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Journal of Neuroscience Methods Feb 2016Malformations of cortical development constitute a variety of pathological brain abnormalities that commonly cause severe, medically-refractory epilepsy, including focal... (Review)
Review
Malformations of cortical development constitute a variety of pathological brain abnormalities that commonly cause severe, medically-refractory epilepsy, including focal lesions, such as focal cortical dysplasia, heterotopias, and tubers of tuberous sclerosis complex, and diffuse malformations, such as lissencephaly. Although some cortical malformations result from environmental insults during cortical development in utero, genetic factors are increasingly recognized as primary pathogenic factors across the entire spectrum of malformations. Genes implicated in causing different cortical malformations are involved in a variety of physiological functions, but many are focused on regulation of cell proliferation, differentiation, and neuronal migration. Advances in molecular genetic methods have allowed the engineering of increasingly sophisticated animal models of cortical malformations and associated epilepsy. These animal models have identified some common mechanistic themes shared by a number of different cortical malformations, but also revealed the diversity and complexity of cellular and molecular mechanisms that lead to the development of the pathological lesions and resulting epileptogenesis.
Topics: Animals; Animals, Genetically Modified; Cerebral Cortex; Disease Models, Animal; Epilepsy; Freezing; Genetic Engineering; Genetic Predisposition to Disease; Malformations of Cortical Development; Mice; Nerve Net; Rats; Rodentia; Species Specificity
PubMed: 25911067
DOI: 10.1016/j.jneumeth.2015.04.007 -
Acta Neuropathologica Communications Mar 2023Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the...
Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.
Topics: Humans; Nervous System Malformations; Malformations of Cortical Development, Group I; Brain; Brain Neoplasms; Focal Cortical Dysplasia
PubMed: 36864519
DOI: 10.1186/s40478-023-01532-x -
Journal of Magnetic Resonance Imaging :... Sep 2021
Topics: Humans; Magnetic Resonance Imaging; Malformations of Cortical Development; Neocortex; Neuroimaging
PubMed: 33890322
DOI: 10.1002/jmri.27644 -
Neuropathology and Applied Neurobiology Feb 2018Over the last decade, there has been increasing evidence that hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is a hallmark of malformations of... (Review)
Review
Over the last decade, there has been increasing evidence that hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is a hallmark of malformations of cortical development such as focal cortical dysplasia (FCD) or hemimegalencephaly. The mTOR pathway governs protein and lipid synthesis, cell growth and proliferation as well as metabolism and autophagy. The molecular genetic aetiology of mTOR hyperactivation has only been recently clarified. This article will review the current and still evolving genetic advances in the elucidation of the molecular basis of FCD. Activating somatic mutations in the MTOR gene are to date the most frequent mutations found in FCD brain specimens.
Topics: Epilepsy; Humans; Malformations of Cortical Development, Group I; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 29359340
DOI: 10.1111/nan.12463 -
CNS Neuroscience & Therapeutics Feb 2015Cortical dysplasia (CD) is a neurodevelopmental disorder due to aberrant cell proliferation and differentiation. Advances in neuroimaging have proven effective in early... (Review)
Review
Cortical dysplasia (CD) is a neurodevelopmental disorder due to aberrant cell proliferation and differentiation. Advances in neuroimaging have proven effective in early identification of the more severe lesions and timely surgical removal to treat epilepsy. However, the exact mechanisms of epileptogenesis are not well understood. This review examines possible mechanisms based on anatomical and electrophysiological studies. CD can be classified as CD type I consisting of architectural abnormalities, CD type II with the presence of dysmorphic cytomegalic neurons and balloon cells, and CD type III which occurs in association with other pathologies. Use of freshly resected brain tissue has allowed a better understanding of basic mechanisms of epileptogenesis and has delineated the role of abnormal cells and synaptic activity. In CD type II, it was demonstrated that balloon cells do not initiate epileptic activity, whereas dysmorphic cytomegalic and immature neurons play an important role in generation and propagation of epileptic discharges. An unexpected finding in pediatric CD was that GABA synaptic activity is not reduced, and in fact, it may facilitate the occurrence of epileptic activity. This could be because neuronal circuits display morphological and functional signs of dysmaturity. In consequence, drugs that increase GABA function may prove ineffective in pediatric CD. In contrast, drugs that counteract depolarizing actions of GABA or drugs that inhibit the mammalian target of rapamycin (mTOR) pathway could be more effective.
