Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions.

Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks. We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behaviour. We processed nine resting-state functional MRI datasets including 32 726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism and fluid intelligence as well as four idiopathic psychiatric conditions. Nine out of 19 pairs of conditions and traits showed significant functional connectivity correlations (rFunctional connectivity), which could be explained by previously published levels of genomic (rGenetic) and transcriptomic (rTranscriptomic) correlations with moderate to high concordance: rGenetic-rFunctional connectivity = 0.71 [0.40-0.87] and rTranscriptomic-rFunctional connectivity = 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms-amenable to intervention-across psychiatric conditions and genetic risks.

Inter-individual variability during neurodevelopment: an investigation of linear and nonlinear resting-state EEG features in an age-homogenous group of infants.

Electroencephalography measures are of interest in developmental neuroscience as potentially reliable clinical markers of brain function. Features extracted from electroencephalography are most often averaged across individuals in a population with a particular condition and compared statistically to the mean of a typically developing group, or a group with a different condition, to define whether a feature is representative of the populations as a whole. However, there can be large variability within a population, and electroencephalography features often change dramatically with age, making comparisons difficult. Combined with often low numbers of trials and low signal-to-noise ratios in pediatric populations, establishing biomarkers can be difficult in practice. One approach is to identify electroencephalography features that are less variable between individuals and are relatively stable in a healthy population during development. To identify such features in resting-state electroencephalography, which can be readily measured in many populations, we introduce an innovative application of statistical measures of variance for the analysis of resting-state electroencephalography data. Using these statistical measures, we quantified electroencephalography features commonly used to measure brain development-including power, connectivity, phase-amplitude coupling, entropy, and fractal dimension-according to their intersubject variability. Results from 51 6-month-old infants revealed that the complexity measures, including fractal dimension and entropy, followed by connectivity were the least variable features across participants. This stability was found to be greatest in the right parietotemporal region for both complexity feature, but no significant region of interest was found for connectivity feature. This study deepens our understanding of physiological patterns of electroencephalography data in developing brains, provides an example of how statistical measures can be used to analyze variability in resting-state electroencephalography in a homogeneous group of healthy infants, contributes to the establishment of robust electroencephalography biomarkers of neurodevelopment through the application of variance analyses, and reveals that nonlinear measures may be most relevant biomarkers of neurodevelopment.

Impact of Macrocephaly, as an Isolated Trait, on EEG Signal as Measured by Spectral Power and Multiscale Entropy during the First Year of Life.

Macrocephaly has been associated with neurodevelopmental disorders; however, it has been mainly studied in the context of pathological or high-risk populations and little is known about its impact, as an isolated trait, on brain development in general population. Electroencephalographic (EEG) power spectral density (PSD) and signal complexity have shown to be sensitive to neurodevelopment and its alterations. We aimed to investigate the impact of macrocephaly, as an isolated trait, on EEG signal as measured by PSD and multiscale entropy during the first year of life. We recorded high-density EEG resting-state activity of 74 healthy full-term infants, 50 control (26 girls), and 24 macrocephalic (12 girls) aged between 3 and 11 months. We used linear regression models to assess group and age effects on EEG PSD and signal complexity. Sex and brain volume measures, obtained via a 3D transfontanellar ultrasound, were also included into the models to evaluate their contribution. Our results showed lower PSD of the low alpha (8-10 Hz) frequency band and lower complexity in the macrocephalic group compared to the control group. In addition, we found an increase in low alpha (8.5-10 Hz) PSD and in the complexity index with age. These findings suggest that macrocephaly as an isolated trait has a significant impact on brain activity during the first year of life.

Sensory processing dysregulations as reliable translational biomarkers in SYNGAP1 haploinsufficiency.

