Publications by authors named "Gavin P Winston"

58 Publications

Detection of covert lesions in focal epilepsy using computational analysis of multimodal magnetic resonance imaging data.

Epilepsia 2021 Mar 10;62(3):807-816. Epub 2021 Feb 10.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Objective: To compare the location of suspect lesions detected by computational analysis of multimodal magnetic resonance imaging data with areas of seizure onset, early propagation, and interictal epileptiform discharges (IEDs) identified with stereoelectroencephalography (SEEG) in a cohort of patients with medically refractory focal epilepsy and radiologically normal magnetic resonance imaging (MRI) scans.

Methods: We developed a method of lesion detection using computational analysis of multimodal MRI data in a cohort of 62 control subjects, and 42 patients with focal epilepsy and MRI-visible lesions. We then applied it to detect covert lesions in 27 focal epilepsy patients with radiologically normal MRI scans, comparing our findings with the areas of seizure onset, early propagation, and IEDs identified at SEEG.

Results: Seizure-onset zones (SoZs) were identified at SEEG in 18 of the 27 patients (67%) with radiologically normal MRI scans. In 11 of these 18 cases (61%), concordant abnormalities were detected by our method. In the remaining seven cases, either early seizure propagation or IEDs were observed within the abnormalities detected, or there were additional areas of imaging abnormalities found by our method that were not sampled at SEEG. In one of the nine patients (11%) in whom SEEG was inconclusive, an abnormality, which may have been involved in seizures, was identified by our method and was not sampled at SEEG.

Significance: Computational analysis of multimodal MRI data revealed covert abnormalities in the majority of patients with refractory focal epilepsy and radiologically normal MRI that co-located with SEEG defined zones of seizure onset. The method could help identify areas that should be targeted with SEEG when considering epilepsy surgery.
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http://dx.doi.org/10.1111/epi.16836DOI Listing
March 2021

Focal to bilateral tonic-clonic seizures are associated with widespread network abnormality in temporal lobe epilepsy.

Epilepsia 2021 Mar 21;62(3):729-741. Epub 2021 Jan 21.

Computational Neuroscience, Neurology, and Psychiatry Lab, Interdisciplinary Computing and Complex BioSystems Research Group, School of Computing, Newcastle University, Newcastle Upon Tyne, UK.

Objective: Our objective was to identify whether the whole-brain structural network alterations in patients with temporal lobe epilepsy (TLE) and focal to bilateral tonic-clonic seizures (FBTCS) differ from alterations in patients without FBTCS.

Methods: We dichotomized a cohort of 83 drug-resistant patients with TLE into those with and without FBTCS and compared each group to 29 healthy controls. For each subject, we used diffusion-weighted magnetic resonance imaging to construct whole-brain structural networks. First, we measured the extent of alterations by performing FBTCS-negative (FBTCS-) versus control and FBTCS-positive (FBTCS+) versus control comparisons, thereby delineating altered subnetworks of the whole-brain structural network. Second, by standardizing each patient's networks using control networks, we measured the subject-specific abnormality at every brain region in the network, thereby quantifying the spatial localization and the amount of abnormality in every patient.

Results: Both FBTCS+ and FBTCS- patient groups had altered subnetworks with reduced fractional anisotropy and increased mean diffusivity compared to controls. The altered subnetwork in FBTCS+ patients was more widespread than in FBTCS- patients (441 connections altered at t > 3, p < .001 in FBTCS+ compared to 21 connections altered at t > 3, p = .01 in FBTCS-). Significantly greater abnormalities-aggregated over the entire brain network as well as assessed at the resolution of individual brain areas-were present in FBTCS+ patients (p < .001, d = .82, 95% confidence interval = .32-1.3). In contrast, the fewer abnormalities present in FBTCS- patients were mainly localized to the temporal and frontal areas.

Significance: The whole-brain structural network is altered to a greater and more widespread extent in patients with TLE and FBTCS. We suggest that these abnormal networks may serve as an underlying structural basis or consequence of the greater seizure spread observed in FBTCS.
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http://dx.doi.org/10.1111/epi.16819DOI Listing
March 2021

Structural Brain Network Abnormalities and the Probability of Seizure Recurrence After Epilepsy Surgery.

Neurology 2021 02 22;96(5):e758-e771. Epub 2020 Dec 22.

From the Translational and Clinical Research Institute (N.S.), Faculty of Medical Sciences, and Computational Neuroscience, Neurology, and Psychiatry Lab (N.S., Y.W., N.M.d.S., P.N.T.), Interdisciplinary Computing and Complex BioSystems Group, School of Computing, Newcastle University, Newcastle Upon Tyne; NIHR University College London Hospitals Biomedical Research Centre (Y.W., A.M., A.W.M., J.d.T., S.B.V., G.P.W., J.S.D., P.N.T.), UCL Institute of Neurology, Queen Square; Centre for Medical Image Computing (S.B.V.), University College London; Epilepsy Society MRI Unit (S.B.V., G.P.W., J.S.D), Chalfont St Peter, UK; and Department of Medicine (G.P.W.,), Division of Neurology, Queen's University, Kingston, Ontario, Canada.

