BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imagin... more BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. RESULTS: Nodules were often noncontiguous (n ϭ 28) and asymmetric (n ϭ 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n ϭ 38). Corpus callosum abnormalities (n ϭ 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n ϭ 22), and colpocephaly was frequent (n ϭ 26). Most (n ϭ 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n ϭ 27), and hippocampal abnormalities were frequent (n ϭ 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures. ABBREVIATIONS: DHPLC ϭ denaturing high-performance liquid chromatography; FLNA ϭ Filamin A gene; PNH ϭ periventricular nodular heterotopia S ubependymal or periventricular nodular heterotopia is the most commonly identified gray matter heterotopia in clinical practice. 1-5 It may be more often associated with other malformations than commonly appreciated. 5 PNH is a collection of sub
Vigabatrin (gamma vinyl GABA, GVG) is an irreversible inhibitor of gamma-aminobutyric acid (GABA)... more Vigabatrin (gamma vinyl GABA, GVG) is an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase, the enzyme that is responsible for degradation of GABA in the CNS. Vigabatrin is effective against partial seizures (Rimmer and Richens, 1984; Mumford and Dam, 1989; Reynolds, 1992). In toxicological studies involving rodents and dogs, high doses of GVG were associated with the development of a site-selective intramyelinic oedema that was accompanied by an astrocytic reaction (Butler et al., 1987; Gibson et al, 1990). A concern has been expressed about whether similar neuropathological changes may develop in human patients receiving long-term GVG therapy. No such changes have been identified in 51 surgical specimens and 13 autopsy cases (Cannon, 1991). Evoked response latencies have been shown to be prolonged in dogs with GVG-associated intramyelinic oedema, and these parameters have not been delayed in GVG-treated patients (Hammond and Wilder, 1985; Tartara et al., 1986). Evoked responses, however, only sample a small part of the neuraxis.
One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm inte... more 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 ...
Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but... more Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of ...
ObjectiveTo determine whether 1-stage, limited corticectomy controls seizures in patients with MR... more ObjectiveTo determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD).MethodsWe reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG.ResultsThirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0–14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasi...
ObjectiveDrug‐resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The d... more ObjectiveDrug‐resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome.MethodsThe MELD (Multi‐centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging‐based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom.ResultsFCDs were nonuniformly distributed, concentrating in the superior frontal su...
Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network... more Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human C...
Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but... more Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem co-expression patterns of epilepsy risk genes. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1,328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patt...
Background and ObjectiveTo test the hypothesis that a multicenter-validated computer deep learnin... more Background and ObjectiveTo test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD).MethodsWe used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2–55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity.ResultsOverall sensitivity was 93% (137 of 1...
AimsThe causes of distinct patterns of reduced cortical thickness in the common human epilepsies,... more AimsThe causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems‐level analysis.MethodsImaging‐based cortical structural maps from a large‐scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell‐type deconvolution, differential expression analysis and cell‐type enrichment analyses were used to identify differences in cell‐type distribution. These differences were followed up in post‐mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell‐type‐specific depletion was used in a murine model of acquired epilepsy.ResultsWe identified elevated fractions of microglia and endothelial cells in regions of reduced cortical...
SUMMARYEpilepsy is increasingly conceptualized as a network disorder. In this cross-sectional meg... more SUMMARYEpilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1,021 adults with epilepsy compared to 1,564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy co-localized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Indices of progressive atrophy further revealed a strong influence of connectome architecture on disease progression in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients, and wer...
Epilepsy is a common and serious neurological disorder, with many different constituent condition... more Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller‐scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well‐established by the ENIGMA Consortium, ENIGMA‐Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural c...
Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and tre... more Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and treatment of epilepsy, particularly when surgery is being considered. Despite previous recommendations and guidelines, practices for the use of MRI are variable worldwide and may not harness the full potential of recent technological advances for the benefit of people with epilepsy. The International League Against Epilepsy Diagnostic Methods Commission has thus charged the 2013‐2017 Neuroimaging Task Force to develop a set of recommendations addressing the following questions: (1) Who should have an MRI? (2) What are the minimum requirements for an MRI epilepsy protocol? (3) How should magnetic resonance (MR) images be evaluated? (4) How to optimize lesion detection? These recommendations target clinicians in established epilepsy centers and neurologists in general/district hospitals. They endorse routine structural imaging in new onset generalized and focal epilepsy alike and describe the...