Amongst the numerous genes associated with intellectual disability, SYNGAP1 stands out for its frequency and penetrance of loss-of-function variants found in patients, as well as the wide range of co-morbid disorders associated with its mutation. Most studies exploring the pathophysiological alterations caused by Syngap1 haploinsufficiency in mouse models have focused on cognitive problems and epilepsy; however, whether and to what extent sensory perception and processing are altered by Syngap1 haploinsufficiency is less clear. By performing EEG recordings in awake mice, we identified specific alterations in multiple aspects of auditory and visual processing, including increased baseline gamma oscillation power, increased theta/gamma phase amplitude coupling following stimulus presentation and abnormal neural entrainment in response to different sensory modality-specific frequencies. We also report lack of habituation to repetitive auditory stimuli and abnormal deviant sound detection. Interestingly, we found that most of these alterations are present in human patients as well, thus making them strong candidates as translational biomarkers of sensory-processing alterations associated with SYNGAP1/Syngap1 haploinsufficiency.

Developmental course of the repetition effect and change detection responses from infancy through childhood: a longitudinal study.

Neuronal repetition effect (repetition suppression and repetition enhancement) and change detection responses are fundamental brain responses that have implications in learning and cognitive development in infants and children. Studies have shown altered neuronal repetition and change detection responses in various clinical populations. However, the developmental course of these neuronal responses from infancy through childhood is still unknown. Using an electroencephalography oddball task, we investigate the developmental peculiarities of repetition effect and change detection responses in 43 children that we followed longitudinally from 3 months to 4 years of age. Analyses were conducted on theta (3-5 Hz), alpha (5-10 Hz), and beta (10-30 Hz) time-frequency windows. Results indicated that in the theta time-frequency window, in frontocentral and frontal regions of the brain, repetition and change detection responses followed a U-shaped pattern from 3 months to 4 years of age. Moreover, the change detection response was stronger in young infants compared to older children in frontocentral regions, regardless of the time-frequency window. Our findings add to the evidence of top-down modulation of perceptual systems in infants and children.

Electroencephalography signals and neurodevelopment after Kawasaki disease: A pilot study.

BACKGROUND: Acute Kawasaki disease (KD) induces central nervous system inflammation and excessive irritability. Long-term impacts on children's neurodevelopment have only been studied marginally. This pilot study aimed to describe the neuropsychological profile of primary school-aged children with a history of KD and to explore the impacts of KD on electroencephalography (EEG) markers associated with attention and brain maturation. METHODS: Fifteen children (8.8 ± 2.5 years) were recruited 4.9 ± 2.7 years after KD onset. Intellectual abilities, long-term memory, and auditory sustained attention were evaluated. Parents completed standardized questionnaires assessing (1) executive functioning; (2) internalizing and externalizing difficulties; (3) attention deficit hyperactivity disorder symptoms; and (4) autism spectrum disorder symptoms. Theta/beta ratio (TBR) and alpha peak (AP) were extracted from resting-state EEG and compared with 32 controls (8.9 ± 2.1 years). The alpha band was analyzed using a feature reduction algorithm to detect potential groupings. RESULTS: Performances showed preserved intellectual abilities and memory. Sustained attention performance was within the lower range for 4/14 participants (29%), with considerable parental reports of inattention (43%), working memory difficulties (50%), and hyperactivity-impulsivity (36%). No alterations in the TBR were found but the KD group presented a significantly lower AP amplitude ratio. A clear separation of KD cohort into two clusters showed that acute irritability is associated with a weaker AP. CONCLUSIONS: Despite overall preserved cognitive functions, there is a possible association between KD and attention deficit concerns. This first EEG-based study indicates alpha peak abnormality after KD, predominantly in children with acute irritability. Longitudinal studies are warranted to better characterize patients' neurodevelopmental trajectory.

Contribution of Fatigue to Cognitive Dysfunction in Childhood Acute Lymphoblastic Leukemia Survivors.

