONCLUSION: The KP group showed higher perfusion but no significant difference in vascular flow compared with the Pm group. WBP and CVF100g correlated significantly, but ASL appeared to have more susceptibility to perfusion differences arising from the different sedation regimes. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;50:1433-1440.

Altered resting-state functional connectivity in children and adolescents born very preterm short title.

The formation of resting-state functional networks in infancy has been reported to be strongly impacted by very preterm birth. Studies in childhood and adolescence have largely focused on language processing networks and identified both decreased and increased functional connectivity. It is unclear, however, whether functional connectivity strength is altered globally in children and adolescents born very preterm and whether these alterations are related to the frequently occurring cognitive deficits. Here, resting-state functional MRI was assessed in a group of 32 school-aged children and adolescents born very preterm with normal intellectual and motor abilities and 39 healthy term-born peers. Functional connectivity within and between a comprehensive set of well-established resting-state networks was compared between the groups. IQ and executive function abilities were tested with standardized tasks and potential associations with connectivity strength were explored. Functional connectivity was weaker in the very preterm compared to the term-born group between the sensorimotor network and the visual and dorsal attention network, within the sensorimotor network and within the central executive network. In contrast, functional connectivity was stronger in the very preterm group between the sensorimotor network and parts of the salience and the central executive network. Little evidence was found that these alterations underlie lower IQ or poorer executive function abilities. This study provides evidence for a long-lasting impact of very preterm birth on the organization of resting-state networks. The potential consequence of these alterations for other neurodevelopmental domains than the ones investigated in the current study warrants further investigation.

Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children (EpoKids): protocol of a prospective follow-up study.

INTRODUCTION: Premature infants are particularly vulnerable to brain injuries with associated cognitive and behavioural deficits. The worldwide first randomised interventional multicentre trial investigating the neuroprotective effects of erythropoietin (entitled 'Does erythropoietin improve outcome in very preterm infants?' (NCT00413946)) included 450 very preterm infants in Switzerland. MRI at term equivalent age showed less white matter (WM) injury in the erythropoietin group compared with the placebo group. Despite these promising imaging findings, neurodevelopmental outcome at 2 years showed no beneficial effect of early erythropoietin. One explanation could be that the assessment of more complex cognitive functions such as executive functions (EFs) is only possible at a later age. We hypothesise that due to improved WM development and fewer WM injuries, children born preterm treated with early erythropoietin will have better EF abilities at 7-12 years than those treated with placebo. METHODS AND ANALYSIS: 365 children who were included into the primary analysis of the original trial (NCT00413946) will be eligible in this prospective follow-up study at the age of 7-12 years. 185 children born at term will be control children. Primary outcome measures are EF abilities and processing speed, while secondary outcomes are academic performance, IQ, fine motor abilities and global brain connectivity. A comprehensive test battery will be applied to assess EFs. MRI will be performed to assess global brain connectivity. Cognitive scores and MRI measures will be compared between both groups using the Wilcoxon test. Propensity score matching will be used to balance gender, age, socioeconomic status and other potentially unbalanced variables between the children born preterm and the healthy control children. ETHICS AND DISSEMINATION: The cantonal ethical committee granted ethical approval for this study (KEK 2017-00521). Written consent will be obtained from the parents. Findings from this study will be disseminated via international and national conference presentations and publications in peer-reviewed journals.

Functional hyperconnectivity vanishes in children with developmental dyscalculia after numerical intervention.

Developmental dyscalculia (DD) is a developmental learning disability associated with deficits in processing numerical and mathematical information. Although behavioural training can reduce these deficits, it is unclear which neuronal resources show a functional reorganization due to training. We examined typically developing (TD) children (N=16, mean age: 9.5 years) and age-, gender-, and handedness-matched children with DD (N=15, mean age: 9.5 years) during the performance of a numerical order task with fMRI and functional connectivity before and after 5-weeks of number line training. Using the intraparietal sulcus (IPS) as seed region, DD showed hyperconnectivity in parietal, frontal, visual, and temporal regions before the training controlling for age and IQ. Hyperconnectivity disappeared after training, whereas math abilities improved. Multivariate classification analysis of task-related fMRI data corroborated the connectivity results as the same group of TD could be discriminated from DD before but not after number line training (86.4 vs. 38.9%, respectively). Our results indicate that abnormally high functional connectivity in DD can be normalized on the neuronal level by intensive number line training. As functional connectivity in DD was indistinguishable to TD's connectivity after training, we conclude that training lead to a re-organization of inter-regional task engagement.

Age-dependent and -independent changes in attention-deficit/hyperactivity disorder (ADHD) during spatial working memory performance.

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) has been associated with spatial working memory as well as frontostriatal core deficits. However, it is still unclear how the link between these frontostriatal deficits and working memory function in ADHD differs in children and adults. This study examined spatial working memory in adults and children with ADHD, focussing on identifying regions demonstrating age-invariant or age-dependent abnormalities. METHODS: We used functional magnetic resonance imaging to examine a group of 26 children and 35 adults to study load manipulated spatial working memory in patients and controls. RESULTS: In comparison to healthy controls, patients demonstrated reduced positive parietal and frontostriatal load effects, i.e., less increase in brain activity from low to high load, despite similar task performance. In addition, younger patients showed negative load effects, i.e., a decrease in brain activity from low to high load, in medial prefrontal regions. Load effect differences between ADHD and controls that differed between age groups were found predominantly in prefrontal regions. Age-invariant load effect differences occurred predominantly in frontostriatal regions. CONCLUSIONS: The age-dependent deviations support the role of prefrontal maturation and compensation in ADHD, while the age-invariant alterations observed in frontostriatal regions provide further evidence that these regions reflect a core pathophysiology in ADHD.