Simultaneous scalp EEG‐fMRI recording is a noninvasive neuroimaging technique for combining elect... more Simultaneous scalp EEG‐fMRI recording is a noninvasive neuroimaging technique for combining electrophysiological and hemodynamic aspects of brain function. Despite the time‐varying nature of both measurements, their relationship is usually considered as time‐invariant. The aim of this study was to detect direct associations between scalp‐recorded EEG and regional changes of hemodynamic brain connectivity in focal epilepsy through a time‐frequency paradigm. To do so, we developed a voxel‐wise framework that analyses wavelet coherence between dynamic regional phase synchrony (DRePS, calculated from fMRI) and band amplitude fluctuation (BAF) of a target EEG electrode with dominant interictal epileptiform discharges (IEDs). As a proof of concept, we applied this framework to seven patients with focal epilepsy. The analysis produced patient‐specific spatial maps of DRePS‐BAF coupling, which highlight regions with a strong link between EEG power and local fMRI connectivity. Although we ob...
ObjectiveTo examine cerebral cortex thickness in asymptomatic first-degree relatives of patients ... more ObjectiveTo examine cerebral cortex thickness in asymptomatic first-degree relatives of patients with mesial temporal lobe epilepsy (MTLE).MethodsWe investigated 127 asymptomatic first-degree relatives of patients with MTLE due to hippocampal sclerosis (HS) (mean age ± SD = 39.4 ± 13 years) and 203 healthy control individuals (mean age ± SD = 36.0 ± 11 years). Participants underwent a comprehensive clinical evaluation and structural brain MRI at 3 study sites. Images were processed simultaneously at each site using a surface-based morphometry method to quantify global brain measures, hippocampal volumes, and cerebral cortical thickness. Differences in brain measures between relatives of patients and controls were examined using generalized models, while controlling for relevant covariates, including age and sex.ResultsNone of the asymptomatic first-degree relatives of MTLE + HS patients showed evidence of HS on qualitative image assessments. Compared to the healthy controls, the asy...
ObjectiveTo investigate whether genetics, underlying pathology, or repeated seizures contribute t... more ObjectiveTo investigate whether genetics, underlying pathology, or repeated seizures contribute to atrophy in specific white matter tracts.MethodsMedically refractory unilateral temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS‐TLE, n = 26) was studied as an archetype of focal epilepsy, using fixel‐based analysis of diffusion‐weighted imaging. A genetic effect was assessed in first‐degree relatives of HS‐TLE subjects who did not have epilepsy themselves (HS‐1°Rel; n = 26). The role of disease process was uncovered by comparing HS‐TLE to unilateral TLE with normal clinical magnetic resonance imaging (MRI‐neg TLE; n = 26, matched for seizure severity). The effect of focal seizures was inferred from lateralized atrophy common to both HS‐TLE and MRI‐neg TLE, in comparison to healthy controls (n = 76).ResultsHS‐1 °Rel had bilaterally small hippocampi, but no focal white matter atrophy was detected, indicating a limited effect of genetics. HS‐TLE subjects had lateralized atrophy...
Epileptic spikes occur on the sub-second timescale and are known to involve not only epileptic fo... more Epileptic spikes occur on the sub-second timescale and are known to involve not only epileptic foci but also large-scale distributed brain networks. There is likely to be a sequence of neural activity in multiple brain regions that occurs within the duration of a single spike, but standard electroencephalography-functional magnetic resonance imaging analyses, which use only the timing of the spikes to model the functional magnetic resonance imaging data, cannot determine the sequence of these activations. Our aim in this study is to temporally resolve these spatial activations to observe the spatiotemporal dynamics of the spike-related neural activity at a sub-second timescale. We studied eight focal epilepsy patients (age 11-42 years, six female) and used amplitude features of the electroencephalogram specific to different spike components (early and late peaks and troughs) to encode temporal information into our functional magnetic resonance imaging models. This enables us to associate each activation with a specific model of each of the spike components to infer the temporal order of these spike-related spatial activations. In seven of eight patients the distributed networks were associated with the late spike component. The focal activations were more variably coupled with time epochs, but tended to precede the distributed network effects. We also found that incorporating electroencephalogram features into the models increased sensitivity and in six patients revealed additional regions unseen in the standard analysis result. This included strong bilateral thalamus activation in two patients. We demonstrate the clinical utility of this approach in a patient who recently underwent a successful surgical resection of the region where we saw enhanced activation using electroencephalogram amplitude information specific to the early spike component. This focal cluster of activation was larger and more precisely tracked the anatomy compared to what was seen using the standard timing-based analysis. Our novel electroencephalography-functional magnetic resonance imaging data fusion approach, which utilizes information based on the single spike variability across all electroencephalogram channels, has the potential to help us better understand epileptic networks and aid in the interpretation of functional magnetic resonance imaging activation maps during treatment planning.