Late effects such as neurocognitive issues and fatigue have been reported in childhood acute lymphoblastic leukemia (cALL) survivors. Yet, their association is often poorly understood. In this study, we wished to (1) describe neurocognitive difficulties and fatigue in a well-characterized cohort of long-term cALL survivors and (2) explore the risk of having neurocognitive deficits as a function of fatigue. Childhood ALL survivors (N = 285) from three Canadian treatment centers completed the DIVERGT battery of cognitive tests and the PedsQL Multidimensional Fatigue Scale. We performed logistic regressions to assess the risk of a survivor to show cognitive deficits (<2.0 SD) depending on their fatigue levels. At least one cognitive deficit on the DIVERGT was present in 31% of participants. Domains primarily affected were working memory, fine motor skills, and verbal fluency. Sleep/rest fatigue in youths was higher than norms (d = 0.35). The risk for cognitive deficits increased independently with levels of fatigue in the domains of cognitive speed and flexibility, working memory, and verbal fluency. For every 10-point increase on general or sleep/rest fatigue on the 0-100 scale, there was a median +23-35% risk of showing a deficit among the 7 tasks significantly associated with fatigue. Fatigue may constitute a complementary target when searching to mitigate cognitive issues in this population.

Multimodal assessment of the GABA system in patients with fragile-X syndrome and neurofibromatosis of type 1.

Fragile-X syndrome (FXS) and Neurofibromatosis of type 1 (NF-1) are two monogenic disorders sharing neurobehavioral symptoms and pathophysiological mechanisms. Namely, preclinical models of both conditions show overactivity of the mTOR signaling pathway as well as GABAergic alterations. However, despite its potential clinical relevance for these disorders, the GABAergic system has not been systematically studied in humans. In the present study, we used an extensive transcranial magnetic stimulation (TMS) assessment battery in combination with magnetic resonance spectroscopy (MRS) to provide a comprehensive picture of the main inhibitory neurotransmitter system in patients with FXS and NF1. Forty-three participants took part in the TMS session (15 FXS, 10 NF1, 18 controls) and 36 in the MRS session (11 FXS, 14 NF1, 11 controls). Results show that, in comparison to healthy control participants, individuals with FXS and NF1 display lower GABA concentration levels as measured with MRS. TMS result show that FXS patients present increased GABAB-mediated inhibition compared to controls and NF1 patients, and that GABAA-mediated intracortical inhibition was associated with increased excitability specifically in the FXS groups. In line with previous reports, correlational analyses between MRS and TMS measures did not show significant relationships between GABA-related metrics, but several TMS measures correlated with glutamate+glutamine (Glx) levels assessed with MRS. Overall, these results suggest a partial overlap in neurophysiological alterations involving the GABA system in NF1 and FXS, and support the hypothesis that MRS and TMS assess different aspects of the neurotransmitter systems.

Conditional canonical correlation estimation based on covariates with random forests.

MOTIVATION: Investigating the relationships between two sets of variables helps to understand their interactions and can be done with canonical correlation analysis (CCA). However, the correlation between the two sets can sometimes depend on a third set of covariates, often subject-related ones such as age, gender or other clinical measures. In this case, applying CCA to the whole population is not optimal and methods to estimate conditional CCA, given the covariates, can be useful. RESULTS: We propose a new method called Random Forest with Canonical Correlation Analysis (RFCCA) to estimate the conditional canonical correlations between two sets of variables given subject-related covariates. The individual trees in the forest are built with a splitting rule specifically designed to partition the data to maximize the canonical correlation heterogeneity between child nodes. We also propose a significance test to detect the global effect of the covariates on the relationship between two sets of variables. The performance of the proposed method and the global significance test is evaluated through simulation studies that show it provides accurate canonical correlation estimations and well-controlled Type-1 error. We also show an application of the proposed method with EEG data. AVAILABILITY AND IMPLEMENTATION: RFCCA is implemented in a freely available R package on CRAN (https://CRAN.R-project.org/package=RFCCA). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genome-wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability.

Genomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs > 50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.

Screening for distress in pediatric cancer survivors: A systematic comparison of one-step and two-step strategies to minimize detection errors.

