The insula is a complex structure involved in a wide range of functions. Tracing studies on nonhuman primates reveal a wide array of cortical connections in the frontal (orbitofrontal and prefrontal ...cortices, cingulate areas and supplementary motor area), parietal (primary and secondary somatosensory cortices) and temporal (temporal pole, auditory, prorhinal and entorhinal cortices) lobes. However, recent human tractography studies have not observed connections between the insula and the cingulate cortices, although these structures are thought to be functionally intimately connected. In this work, we try to unravel the structural connectivity between these regions and other known functionally connected structures, benefiting from a higher number of subjects and the latest state-of-the-art high angular resolution diffusion imaging (HARDI) tractography algorithms with anatomical priors. By performing an HARDI tractography analysis on 46 young normal adults, our study reveals a wide array of connections between the insula and the frontal, temporal, parietal and occipital lobes as well as limbic regions, with a rostro-caudal organization in line with tracing studies in macaques. Notably, we reveal for the first time in humans a clear structural connectivity between the insula and the cingulate, parahippocampal, supramarginal and angular gyri as well as the precuneus and occipital regions.
A number of studies have characterized the changes in variability of brain signals with brain maturation from the perspective of considering the human brain as a complex system. Specifically, it has ...been shown that complexity of brain signals increases in development. On one hand, such an increase in complexity can be attributed to more specialized and differentiated brain regions able to express a higher repertoire of mental microstates. On the other hand, it can be explained by increased integration between widely distributed neuronal populations and establishment of new connections. The goal of this study was to see which of these two mechanisms is dominant, accounting for the previously observed increase in signal complexity. Using information-theoretic tools based on scalp-recorded EEG measurements, we examined the trade-off between local and distributed variability of brain signals in infants and children separated into age groups of 1-2, 2-8, 9-24, and 24-66 months old. We found that developmental changes were characterized by a decrease in the amount of information processed locally, with a peak in alpha frequency range. This effect was accompanied by an increase in the variability of brain signals processed as a distributed network. Complementary analysis of phase locking revealed an age-related pattern of increased synchronization in the lower part of the spectrum, up to the alpha rhythms. At the same time, we observed the desynchronization effects associated with brain development in the higher beta to lower gamma range.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neurodevelopmental disorders (NDDs) are mostly diagnosed around the age of 4-5 years, which is too late considering that the brain is most susceptive to interventions during the first two years of ...life. Currently, diagnosis of NDDs is based on observed behaviors and symptoms, but identification of objective biomarkers would allow for earlier screening. In this longitudinal study, we investigated the relationship between repetition and change detection responses measured using an EEG oddball task during the first year of life and at two years of age, and cognitive abilities and adaptive functioning during preschool years (4 years old). Identification of early biomarkers is challenging given that there is a lot of variability in developmental courses among young infants. Therefore, the second aim of this study is to assess whether brain growth is a factor of interindividual variability that influences repetition and change detection responses. To obtain variability in brain growth beyond the normative range, infants with macrocephaly were included in our sample. Thus, 43 normocephalic children and 20 macrocephalic children were tested. Cognitive abilities at preschool age were assessed with the WPPSI-IV and adaptive functioning was measured with the ABAS-II. Time-frequency analyses were conducted on the EEG data. Results indicated that repetition and change detection responses in the first year of life predict adaptive functioning at 4 years of age, independently of head circumference. Moreover, our findings suggested that brain growth explains variability in neural responses mostly in the first years of life, so that macrocephalic children did not display repetition suppression responses, while normocephalic children did. This longitudinal study demonstrates that the first year of life is an important period for the early screening of children at risk of developing NDDs.