SummaryObjectiveThere is considerable difficulty in diagnosing hippocampal malrotation (HIMAL), w... more SummaryObjectiveThere is considerable difficulty in diagnosing hippocampal malrotation (HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging (MRI)–negative temporal lobe epilepsy (TLE).MethodsWe studied the MRI of 155 adult patients with MRI‐negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI‐negative TLE.ResultsWe found that the features that are most correlated with the expert diagnosis of HIMAL are hippocampal shape change with hippocampal diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus (DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of u...
Ipsilateral loss of anterior temporal gray-white matter definition, due mainly to white matter si... more Ipsilateral loss of anterior temporal gray-white matter definition, due mainly to white matter signal intensity abnormality, is frequently seen on MR images of patients with hippocampal sclerosis. Our aim was to determine the prevalence and clinical correlations of these anterior temporal changes in pediatric cases of hippocampal sclerosis and to determine whether cumulative damage from seizures is important for their development. We reviewed the MR images and clinical details of 54 children (age range, 1.5-19 years) with typical hippocampal sclerosis. Specific imaging features noted included hippocampal sclerosis, anterior temporal changes, anterior temporal atrophy, and extra-hippocampal abnormality. Thirty-one (57%) of 54 children with hippocampal sclerosis had associated ipsilateral anterior temporal changes. Ipsilateral anterior temporal atrophy was associated with anterior temporal changes (P <.03). Children whose images showed anterior temporal changes were younger at onse...
We describe the clinical and radiological features of a family with a homozygous mutation in TBC1... more We describe the clinical and radiological features of a family with a homozygous mutation in TBC1D24. The phenotype comprised onset of focal seizures at 2 months with prominent eye-blinking, facial and limb jerking with an oral sensory aura. These were controllable with medication but persisted into adult life. Associated features were mild to moderate intellectual disability and cerebellar features. MRI showed subtle cortical thickening with cerebellar atrophy and high signal confined to the ansiform lobule. The disorder is allelic with familial infantile myoclonic epilepsy, where intellect and neurologic examination are normal, highlighting the phenotypic variation with mutations of TBC1D24.
BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imagin... more BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. RESULTS: Nodules were often noncontiguous (n ϭ 28) and asymmetric (n ϭ 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n ϭ 38). Corpus callosum abnormalities (n ϭ 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n ϭ 22), and colpocephaly was frequent (n ϭ 26). Most (n ϭ 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n ϭ 27), and hippocampal abnormalities were frequent (n ϭ 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures. ABBREVIATIONS: DHPLC ϭ denaturing high-performance liquid chromatography; FLNA ϭ Filamin A gene; PNH ϭ periventricular nodular heterotopia S ubependymal or periventricular nodular heterotopia is the most commonly identified gray matter heterotopia in clinical practice. 1-5 It may be more often associated with other malformations than commonly appreciated. 5 PNH is a collection of sub
Vigabatrin (gamma vinyl GABA, GVG) is an irreversible inhibitor of gamma-aminobutyric acid (GABA)... more Vigabatrin (gamma vinyl GABA, GVG) is an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase, the enzyme that is responsible for degradation of GABA in the CNS. Vigabatrin is effective against partial seizures (Rimmer and Richens, 1984; Mumford and Dam, 1989; Reynolds, 1992). In toxicological studies involving rodents and dogs, high doses of GVG were associated with the development of a site-selective intramyelinic oedema that was accompanied by an astrocytic reaction (Butler et al., 1987; Gibson et al, 1990). A concern has been expressed about whether similar neuropathological changes may develop in human patients receiving long-term GVG therapy. No such changes have been identified in 51 surgical specimens and 13 autopsy cases (Cannon, 1991). Evoked response latencies have been shown to be prolonged in dogs with GVG-associated intramyelinic oedema, and these parameters have not been delayed in GVG-treated patients (Hammond and Wilder, 1985; Tartara et al., 1986). Evoked responses, however, only sample a small part of the neuraxis.
One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm inte... more 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 ...
Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but... more Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of ...
ObjectiveTo determine whether 1-stage, limited corticectomy controls seizures in patients with MR... more ObjectiveTo determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD).MethodsWe reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG.ResultsThirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0–14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasi...
ObjectiveDrug‐resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The d... more ObjectiveDrug‐resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome.MethodsThe MELD (Multi‐centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging‐based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom.ResultsFCDs were nonuniformly distributed, concentrating in the superior frontal su...
Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network... more Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human C...
Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but... more Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem co-expression patterns of epilepsy risk genes. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1,328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patt...
Background and ObjectiveTo test the hypothesis that a multicenter-validated computer deep learnin... more Background and ObjectiveTo test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD).MethodsWe used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2–55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity.ResultsOverall sensitivity was 93% (137 of 1...
AimsThe causes of distinct patterns of reduced cortical thickness in the common human epilepsies,... more AimsThe causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems‐level analysis.MethodsImaging‐based cortical structural maps from a large‐scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell‐type deconvolution, differential expression analysis and cell‐type enrichment analyses were used to identify differences in cell‐type distribution. These differences were followed up in post‐mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell‐type‐specific depletion was used in a murine model of acquired epilepsy.ResultsWe identified elevated fractions of microglia and endothelial cells in regions of reduced cortical...
SUMMARYEpilepsy is increasingly conceptualized as a network disorder. In this cross-sectional meg... more SUMMARYEpilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1,021 adults with epilepsy compared to 1,564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy co-localized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Indices of progressive atrophy further revealed a strong influence of connectome architecture on disease progression in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients, and wer...
Epilepsy is a common and serious neurological disorder, with many different constituent condition... more Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller‐scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well‐established by the ENIGMA Consortium, ENIGMA‐Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural c...
Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and tre... more Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and treatment of epilepsy, particularly when surgery is being considered. Despite previous recommendations and guidelines, practices for the use of MRI are variable worldwide and may not harness the full potential of recent technological advances for the benefit of people with epilepsy. The International League Against Epilepsy Diagnostic Methods Commission has thus charged the 2013‐2017 Neuroimaging Task Force to develop a set of recommendations addressing the following questions: (1) Who should have an MRI? (2) What are the minimum requirements for an MRI epilepsy protocol? (3) How should magnetic resonance (MR) images be evaluated? (4) How to optimize lesion detection? These recommendations target clinicians in established epilepsy centers and neurologists in general/district hospitals. They endorse routine structural imaging in new onset generalized and focal epilepsy alike and describe the...
Simultaneous scalp EEG‐fMRI recording is a noninvasive neuroimaging technique for combining elect... more Simultaneous scalp EEG‐fMRI recording is a noninvasive neuroimaging technique for combining electrophysiological and hemodynamic aspects of brain function. Despite the time‐varying nature of both measurements, their relationship is usually considered as time‐invariant. The aim of this study was to detect direct associations between scalp‐recorded EEG and regional changes of hemodynamic brain connectivity in focal epilepsy through a time‐frequency paradigm. To do so, we developed a voxel‐wise framework that analyses wavelet coherence between dynamic regional phase synchrony (DRePS, calculated from fMRI) and band amplitude fluctuation (BAF) of a target EEG electrode with dominant interictal epileptiform discharges (IEDs). As a proof of concept, we applied this framework to seven patients with focal epilepsy. The analysis produced patient‐specific spatial maps of DRePS‐BAF coupling, which highlight regions with a strong link between EEG power and local fMRI connectivity. Although we ob...
ObjectiveTo examine cerebral cortex thickness in asymptomatic first-degree relatives of patients ... more ObjectiveTo examine cerebral cortex thickness in asymptomatic first-degree relatives of patients with mesial temporal lobe epilepsy (MTLE).MethodsWe investigated 127 asymptomatic first-degree relatives of patients with MTLE due to hippocampal sclerosis (HS) (mean age ± SD = 39.4 ± 13 years) and 203 healthy control individuals (mean age ± SD = 36.0 ± 11 years). Participants underwent a comprehensive clinical evaluation and structural brain MRI at 3 study sites. Images were processed simultaneously at each site using a surface-based morphometry method to quantify global brain measures, hippocampal volumes, and cerebral cortical thickness. Differences in brain measures between relatives of patients and controls were examined using generalized models, while controlling for relevant covariates, including age and sex.ResultsNone of the asymptomatic first-degree relatives of MTLE + HS patients showed evidence of HS on qualitative image assessments. Compared to the healthy controls, the asy...