Objective: We assessed preoperative structural brain networks and clinical characteristics of patients with drug-resistant temporal lobe epilepsy (TLE) to identify correlates of postsurgical seizure recurrences.

Methods: We examined data from 51 patients with TLE who underwent anterior temporal lobe resection (ATLR) and 29 healthy controls. For each patient, using the preoperative structural, diffusion, and postoperative structural MRI, we generated 2 networks: presurgery network and surgically spared network. Standardizing these networks with respect to controls, we determined the number of abnormal nodes before surgery and expected to be spared by surgery. We incorporated these 2 abnormality measures and 13 commonly acquired clinical data from each patient into a robust machine learning framework to estimate patient-specific chances of seizures persisting after surgery.

Results: Patients with more abnormal nodes had a lower chance of complete seizure freedom at 1 year and, even if seizure-free at 1 year, were more likely to relapse within 5 years. The number of abnormal nodes was greater and their locations more widespread in the surgically spared networks of patients with poor outcome than in patients with good outcome. We achieved an area under the curve of 0.84 ± 0.06 and specificity of 0.89 ± 0.09 in predicting unsuccessful seizure outcomes (International League Against Epilepsy [ILAE] 3-5) as opposed to complete seizure freedom (ILAE 1) at 1 year. Moreover, the model-predicted likelihood of seizure relapse was significantly correlated with the grade of surgical outcome at year 1 and associated with relapses up to 5 years after surgery.

Conclusion: Node abnormality offers a personalized, noninvasive marker that can be combined with clinical data to better estimate the chances of seizure freedom at 1 year and subsequent relapse up to 5 years after ATLR.

Classification Of Evidence: This study provides Class II evidence that node abnormality predicts postsurgical seizure recurrence.
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http://dx.doi.org/10.1212/WNL.0000000000011315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884990PMC
February 2021

Multivariate white matter alterations are associated with epilepsy duration.

Eur J Neurosci 2021 Apr 11;53(8):2788-2803. Epub 2020 Dec 11.

CNNP Lab, Interdisciplinary Computing and Complex BioSystems Group, School of Computing, Newcastle University, Newcastle upon Tyne, UK.

Previous studies investigating associations between white matter alterations and duration of temporal lobe epilepsy (TLE) have shown differing results, and were typically limited to univariate analyses of tracts in isolation. In this study, we apply a multivariate measure (the Mahalanobis distance), which captures the distinct ways white matter may differ in individual patients, and relate this to epilepsy duration. Diffusion MRI, from a cohort of 94 subjects (28 healthy controls, 33 left-TLE and 33 right-TLE), was used to assess the association between tract fractional anisotropy (FA) and epilepsy duration. Using ten white matter tracts, we analysed associations using the traditional univariate analysis (z-scores) and a complementary multivariate approach (Mahalanobis distance), incorporating multiple white matter tracts into a single unified analysis. For patients with right-TLE, FA was not significantly associated with epilepsy duration for any tract studied in isolation. For patients with left-TLE, the FA of two limbic tracts (ipsilateral fornix, contralateral cingulum gyrus) were significantly negatively associated with epilepsy duration (Bonferonni corrected p < .05). Using a multivariate approach we found significant ipsilateral positive associations with duration in both left, and right-TLE cohorts (left-TLE: Spearman's ρ = 0.487, right-TLE: Spearman's ρ = 0.422). Extrapolating our multivariate results to duration equals zero (i.e., at onset) we found no significant difference between patients and controls. Associations using the multivariate approach were more robust than univariate methods. The multivariate Mahalanobis distance measure provides non-overlapping and more robust results than traditional univariate analyses. Future studies should consider adopting both frameworks into their analysis in order to ascertain a more complete understanding of epilepsy progression, regardless of laterality.
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http://dx.doi.org/10.1111/ejn.15055DOI Listing
April 2021

Thalamus and focal to bilateral seizures: A multiscale cognitive imaging study.

Neurology 2020 10 26;95(17):e2427-e2441. Epub 2020 Aug 26.

From the Department of Clinical and Experimental Epilepsy (L.C., L.A.A., K.T., S.B.V., M.C., M.G., M.K.S., P.J.T., G.P.W., J.S.D., M.J.K.) and Neuroradiological Academic Unit (S.B.V.), UCL Queen Square Institute of Neurology, London; MRI Unit (L.C., L.A.A., K.T., S.B.V., M.C., M.G., M.K.S., P.J.T., G.P.W., J.S.D., M.J.K.), Epilepsy Society, Chalfont St Peter, Buckinghamshire, UK; Departments of Bioengineering (L.C., X.H., D.S.B.), Physics and Astronomy (D.S.B.), Electrical and Systems Engineering (D.S.B.), Neurology (D.S.B.), and Psychiatry (D.S.B.), University of Pennsylvania, Philadelphia; Department of Neurology (K.T.), Medical University of Vienna, Austria; Centre for Medical Image Computing (S.B.V.), University College London, UK; Department of Neurology (M.G.), University Hospital Zurich, Switzerland; Santa Fe Institute (D.S.B.), NM; Department of Medicine, Division of Neurology (G.P.W.), Queen's University, Kingston, Canada; and Department of Neurology (M.R.S.), Thomas Jefferson University, Philadelphia, PA.