BACKGROUND: Childhood cancer survivors should be routinely screened for psychological distress. However, existing screening tools promoted by cancer care institutions, such as the Distress Thermometer (DT) generate high rates of errors. The aim of this study is to help refining strategies of screening psychological distress in this population by exploring two-step methods combining the DT on step #1 with one question on step #2. PROCEDURE: Data from 255 survivors of childhood acute lymphoblastic leukemia aged 13-40 years were analyzed (38% 13-18 years, 62% 19+ years, 53% females). We used the DT on step #1 and the individual emotion items from the Pediatric Quality of Life Questionnaire (PedsQL) on step #2, to detect distress, depression and anxiety as measured by standard instruments. We compared sensitivity, specificity, negative and positive predictive values, Youden index, and clinical utility indices, in newly developed two-step strategies. RESULTS: The best two-step strategies to screen anxious-depressive distress were DT ≥ 2 on step #1, with the item of Sadness on step #2, and DT ≥ 2 combined with the item of Concerns. Two-step strategies outperformed the DT alone on the correct identification of distressed survivors. However, two-step strategies did not outperform the DT used alone on the correct detection of no distressed survivors. Results were similar when predicting depression or anxiety alone. CONCLUSION: Completing the DT with one single question on emotions from the PedsQL may minimize the number of participants falsely identified as distressed, which could be particularly pertinent in resource-limited clinics.

Infant repetition effects and change detection: Are they related to adaptive skills?

Repetition effects and change detection response have been proposed as neuro-electrophysiological correlates of fundamental learning processes. As such, they could be a good predictor of brain maturation and cognitive development. We recorded high density EEG in 71 healthy infants (32 females) aged between 3 and 9 months, while they listened to vowel sequences (standard /a/a/a/i/ [80%] and deviant /a/a/a/a/ [20%]). Adaptive skills, a surrogate of cognitive development, were measured via the parent form of the Adaptive Behavior Assessment System Second Edition (ABAS-II). Cortical auditory-evoked potentials (CAEPs) analyses, time-frequency analyses and a statistical approach using linear mixed models (LMMs) and linear regression models were performed. Age and adaptive skills were tested as predictors. Age modulation of repetition effects and change detection response was observed in theta (3-5 Hz), alpha (5-10 Hz) and high gamma (80-90 Hz) oscillations and in all CAEPs. Moreover, adaptive skills modulation of repetition effects was evidenced in theta (3-5 Hz), high gamma oscillations (80-90 Hz), N250/P350 peak-to-peak amplitude and P350 latency. Finally, adaptive skills modulation of change detection response was observed in the N250/P350 peak-to-peak amplitude. Our results confirm that repetition effects and change detection response evolve with age. Moreover, our results suggest that repetition effects and change detection response vary according to adaptive skills displayed by infants during the first year of life, demonstrating their predictive value for neurodevelopment.

Nurturing and quiet intervention (NeuroN-QI) on preterm infants' neurodevelopment and maternal stress and anxiety: A pilot randomized clinical trial protocol.

OBJECTIVES: Primary objective of this pilot study is to evaluate the feasibility and acceptability of the NeuroN-QI and the study procedures. Secondary objectives are to assess the feasibility and acceptability of the NeuroN-QI by the nurses, assess the nurses' training needs about the components of the NeuroN-QI, and estimate the preliminary effects of the NeuroN-QI on infants' neurodevelopment as well as maternal stress and anxiety at infants' 36 weeks of gestational age. DESIGN: A two-group pilot parallel randomized clinical trial stratified by center. METHODS: The pilot study will be conducted in two neonatal intensive care units (NICUs). A sample of 24 mother-infant dyads born between 26 and 316/7 gestational age will be randomized into an experimental or control group. Fifty nurses will be recruited. The NeuroN-QI consists of four 2-hour skin-to-skin contact sessions/week with a 15-minute auditory stimulation by mothers with controlled ambient levels of light and noise. A 1-hour quiet period will follow where infants will rest in their incubator/crib with their mother's milk for olfactory stimulation and where the light and noise control will be continued. In the control group, mother-infant dyads will do four skin-to-skin contacts per week and receive standard care. Acceptability and feasibility of the NeuroN-QI in addition to maternal stress and anxiety will be measured through questionnaires, while infants' neurodevelopment will be assessed with Assessment of Preterm Infant Behaviour and General Movement Assessment. CONCLUSIONS: This pilot trial will address knowledge gaps and generate evidence in neonatal care by evaluating the feasibility and acceptability of a multi-component developmental care intervention. IMPACT: This project is an innovative step towards optimizing the neurodevelopmental trajectory of infants in NICUs and consequently promoting their long-term health outcomes. TRIAL REGISTRATION: NCT04593095.