Developmental coordination disorder (DCD) is a neurodevelopmental disorder affecting primarily motor skills, but attentional and executive impairments are common in affected individuals. Moreover, ...the presence of neurodevelopmental comorbidities is frequent in this population, which certainly influences the cognitive profile of the children concerned. Previous studies have reported deficits in visuospatial/nonverbal and planning tasks. This systematic review of the literature aims to determine if impairments can be found in other attentional and executive functions as well. The type of cognitive tasks, the tasks' modality (verbal/nonverbal), and the influence of comorbid disorders on attentional and executive profiles are systematically considered. Forty-one studies were identified through the PubMed/Medline and PsycINFO databases according to pre-established eligibility criteria. The results reveal weaknesses in inhibitory control, working memory, planning, nonverbal fluency, and general executive functioning in children with DCD. The presence of comorbid disorders seemingly contributes to the verbal working memory difficulties findings. This review contributes to a better understanding of the cognitive impairments in DCD and of the needs of children with this disorder, allowing to optimize practitioners' therapeutic interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Mutations in the GATOR1 complex genes, DEPDC5 and NPRL3, play a major role in the development of lesional and non-lesional focal epilepsy through increased mTORC1 signalling. We aimed to assess the ...effects of mTORC1 hyperactivation on GABAergic inhibitory circuits, in 3 and 5 individuals carrying DEPDC5 and NPRL3 mutations respectively using a multimodal approach including transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy (MRS), and electroencephalography (EEG).
Inhibitory functions probed by TMS and MRS showed no effect of mutations on cortical GABAergic receptor-mediated inhibition and GABA concentration, in both cortical and subcortical regions. However, stronger EEG theta oscillations and stronger and more synchronous gamma oscillations were observed in DEPDC5 and NPRL3 mutations carriers.
These results suggest that DEPDC5 and NPRL3-related epileptic mTORopathies may not directly modulate GABAergic functions but are nonetheless characterized by a stronger neural entrainment that may be reflective of a cortical hyperexcitability mediated by increased mTORC1 signaling.
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.
•We used TMS and MRS to investigate GABA function in patients with NF1 and FXS.•NF1 and FXS patients show reduced GABA concentration levels.•Several TMS measures correlate with Glx levels assessed with MRS.•There is a partial overlap in GABA alterations in NF1 and FXS.
Sub-cortical brain structure segmentation using F-CNN'S Shakeri, Mahsa; Tsogkas, Stavros; Ferrante, Enzo ...
2016 IEEE 13th International Symposium on Biomedical Imaging (ISBI),
04/2016
Conference Proceeding, Journal Article
Odprti dostop
In this paper we propose a deep learning approach for segmenting sub-cortical structures of the human brain in Magnetic Resonance (MR) image data. We draw inspiration from a state-of-the-art ...Fully-Convolutional Neural Network (F-CNN) architecture for semantic segmentation of objects in natural images, and adapt it to our task. Unlike previous CNN-based methods that operate on image patches, our model is applied on a full blown 2D image, without any alignment or registration steps at testing time. We further improve segmentation results by interpreting the CNN output as potentials of a Markov Random Field (MRF), whose topology corresponds to a volumetric grid. Alpha-expansion is used to perform approximate inference imposing spatial volumetric homogeneity to the CNN priors. We compare the performance of the proposed pipeline with a similar system using Random Forest-based priors, as well as state-of-art segmentation algorithms, and show promising results on two different brain MRI datasets.
Acute lymphoblastic leukemia (ALL) stands as the most prevalent form of pediatric cancer in North America, with a current five-year survival rate of 85%. While more children achieved ALL remission ...and transition into adulthood, the prevalence of long-term treatment-related effects, especially neurocognitive sequelae, remains significant. This study pursues two objectives. Firstly, it investigates if Magnetization Transfer Ratio (MTR), a method assessing myelin integrity, is sensitive to white matter (WM) microstructural changes in long-term ALL survivors and whether these relate to cognitive impairments. Secondly, it examines the dose-related effects of chemotherapy agents on the MTR and its relationship to other risk factors such as female sex, early age diagnosis, and cranial radiotherapy. Magnetization transfer imaging was utilized to assess WM integrity in 35 survivors at a mean of 18.9 years after the onset of ALL (range since diagnosis: 6.9-26.8). Additionally, 21 controls matched for age, sex, and education level, with no history of cancer, were included. MTR was extracted from both the entire brain's WM and the corpus callosum through semi-automated procedures. The results indicated lower MTR means in survivors, which is linked to cognitive function. Negative associations between MTR means and intrathecal agents' (MTX, cytarabine, and hydrocortisone) cumulative doses received were highlighted. This study offers valuable insights into the connections between myelin deterioration, cognitive impairment, and the implications of IT chemotherapy, enhancing our understanding of ALL survivorship dynamics. It underscores MTR's relevance in monitoring neurotoxicity during oncological drug follow-up examinations.
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