Objective: To investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e., focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality.

Methods: FBTCS occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three patients (29%) had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12-derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality.

Results: Individuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamotemporal and thalamomotor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS.

Conclusions: In TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamotemporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization.
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http://dx.doi.org/10.1212/WNL.0000000000010645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682917PMC
October 2020

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study.

Brain 2020 08;143(8):2454-2473

Department of Neurology, Medical University of South Carolina, Charleston 29425 SC, USA.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.
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http://dx.doi.org/10.1093/brain/awaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567169PMC
August 2020

Clinical evaluation of automated quantitative MRI reports for assessment of hippocampal sclerosis.

Eur Radiol 2021 Jan 4;31(1):34-44. Epub 2020 Aug 4.

Centre for Medical Image Computing (CMIC), University College London, London, UK.

Objectives: Hippocampal sclerosis (HS) is a common cause of temporal lobe epilepsy. Neuroradiological practice relies on visual assessment, but quantification of HS imaging biomarkers-hippocampal volume loss and T2 elevation-could improve detection. We tested whether quantitative measures, contextualised with normative data, improve rater accuracy and confidence.

Methods: Quantitative reports (QReports) were generated for 43 individuals with epilepsy (mean age ± SD 40.0 ± 14.8 years, 22 men; 15 histologically unilateral HS; 5 bilateral; 23 MR-negative). Normative data was generated from 111 healthy individuals (age 40.0 ± 12.8 years, 52 men). Nine raters with different experience (neuroradiologists, trainees, and image analysts) assessed subjects' imaging with and without QReports. Raters assigned imaging normal, right, left, or bilateral HS. Confidence was rated on a 5-point scale.

Results: Correct designation (normal/abnormal) was high and showed further trend-level improvement with QReports, from 87.5 to 92.5% (p = 0.07, effect size d = 0.69). Largest magnitude improvement (84.5 to 93.8%) was for image analysts (d = 0.87). For bilateral HS, QReports significantly improved overall accuracy, from 74.4 to 91.1% (p = 0.042, d = 0.7). Agreement with the correct diagnosis (kappa) tended to increase from 0.74 ('fair') to 0.86 ('excellent') with the report (p = 0.06, d = 0.81). Confidence increased when correctly assessing scans with the QReport (p < 0.001, η = 0.945).

Conclusions: QReports of HS imaging biomarkers can improve rater accuracy and confidence, particularly in challenging bilateral cases. Improvements were seen across all raters, with large effect sizes, greatest for image analysts. These findings may have positive implications for clinical radiology services and justify further validation in larger groups.

Key Points: • Quantification of imaging biomarkers for hippocampal sclerosis-volume loss and raised T2 signal-could improve clinical radiological detection in challenging cases. • Quantitative reports for individual patients, contextualised with normative reference data, improved diagnostic accuracy and confidence in a group of nine raters, in particular for bilateral HS cases. • We present a pre-use clinical validation of an automated imaging assessment tool to assist clinical radiology reporting of hippocampal sclerosis, which improves detection accuracy.
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http://dx.doi.org/10.1007/s00330-020-07075-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755617PMC
January 2021

Peri-ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic-clonic seizures.

Epilepsia 2020 08 19;61(8):1570-1580. Epub 2020 Jul 19.

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

Objectives: Hypoxia, or abnormally low blood-oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored.

Methods: We analyzed high-resolution T1-weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic-clonic seizures (GTCS) recorded during long-term video-electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age- and sex-matched healthy controls (n = 43). Subjects were sub-divided into those with mild/moderate (GTCS-hypox-mild/moderate, n = 12) and severe (GTCS-hypox-severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO ) during VEEG. Whole-brain voxel-based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS.

Results: Morphometric and volumetric alterations appeared in association with peri-GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration.

Significance: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.
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http://dx.doi.org/10.1111/epi.16615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496610PMC
August 2020

Network reorganisation following anterior temporal lobe resection and relation with post-surgery seizure relapse: A longitudinal study.

Neuroimage Clin 2020 26;27:102320. Epub 2020 Jun 26.

CNNP lab(1), Interdisciplinary Complex Systems Group, School of Computing, Newcastle University, Newcastle upon Tyne, United Kingdom; NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, Queen Square, London, United Kingdom. Electronic address:

Objective: To characterise temporal lobe epilepsy (TLE) surgery-induced changes in brain network properties, as measured using diffusion weighted MRI, and investigate their association with postoperative seizure-freedom.