Inconsistencies between measures of cognitive dysfunction in childhood acute lymphoblastic leukemia survivors: Description and understanding.

OBJECTIVES: The frequency of cognitive difficulties in childhood cancer survivors varies according to the measurement strategy. The goal of this research is to (a) describe agreements and differences between measures of working memory and attention (b) identify contributors of these differences, such as emotional distress, affects, and fatigue. METHODS: We used data available for 138 adults successfully treated for childhood acute lymphoblastic leukemia (ALL) (PETALE cohort). Working memory and attention were assessed using subtests from the WAIS-IV and self-reported questionnaires (BRIEF-SR and CAARS-S:L). Potential contributors included emotional distress, anxiety, depression (BSI-18), affects (PANAS), and fatigue (PedsQL-MFS). We explored measurement agreements and differences using diagnostic indices and multivariate regression models. RESULTS: The frequencies of working memory and attention deficits were higher when using cognitive tests (15%-21%) than with self-reports (10%-11%). Self-reported questionnaires showed high specificity (median 0.87) and low sensitivity (median 0.10), suggesting they did not reliably identify positive cases on cognitive tests. We identified negative affectivity as a possible contributor to inconsistencies between self-report and test results. CONCLUSIONS: When measuring working memory and attention in childhood ALL survivors, cognitive test results and self-reports should not be considered equivalent. At best, self-report may be used for screening (high specificity), but not to assess prevalence in large samples. Self-reported difficulties are also probably influenced by the negative mood in this population.

The effect of cardiorespiratory fitness and physical activity levels on cognitive functions in survivors of childhood acute lymphoblastic leukemia.

Introduction. Most childhood acute lymphoblastic leukemia (ALL) survivors develop chronic treatment-related adverse effects several years after the end of the treatment. Regular physical activity and a good cardiorespiratory fitness can decrease the risks of neurological disturbances and increase cognitive function scores. The aim of this study was to examine the effect of good cardiorespiratory fitness and physical activity levels on cognitive functions.Methods. We enrolled 219 survivors of childhood ALL. The participants underwent a cardiopulmonary exercise test, neuropsychological tests of executive functions (i.e. verbal fluency, cognitive flexibility, working memory, processing speed) and completed a physical activity questionnaire. We calculated the odds ratio to obtain the preventive fraction of physical activity and cardiorespiratory fitness levels on cognitive functions.Results. The cohort is 52% male and 48% female. A total of 182 survivors (83%) have a cardiorespiratory fitness below their predicted (<100%). Our analyses show that there is an association between good cardiorespiratory fitness and processing speed (preventive fraction of 70% for dominant hand (p < 0.01) and 65% for non-dominant hand (p < 0.01)) and with cognitive flexibility identified as the category switching measure of the D-KEFS verbal fluency (preventive fraction of 61%; p < 0.05).Conclusion. Good cardiorespiratory fitness and good levels of physical activity were associated to a preventive fraction for most cognitive function parameters measured. Good cardiorespiratory fitness levels were significantly associated with a lower prevalence of deficits in processing speed (i.e., dominant hand and non-dominant hand) and in cognitive flexibility (i.e., category switching) in childhood acute lymphoblastic leukemia survivors.

Impact of visual and auditory deprivation on speech perception and production in adults.