ObjectiveTo investigate whether genetics, underlying pathology, or repeated seizures contribute t... more ObjectiveTo investigate whether genetics, underlying pathology, or repeated seizures contribute to atrophy in specific white matter tracts.MethodsMedically refractory unilateral temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS‐TLE, n = 26) was studied as an archetype of focal epilepsy, using fixel‐based analysis of diffusion‐weighted imaging. A genetic effect was assessed in first‐degree relatives of HS‐TLE subjects who did not have epilepsy themselves (HS‐1°Rel; n = 26). The role of disease process was uncovered by comparing HS‐TLE to unilateral TLE with normal clinical magnetic resonance imaging (MRI‐neg TLE; n = 26, matched for seizure severity). The effect of focal seizures was inferred from lateralized atrophy common to both HS‐TLE and MRI‐neg TLE, in comparison to healthy controls (n = 76).ResultsHS‐1 °Rel had bilaterally small hippocampi, but no focal white matter atrophy was detected, indicating a limited effect of genetics. HS‐TLE subjects had lateralized atrophy...
Epileptic spikes occur on the sub-second timescale and are known to involve not only epileptic fo... more Epileptic spikes occur on the sub-second timescale and are known to involve not only epileptic foci but also large-scale distributed brain networks. There is likely to be a sequence of neural activity in multiple brain regions that occurs within the duration of a single spike, but standard electroencephalography-functional magnetic resonance imaging analyses, which use only the timing of the spikes to model the functional magnetic resonance imaging data, cannot determine the sequence of these activations. Our aim in this study is to temporally resolve these spatial activations to observe the spatiotemporal dynamics of the spike-related neural activity at a sub-second timescale. We studied eight focal epilepsy patients (age 11-42 years, six female) and used amplitude features of the electroencephalogram specific to different spike components (early and late peaks and troughs) to encode temporal information into our functional magnetic resonance imaging models. This enables us to associate each activation with a specific model of each of the spike components to infer the temporal order of these spike-related spatial activations. In seven of eight patients the distributed networks were associated with the late spike component. The focal activations were more variably coupled with time epochs, but tended to precede the distributed network effects. We also found that incorporating electroencephalogram features into the models increased sensitivity and in six patients revealed additional regions unseen in the standard analysis result. This included strong bilateral thalamus activation in two patients. We demonstrate the clinical utility of this approach in a patient who recently underwent a successful surgical resection of the region where we saw enhanced activation using electroencephalogram amplitude information specific to the early spike component. This focal cluster of activation was larger and more precisely tracked the anatomy compared to what was seen using the standard timing-based analysis. Our novel electroencephalography-functional magnetic resonance imaging data fusion approach, which utilizes information based on the single spike variability across all electroencephalogram channels, has the potential to help us better understand epileptic networks and aid in the interpretation of functional magnetic resonance imaging activation maps during treatment planning.
SummaryObjectiveThere is considerable difficulty in diagnosing hippocampal malrotation (HIMAL), w... more SummaryObjectiveThere is considerable difficulty in diagnosing hippocampal malrotation (HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging (MRI)–negative temporal lobe epilepsy (TLE).MethodsWe studied the MRI of 155 adult patients with MRI‐negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI‐negative TLE.ResultsWe found that the features that are most correlated with the expert diagnosis of HIMAL are hippocampal shape change with hippocampal diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus (DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of u...
Ipsilateral loss of anterior temporal gray-white matter definition, due mainly to white matter si... more Ipsilateral loss of anterior temporal gray-white matter definition, due mainly to white matter signal intensity abnormality, is frequently seen on MR images of patients with hippocampal sclerosis. Our aim was to determine the prevalence and clinical correlations of these anterior temporal changes in pediatric cases of hippocampal sclerosis and to determine whether cumulative damage from seizures is important for their development. We reviewed the MR images and clinical details of 54 children (age range, 1.5-19 years) with typical hippocampal sclerosis. Specific imaging features noted included hippocampal sclerosis, anterior temporal changes, anterior temporal atrophy, and extra-hippocampal abnormality. Thirty-one (57%) of 54 children with hippocampal sclerosis had associated ipsilateral anterior temporal changes. Ipsilateral anterior temporal atrophy was associated with anterior temporal changes (P <.03). Children whose images showed anterior temporal changes were younger at onse...
We describe the clinical and radiological features of a family with a homozygous mutation in TBC1... more We describe the clinical and radiological features of a family with a homozygous mutation in TBC1D24. The phenotype comprised onset of focal seizures at 2 months with prominent eye-blinking, facial and limb jerking with an oral sensory aura. These were controllable with medication but persisted into adult life. Associated features were mild to moderate intellectual disability and cerebellar features. MRI showed subtle cortical thickening with cerebellar atrophy and high signal confined to the ansiform lobule. The disorder is allelic with familial infantile myoclonic epilepsy, where intellect and neurologic examination are normal, highlighting the phenotypic variation with mutations of TBC1D24.
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Papers by Graeme Jackson