Methods: For 48 patients who underwent anterior temporal lobe resection, diffusion weighted MRI was acquired pre-operatively, 3-4 months post-operatively (N = 48), and again 12 months post-operatively (N = 13). Data for 17 controls were also acquired over the same period. After registering all subjects to a common space, we performed two complementary analyses of the subjects' quantitative anisotropy (QA) maps. 1) A connectometry analysis which is sensitive to changes in subsections of fasciculi. 2) A graph theory approach which integrates connectivity information across the wider brain network.

Results: We found significant postoperative alterations in QA in patients relative to controls measured over the same period. Reductions were primarily located in the uncinate fasciculus and inferior fronto-occipital fasciculus ipsilaterally for all patients. Larger reductions were associated with postoperative seizure-freedom in left TLE. Increased QA was mainly located in corona radiata and corticopontine tracts. Graph theoretic analysis revealed widespread increases in nodal betweenness centrality, which were not associated with patient outcomes.

Conclusion: Substantial alterations in QA occur in the months after epilepsy surgery, suggesting Wallerian degeneration and strengthening of specific white matter tracts. Greater reductions in QA were related to postoperative seizure freedom in left TLE.
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http://dx.doi.org/10.1016/j.nicl.2020.102320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334605PMC
June 2020

Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.

Epilepsia 2020 07 25;61(7):1438-1452. Epub 2020 Jun 25.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Objective: Juvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected siblings, and (b) validate those as endophenotypes of JME.

Methods: This prospective cross-sectional investigation included 32 patients with JME, 12 unaffected siblings, and 26 controls, comparable for age, sex, handedness, language laterality, neuropsychological performance, and anxiety and depression scores. We investigated patterns of motor system activation during episodic memory encoding and verb generation functional magnetic resonance imaging (fMRI) tasks.

Results: During both tasks, patients and unaffected siblings showed increased activation of motor system areas compared to controls. Effects were more prominent during memory encoding, which entailed hand motion via joystick responses. Subgroup analyses identified stronger activation of the motor cortex in JME patients with ongoing seizures compared to seizure-free patients. Receiver-operating characteristic curves, based on measures of motor activation, accurately discriminated both patients with JME and their siblings from healthy controls (area under the curve: 0.75 and 0.77, for JME and a combined patient-sibling group against controls, respectively; P < .005).

Significance: Motor system hyperactivation represents a cognitive, domain-independent endophenotype of JME. We propose measures of motor system activation as quantitative traits for future genetic imaging studies in this syndrome.
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http://dx.doi.org/10.1111/epi.16575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681252PMC
July 2020

Hippocampal Shape Is Associated with Memory Deficits in Temporal Lobe Epilepsy.

Ann Neurol 2020 07 28;88(1):170-182. Epub 2020 May 28.

Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, United Kingdom.

Objective: Cognitive problems, especially disturbances in episodic memory, and hippocampal sclerosis are common in temporal lobe epilepsy (TLE), but little is known about the relationship of hippocampal morphology with memory. We aimed to relate hippocampal surface-shape patterns to verbal and visual learning.

Methods: We analyzed hippocampal surface shapes on high-resolution magnetic resonance images and the Adult Memory and Information Processing Battery in 145 unilateral refractory TLE patients undergoing epilepsy surgery, a validation set of 55 unilateral refractory TLE patients, and 39 age- and sex-matched healthy volunteers.

Results: Both left TLE (LTLE) and right TLE (RTLE) patients had lower verbal (LTLE 44 ± 11; RTLE 45 ± 10) and visual learning (LTLE 34 ± 8, RTLE 30 ± 8) scores than healthy controls (verbal 58 ± 8, visual 39 ± 6; p < 0.001). Verbal learning was more impaired the greater the atrophy of the left superolateral hippocampal head. In contrast, visual memory was worse with greater bilateral inferomedial hippocampal atrophy. Postsurgical verbal memory decline was more common in LTLE than in RTLE (reliable change index in LTLE 27% vs RTLE 7%, p = 0.006), whereas there were no differences in postsurgical visual memory decline between those groups. Preoperative atrophy of the left hippocampal tail predicted postsurgical verbal memory decline.

Interpretation: Memory deficits in TLE are associated with specific morphological alterations of the hippocampus, which could help stratify TLE patients into those at high versus low risk of presurgical or postsurgical memory deficits. This knowledge could improve planning and prognosis of selective epilepsy surgery and neuropsychological counseling in TLE. ANN NEUROL 2020 ANN NEUROL 2020;88:170-182.
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http://dx.doi.org/10.1002/ana.25762DOI Listing
July 2020

Microstructural Investigations of the Visual Pathways in Pediatric Epilepsy Neurosurgery: Insights From Multi-Shell Diffusion Magnetic Resonance Imaging.

Front Neurosci 2020 8;14:269. Epub 2020 Apr 8.

Developmental Imaging and Biophysics Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.