Topics: Animals; Brain; Epilepsy; Humans; Malformations of Cortical Development, Group II; Neurons; Signal Transduction; Sirolimus; gamma-Aminobutyric Acid
PubMed: 25404064
DOI: 10.1111/cns.12345 -
Brain : a Journal of Neurology Nov 2022One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle...
One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.
Topics: Humans; Retrospective Studies; Malformations of Cortical Development; Epilepsy; Magnetic Resonance Imaging; Machine Learning; Epilepsies, Partial
PubMed: 35953082
DOI: 10.1093/brain/awac224 -
Biomedical Engineering Online Feb 2020Focal cortical dysplasia (FCD) is a neuronal migration disorder and is a major cause of drug-resistant epilepsy. However, many focal abnormalities remain undetected...
BACKGROUND
Focal cortical dysplasia (FCD) is a neuronal migration disorder and is a major cause of drug-resistant epilepsy. However, many focal abnormalities remain undetected during routine visual inspection, and many patients with histologically confirmed FCD have normal fluid-attenuated inversion recovery (FLAIR-negative) images. The aim of this study was to quantitatively evaluate the changes in cortical thickness with magnetic resonance (MR) imaging of patients to identify FCD lesions from FLAIR-negative images.
METHODS
We first used the three-dimensional (3D) Laplace method to calculate the cortical thickness for individuals and obtained the cortical thickness mean image and cortical thickness standard deviation (SD) image based on all 32 healthy controls. Then, a cortical thickness extension map was computed by subtracting the cortical thickness mean image from the cortical thickness image of each patient and dividing the result by the cortical thickness SD image. Finally, clusters of voxels larger than three were defined as the FCD lesion area from the cortical thickness extension map.
RESULTS
The results showed that three of the four lesions that occurred in non-temporal areas were detected in three patients, but the detection failed in three patients with lesions that occurred in the temporal area. The quantitative analysis of the detected lesions in voxel-wise on images revealed the following: specificity (99.78%), accuracy (99.76%), recall (67.45%), precision (20.42%), Dice coefficient (30.01%), Youden index (67.23%) and area under the curve (AUC) (83.62%).
CONCLUSION
Our studies demonstrate an effective method to localize lesions in non-temporal lobe regions. This novel method automatically detected FCD lesions using only FLAIR-negative images from patients and was based only on cortical thickness feature. The method is noninvasive and more effective than a visual analysis for helping doctors make a diagnosis.
Topics: Adult; Brain; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Malformations of Cortical Development
PubMed: 32087703
DOI: 10.1186/s12938-020-0757-8 -
Scientific Reports Aug 2023Focal cortical dysplasia (FCD) is a brain malformation that causes medically refractory epilepsy. FCD is classified into three categories based on structural and...
Focal cortical dysplasia (FCD) is a brain malformation that causes medically refractory epilepsy. FCD is classified into three categories based on structural and cellular abnormalities, with FCD type II being the most common and characterized by disrupted organization of the cortex and abnormal neuronal development. In this study, we employed cell-type deconvolution and single-cell signatures to analyze bulk RNA-seq from multiple transcriptomic studies, aiming to characterize the cellular composition of brain lesions in patients with FCD IIa and IIb subtypes. Our deconvolution analyses revealed specific cellular changes in FCD IIb, including neuronal loss and an increase in reactive astrocytes (astrogliosis) when compared to FCD IIa. Astrogliosis in FCD IIb was further supported by a gene signature analysis and histologically confirmed by glial fibrillary acidic protein (GFAP) immunostaining. Overall, our findings demonstrate that FCD II subtypes exhibit differential neuronal and glial compositions, with astrogliosis emerging as a hallmark of FCD IIb. These observations, validated in independent patient cohorts and confirmed using immunohistochemistry, offer novel insights into the involvement of glial cells in FCD type II pathophysiology and may contribute to the development of targeted therapies for this condition.