Speech perception relies on auditory and visual cues and there are strong links between speech perception and production. We aimed to evaluate the role of auditory and visual modalities on speech perception and production in adults with impaired hearing or sight versus those with normal hearing and sight. We examined speech perception and production of three isolated vowels (/i/, /y/, /u/), which were selected based on their different auditory and visual perceptual saliencies, in 12 deaf adults who used one or two cochlear implants (CIs), 14 congenitally blind adults, and 16 adults with normal sight and hearing. The results showed that the deaf adults who used a CI had worse vowel identification and discrimination perception and they also produced vowels that were less typical or precise than other participants. They had different tongue positions in speech production, which possibly partly explains the poorer quality of their spoken vowels. Blind individuals had larger lip openings and smaller lip protrusions for the rounded vowel and unrounded vowels, compared to the other participants, but they still produced vowels that were similar to those produced by the adults with normal sight and hearing. In summary, the deaf adults, even though they used CIs, had greater difficulty in producing accurate vowel targets than the blind adults, whereas the blind adults were still able to produce accurate vowel targets, even though they used different articulatory strategies.

Visual short-term memory activation patterns in adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Treatments against ALL might lead to later cognitive effects and alterations in brain structure in survivors but to the authors' knowledge the observed variability in the severity of neurocognitive deficits is not fully understood. The objective of the current study was to investigate abnormalities in visual short-term memory (VSTM) brain activation in survivors of childhood ALL using magnetoencephalography. METHODS: A VSTM task was completed by 40 survivors of ALL and 26 controls. VSTM capacity (Cowan K) and brain activation were assessed during the retention period of the task (400-1400 milliseconds) using a standard minimum norm source localization method. RESULTS: Performance (Cowan K) was found to be similar between survivors of ALL and controls. Atypical brain activation was found in survivors of ALL during the task, including overactivation of regions usually involved in VSTM (lateral occipital, precentral gyrus, and postcentral gyrus), recruitment of regions that typically are not involved in VSTM (superior/middle temporal gyrus and supramarginal gyrus), and lower activation of frontal brain regions (inferior frontal gyrus). These patterns of activation were modulated by the age at the time of cancer onset (P = .01) because activity was found to be reduced in participants who were younger at diagnosis. CONCLUSIONS: The results of the current study suggest a pattern of neural inefficiency and compensatory activity during VSTM in survivors of ALL.

A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01.

BACKGROUND: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. METHODS: The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. DISCUSSION: Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

Febrile seizures and increased stress sensitivity in children: How it relates to seizure characteristics.

BACKGROUND: Studies suggest that the relationship between seizures and stress starts early in life. However, evidence of long-term altered stress reactivity following early-life seizures is lacking. Our objectives were to assess alterations in stress hormone reactivity in children with past febrile seizures (FS) and investigate how these alterations relate to clinical characteristics. METHOD: This case-control study compared a convenience sample of children with simple FS (n = 24), complex FS (n = 18), and matched healthy controls (n = 42). Stress was induced by electrode placement for an electroencephalography (EEG) exam. Salivary cortisol to stress, using three samples collected before and after the stressor, was compared between groups and sex. The relationship between stress reactivity and clinical characteristics (i.e., FS duration, age at first FS, time since the last FS) was investigated. RESULTS: Cortisol reactivity to stress was significantly different depending on study groups, F(1, 78) = 6.415, p = 0.003, η2p = 0.141, but not sex nor was there a significant interaction between group and sex (p ≥ 0.581). Participants with simple FS showed higher cortisol reactivity to stress (M = 14.936, Standard deviation (SD) = 26.852) compared with those with complex FS (M = -4.663, SD = 18.649, p = 0.015) and controls (M = -3.817, SD = 18.907, p = 0.003). There was no significant difference between participants with complex FS and controls (p > 0.999). Stress reactivity was not linked to clinical characteristics. CONCLUSIONS: Children with past simple FS showed greater changes in salivary cortisol following stress, suggesting enhanced stress sensitivity. As similar results were not found in a population with complex FS, our study shows that stress alterations are not caused by seizure severity. Future studies are needed to investigate whether stress sensitivity may be premorbid to simple FS and may contribute to simple FS incidence.