Background: Surgery is a key approach for achieving seizure freedom in children with focal onset epilepsy. However, the resection can affect or be in the vicinity of the optic radiations. Multi-shell diffusion MRI and tractography can better characterize tissue structure and provide guidance to help minimize surgical related deficits. Whilst in adults tractography has been used to demonstrate that damage to the optic radiations leads to postoperative visual field deficits, this approach has yet to be properly explored in children.

Objective: To demonstrate the capabilities of multi-shell diffusion MRI and tractography in characterizing microstructural changes in children with epilepsy pre- and post-surgery affecting the occipital, parietal or temporal lobes.

Methods: Diffusion Tensor Imaging and the Spherical Mean Technique were used to investigate the microstructure of the optic radiations. Furthermore, tractography was used to evaluate whether pre-surgical reconstructions of the optic radiations overlap with the resection margin as measured using anatomical post-surgical T1-weighted MRI.

Results: Increased diffusivity in patients compared to controls at baseline was observed with evidence of decreased diffusivity, anisotropy, and neurite orientation distribution in contralateral hemisphere after surgery. Pre-surgical optic radiation tractography overlapped with post-surgical resection margins in 20/43 (46%) children, and where visual data was available before and after surgery, the presence of overlap indicated a visual field deficit.

Conclusion: This is the first report in a pediatric series which highlights the relevance of tractography for future pre-surgical evaluation in children undergoing epilepsy surgery and the usefulness of multi-shell diffusion MRI to characterize brain microstructure in these patients.
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http://dx.doi.org/10.3389/fnins.2020.00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158873PMC
April 2020

Corrigendum to "Assessing various sensorimotor and cognitive functions in people with epilepsy is feasible with robotics" [Epilepsy Behav 103(A) 2020].

Epilepsy Behav 2020 May 16;106:107020. Epub 2020 Mar 16.

Centre for Neuroscience Studies, Queen's University, Botterell Hall, 18 Stuart Street, Kingston, ON K7L 3N6, Canada; Department of Medicine, Division of Neurology, Queen's University, Etherington Hall, 94 Stuart Street, Kingston, ON K7L 3N6, Canada; Kingston Health Sciences Centre, 76 Stuart St., Kingston, ON K7L 2V7, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.yebeh.2020.107020DOI Listing
May 2020

Microstructural imaging in temporal lobe epilepsy: Diffusion imaging changes relate to reduced neurite density.

Neuroimage Clin 2020 28;26:102231. Epub 2020 Feb 28.

Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, UK.

Purpose: Previous imaging studies in patients with refractory temporal lobe epilepsy (TLE) have examined the spatial distribution of changes in imaging parameters such as diffusion tensor imaging (DTI) metrics and cortical thickness. Multi-compartment models offer greater specificity with parameters more directly related to known changes in TLE such as altered neuronal density and myelination. We studied the spatial distribution of conventional and novel metrics including neurite density derived from NODDI (Neurite Orientation Dispersion and Density Imaging) and myelin water fraction (MWF) derived from mcDESPOT (Multi-Compartment Driven Equilibrium Single Pulse Observation of T1/T2)] to infer the underlying neurobiology of changes in conventional metrics.

Methods: 20 patients with TLE and 20 matched controls underwent magnetic resonance imaging including a volumetric T1-weighted sequence, multi-shell diffusion from which DTI and NODDI metrics were derived and a protocol suitable for mcDESPOT fitting. Models of the grey matter-white matter and grey matter-CSF surfaces were automatically generated from the T1-weighted MRI. Conventional diffusion and novel metrics of neurite density and MWF were sampled from intracortical grey matter and subcortical white matter surfaces and cortical thickness was measured.

Results: In intracortical grey matter, diffusivity was increased in the ipsilateral temporal and frontopolar cortices with more restricted areas of reduced neurite density. Diffusivity increases were largely related to reductions in neurite density, and to a lesser extent CSF partial volume effects, but not MWF. In subcortical white matter, widespread bilateral reductions in fractional anisotropy and increases in radial diffusivity were seen. These were primarily related to reduced neurite density, with an additional relationship to reduced MWF in the temporal pole and anterolateral temporal neocortex. Changes were greater with increasing epilepsy duration. Bilaterally reduced cortical thickness in the mesial temporal lobe and centroparietal cortices was unrelated to neurite density and MWF.

Conclusions: Diffusivity changes in grey and white matter are primarily related to reduced neurite density with an additional relationship to reduced MWF in the temporal pole. Neurite density may represent a more sensitive and specific biomarker of progressive neuronal damage in refractory TLE that deserves further study.
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http://dx.doi.org/10.1016/j.nicl.2020.102231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063236PMC
February 2021

Validation of computational lesion detection methods in magnetic resonance imaging-negative, focal epilepsy.

Epilepsia 2020 04 25;61(4):828-830. Epub 2020 Feb 25.

Department of Clinical and Experimental Epilepsy, Queen Square Institute of Neurology, University College London, London, UK.

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http://dx.doi.org/10.1111/epi.16461DOI Listing
April 2020

Assessing various sensorimotor and cognitive functions in people with epilepsy is feasible with robotics.