Topics: Humans; Focal Cortical Dysplasia; Gliosis; Malformations of Cortical Development, Group I; Neuroglia
PubMed: 37587190
DOI: 10.1038/s41598-023-40240-3 -
BMC Neurology Aug 2021The aim of this study was to investigate alterations in structural connectivity and structural co-variance network in patients with focal cortical dysplasia (FCD).
BACKGROUND
The aim of this study was to investigate alterations in structural connectivity and structural co-variance network in patients with focal cortical dysplasia (FCD).
METHODS
We enrolled 37 patients with FCD and 35 healthy controls. All subjects underwent brain MRI with the same scanner and with the same protocol, which included diffusion tensor imaging (DTI) and T1-weighted imaging. We analyzed the structural connectivity based on DTI, and structural co-variance network based on the structural volume with T1-weighted imaging. We created a connectivity matrix and obtained network measures from the matrix using the graph theory. We tested the difference in network measure between patients with FCD and healthy controls.
RESULTS
In the structural connectivity analysis, we found that the local efficiency in patients with FCD was significantly lower than in healthy controls (2.390 vs. 2.578, p = 0.031). Structural co-variance network analysis revealed that the mean clustering coefficient, global efficiency, local efficiency, and transitivity were significantly decreased in patients with FCD compared to those in healthy controls (0.527 vs. 0.635, p = 0.036; 0.545 vs. 0.648, p = 0.026; 2.699 vs. 3.801, p = 0.019; 0.791 vs. 0.954, p = 0.026, respectively).
CONCLUSIONS
We demonstrate that there are significant alterations in structural connectivity, based on DTI, and structural co-variance network, based on the structural volume, in patients with FCD compared to healthy controls. These findings suggest that focal lesions with FCD could affect the whole-brain network and that FCD is a network disease.
Topics: Brain; Diffusion Tensor Imaging; Humans; Magnetic Resonance Imaging; Malformations of Cortical Development; Neuroimaging
PubMed: 34452597
DOI: 10.1186/s12883-021-02358-7 -
Molecular Neurobiology Aug 2023Focal cortical dysplasia (FCD), a common malformation of cortical development, is frequently associated with pharmacoresistant epilepsy in both children and adults....
Focal cortical dysplasia (FCD), a common malformation of cortical development, is frequently associated with pharmacoresistant epilepsy in both children and adults. Adenosine is an inhibitory modulator of brain activity and a prospective anti-seizure agent with potential for clinical translation. Our previous results demonstrated that the major adenosine-metabolizing enzyme adenosine kinase (ADK) was upregulated in balloon cells (BCs) within FCD type IIB lesions, suggesting that dysfunction of the adenosine system is implicated in the pathophysiology of FCD. In our current study, we therefore performed a comprehensive analysis of adenosine signaling in surgically resected cortical specimens from patients with FCD type I and type II via immunohistochemistry and immunoblot analysis. Adenosine enzyme signaling was assessed by quantifying the levels of the key enzymes of adenosine metabolism, i.e., ADK, adenosine deaminase (ADA), and ecto-5'-nucleotidase (CD73). Adenosine receptor signaling was assessed by quantifying the levels of adenosine A receptor (AR) and putative downstream mediators of adenosine, namely, glutamate transporter-1 (GLT-1) and mammalian target of rapamycin (mTOR). Within lesions in FCD specimens, we found that the adenosine-metabolizing enzymes ADK and ADA, as well as the adenosine-producing enzyme CD73, were upregulated. We also observed an increase in AR density, as well as a decrease in GLT-1 levels and an increase in mTOR levels, in FCD specimens compared with control tissue. These results suggest that dysregulation of the adenosine system is a common pathologic feature of both FCD type I and type II. The adenosine system might therefore be a therapeutic target for the treatment of epilepsy associated with FCD.
Topics: Child; Adult; Humans; Focal Cortical Dysplasia; Epilepsy; Malformations of Cortical Development, Group I; Signal Transduction; Malformations of Cortical Development; TOR Serine-Threonine Kinases
PubMed: 37103687
DOI: 10.1007/s12035-023-03351-6