Epilepsy Behav 2020 02 7;103(Pt A):106859. Epub 2020 Jan 7.

Centre for Neuroscience Studies, Botterell Hall, 18 Stuart Street, Queen's University, Kingston, ON K7L 3N6, Canada; Department of Medicine, Division of Neurology, Etherington Hall, 94 Stuart Street, Queen's University, Kingston, ON K7L 3N6, Canada; Kingston Health Sciences Centre, 76 Stuart St, Kingston, ON K7L 2V7, Canada. Electronic address:

Background: Epilepsy is a common neurological disorder characterized by recurrent seizures, along with comorbid cognitive and psychosocial impairment. Current gold standards of assessment can quantify cognitive and motor performance, but may not capture all subtleties of behavior. Here, we study the feasibility of assessing various upper limb sensorimotor and cognition functions in people with epilepsy using the Kinarm robotic assessment system. We quantify performance across multiple behavioral domains and additionally consider the possible effects of epilepsy subtype and medication.

Methods: We recruited individuals with a variety of epilepsy subtypes. Participants performed 8 behavioral tasks that tested motor, cognitive, and sensory domains. We collected data on the same tasks from a group of control participants that had no known neurological impairments. We quantified performance using Task Scores, which provide a composite measure of overall performance on a given task and are adjusted for age, sex, and handedness.

Results: We collected data from 46 individuals with epilepsy and 92 control participants. The assessment was well-tolerated, with no adverse events recorded. Cognitive tasks testing spatial working memory, executive function, and motor response inhibition were the most frequently impaired in the epilepsy cohort, with 33/46 (72%) being outside the normal range on at least one of these tasks. Additionally, 29/46 (63%) were impaired on at least one task testing primarily motor skill, and 14/46 (30%) were impaired on a proprioceptive sensory task. People with either focal epilepsy or generalized epilepsy performed significantly worse on both motor and cognitive tasks than control participants after correcting for multiple comparisons. There were no statistical differences between generalized and focal epilepsy groups on Task Scores. Finally, individuals taking topiramate trended toward having worse performance on a spatial working memory task than other individuals with epilepsy who were not taking topiramate.

Conclusions: Kinarm robotic assessment is feasible in individuals with epilepsy and is well-tolerated. Our robotic paradigm can detect impairments in various sensorimotor and cognitive functions across the population with epilepsy. Future studies will explore the role of epilepsy subtype and medications.
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http://dx.doi.org/10.1016/j.yebeh.2019.106859DOI Listing
February 2020

Hippocampal profiling: Localized magnetic resonance imaging volumetry and T2 relaxometry for hippocampal sclerosis.

Epilepsia 2020 02 24;61(2):297-309. Epub 2019 Dec 24.

Epilepsy Society MRI Unit, Chalfont St Peter, UK.

Objective: Hippocampal sclerosis (HS) is the most common cause of drug-resistant temporal lobe epilepsy, and its accurate detection is important to guide epilepsy surgery. Radiological features of HS include hippocampal volume loss and increased T2 signal, which can both be quantified to help improve detection. In this work, we extend these quantitative methods to generate cross-sectional area and T2 profiles along the hippocampal long axis to improve the localization of hippocampal abnormalities.

Methods: T1-weighted and T2 relaxometry data from 69 HS patients (32 left, 32 right, 5 bilateral) and 111 healthy controls were acquired on a 3-T magnetic resonance imaging (MRI) scanner. Automated hippocampal segmentation and T2 relaxometry were performed and used to calculate whole-hippocampal volumes and to estimate quantitative T2 (qT2) values. By generating a group template from the controls, and aligning this so that the hippocampal long axes were along the anterior-posterior axis, we were able to calculate hippocampal cross-sectional area and qT2 by a slicewise method to localize any volume loss or T2 hyperintensity. Individual patient profiles were compared with normative data generated from the healthy controls.

Results: Profiling of hippocampal volumetric and qT2 data could be performed automatically and reproducibly. HS patients commonly showed widespread decreases in volume and increases in T2 along the length of the affected hippocampus, and focal changes may also be identified. Patterns of atrophy and T2 increase in the left hippocampus were similar between left, right, and bilateral HS. These profiles have potential to distinguish between sclerosis affecting volume and qT2 in the whole or parts of the hippocampus, and may aid the radiological diagnosis in uncertain cases or cases with subtle or focal abnormalities where standard whole-hippocampal measurements yield normal values.

Significance: Hippocampal profiling of volumetry and qT2 values can help spatially localize hippocampal MRI abnormalities and work toward improved sensitivity of subtle focal lesions.
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http://dx.doi.org/10.1111/epi.16416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065164PMC
February 2020

Learning to see the invisible: A data-driven approach to finding the underlying patterns of abnormality in visually normal brain magnetic resonance images in patients with temporal lobe epilepsy.

Epilepsia 2019 12 6;60(12):2499-2507. Epub 2019 Nov 6.

Department of Clinical and Experimental Epilepsy, Queen Square Institute of Neurology, University College London, London, UK.

Objective: To find the covert patterns of abnormality in patients with unilateral temporal lobe epilepsy (TLE) and visually normal brain magnetic resonance images (MRI-negative), comparing them to those with visible abnormalities (MRI-positive).

Methods: We used multimodal brain MRI from patients with unilateral TLE and employed contemporary machine learning methods to predict the known laterality of seizure onset in 104 subjects (82 MRI-positive, 22 MRI-negative). A visualization approach entitled "Importance Maps" was developed to highlight image features predictive of seizure laterality in both the MRI-positive and MRI-negative cases.

Results: Seizure laterality could be predicted with an area under the receiver operating characteristic curve of 0.981 (95% confidence interval [CI] =0.974-0.989) in MRI-positive and 0.842 (95% CI = 0.736-0.949) in MRI-negative cases. The known image features arising from the hippocampus were the leading predictors of seizure laterality in the MRI-positive cases, whereas widespread temporal lobe abnormalities were revealed in the MRI-negative cases.

Significance: Covert abnormalities not discerned on visual reading were detected in MRI-negative TLE, with a spatial pattern involving the whole temporal lobe, rather than just the hippocampus. This suggests that MRI-negative TLE may be associated with subtle but widespread temporal lobe abnormalities. These abnormalities merit close inspection and postacquisition processing if there is no overt lesion.
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http://dx.doi.org/10.1111/epi.16380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972547PMC
December 2019

Abnormal hippocampal structure and function in juvenile myoclonic epilepsy and unaffected siblings.

Brain 2019 09;142(9):2670-2687

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London, UK.

Juvenile myoclonic epilepsy is the most common genetic generalized epilepsy syndrome, characterized by a complex polygenetic aetiology. Structural and functional MRI studies demonstrated mesial or lateral frontal cortical derangements and impaired fronto-cortico-subcortical connectivity in patients and their unaffected siblings. The presence of hippocampal abnormalities and associated memory deficits is controversial, and functional MRI studies in juvenile myoclonic epilepsy have not tested hippocampal activation. In this observational study, we implemented multi-modal MRI and neuropsychological data to investigate hippocampal structure and function in 37 patients with juvenile myoclonic epilepsy, 16 unaffected siblings and 20 healthy controls, comparable for age, gender, handedness and hemispheric dominance as assessed with language laterality indices. Automated hippocampal volumetry was complemented by validated qualitative and quantitative morphological criteria to detect hippocampal malrotation, assumed to represent a neurodevelopmental marker. Neuropsychological measures of verbal and visuo-spatial learning and an event-related verbal and visual memory functional MRI paradigm addressed mesiotemporal function. We detected a reduction of mean left hippocampal volume in patients and their siblings compared with controls (P < 0.01). Unilateral or bilateral hippocampal malrotation was identified in 51% of patients and 50% of siblings, against 15% of controls (P < 0.05). For bilateral hippocampi, quantitative markers of verticalization had significantly larger values in patients and siblings compared with controls (P < 0.05). In the patient subgroup, there was no relationship between structural measures and age at disease onset or degree of seizure control. No overt impairment of verbal and visual memory was identified with neuropsychological tests. Functional mapping highlighted atypical patterns of hippocampal activation, pointing to abnormal recruitment during verbal encoding in patients and their siblings [P < 0.05, familywise error (FWE)-corrected]. Subgroup analyses indicated distinct profiles of hypoactivation along the hippocampal long axis in juvenile myoclonic epilepsy patients with and without malrotation; patients with malrotation also exhibited reduced frontal recruitment for verbal memory, and more pronounced left posterior hippocampal involvement for visual memory. Linear models across the entire study cohort indicated significant associations between morphological markers of hippocampal positioning and hippocampal activation for verbal items (all P < 0.05, FWE-corrected). We demonstrate abnormalities of hippocampal volume, shape and positioning in patients with juvenile myoclonic epilepsy and their siblings, which are associated with reorganization of function and imply an underlying neurodevelopmental mechanism with expression during the prenatal stage. Co-segregation of abnormal hippocampal morphology in patients and their siblings is suggestive of a genetic imaging phenotype, independent of disease activity, and can be construed as a novel endophenotype of juvenile myoclonic epilepsy.
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http://dx.doi.org/10.1093/brain/awz215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776114PMC
September 2019

Automated fiber tract reconstruction for surgery planning: Extensive validation in language-related white matter tracts.

Neuroimage Clin 2019 28;23:101883. Epub 2019 May 28.

School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK.

Diffusion MRI and tractography hold great potential for surgery planning, especially to preserve eloquent white matter during resections. However, fiber tract reconstruction requires an expert with detailed understanding of neuroanatomy. Several automated approaches have been proposed, using different strategies to reconstruct the white matter tracts in a supervised fashion. However, validation is often limited to comparison with manual delineation by overlap-based measures, which is limited in characterizing morphological and topological differences. In this work, we set up a fully automated pipeline based on anatomical criteria that does not require manual intervention, taking advantage of atlas-based criteria and advanced acquisition protocols available on clinical-grade MRI scanners. Then, we extensively validated it on epilepsy patients with specific focus on language-related bundles. The validation procedure encompasses different approaches, including simple overlap with manual segmentations from two experts, feasibility ratings from external multiple clinical raters and relation with task-based functional MRI. Overall, our results demonstrate good quantitative agreement between automated and manual segmentation, in most cases better performances of the proposed method in qualitative terms, and meaningful relationships with task-based fMRI. In addition, we observed significant differences between experts in terms of both manual segmentation and external ratings. These results offer important insights on how different levels of validation complement each other, supporting the idea that overlap-based measures, although quantitative, do not offer a full perspective on the similarities and differences between automated and manual methods.
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http://dx.doi.org/10.1016/j.nicl.2019.101883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545442PMC
June 2020

Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy.

Epilepsia 2019 04 14;60(4):718-729. Epub 2019 Mar 14.

Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, UK.

Objective: The processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk.

Methods: We retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high-risk (n = 25) or low-risk (n = 23), and age- and sex-matched healthy controls (n = 25) with identical high-resolution T1-weighted scans. Regional gray matter volume, determined by voxel-based morphometry, and segmentation-derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex.

Results: Substantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high-risk subjects and absent in low-risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High-risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high-risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging.

Significance: SUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.
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http://dx.doi.org/10.1111/epi.14689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479118PMC
April 2019

Association of Piriform Cortex Resection With Surgical Outcomes in Patients With Temporal Lobe Epilepsy.

JAMA Neurol 2019 06;76(6):690-700

UK National Institute for Health Research, University College London (UCL) Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom.

Importance: A functional area associated with the piriform cortex, termed area tempestas, has been implicated in animal studies as having a crucial role in modulating seizures, but similar evidence is limited in humans.

Objective: To assess whether removal of the piriform cortex is associated with postoperative seizure freedom in patients with temporal lobe epilepsy (TLE) as a proof-of-concept for the relevance of this area in human TLE.

Design, Setting, And Participants: This cohort study used voxel-based morphometry and volumetry to assess differences in structural magnetic resonance imaging (MRI) scans in consecutive patients with TLE who underwent epilepsy surgery in a single center from January 1, 2005, through December 31, 2013. Participants underwent presurgical and postsurgical structural MRI and had at least 2 years of postoperative follow-up (median, 5 years; range, 2-11 years). Patients with MRI of insufficient quality were excluded. Findings were validated in 2 independent cohorts from tertiary epilepsy surgery centers. Study follow-up was completed on September 23, 2016, and data were analyzed from September 24, 2016, through April 24, 2018.

Exposures: Standard anterior temporal lobe resection.

Main Outcomes And Measures: Long-term postoperative seizure freedom.

Results: In total, 107 patients with unilateral TLE (left-sided in 68; 63.6% women; median age, 37 years [interquartile range {IQR}, 30-45 years]) were included in the derivation cohort. Reduced postsurgical gray matter volumes were found in the ipsilateral piriform cortex in the postoperative seizure-free group (n = 46) compared with the non-seizure-free group (n = 61). A larger proportion of the piriform cortex was resected in the seizure-free compared with the non-seizure-free groups (median, 83% [IQR, 64%-91%] vs 52% [IQR, 32%-70%]; P < .001). The results were seen in left- and right-sided TLE and after adjusting for clinical variables, presurgical gray matter alterations, presurgical hippocampal volumes, and the proportion of white matter tract disconnection. Findings were externally validated in 2 independent cohorts (31 patients; left-sided TLE in 14; 54.8% women; median age, 41 years [IQR, 31-46 years]). The resected proportion of the piriform cortex was individually associated with seizure outcome after surgery (derivation cohort area under the curve, 0.80 [P < .001]; external validation cohorts area under the curve, 0.89 [P < .001]). Removal of at least half of the piriform cortex increased the odds of becoming seizure free by a factor of 16 (95% CI, 5-47; P < .001). Other mesiotemporal structures (ie, hippocampus, amygdala, and entorhinal cortex) and the overall resection volume were not associated with outcomes.

Conclusions And Relevance: These results support the importance of resecting the piriform cortex in neurosurgical treatment of TLE and suggest that this area has a key role in seizure generation.
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http://dx.doi.org/10.1001/jamaneurol.2019.0204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490233PMC
June 2019

The impact of epilepsy surgery on the structural connectome and its relation to outcome.

Neuroimage Clin 2018 31;18:202-214. Epub 2018 Jan 31.

NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter SL9 0LR, UK.

Background: Temporal lobe surgical resection brings seizure remission in up to 80% of patients, with long-term complete seizure freedom in 41%. However, it is unclear how surgery impacts on the structural white matter network, and how the network changes relate to seizure outcome.

Methods: We used white matter fibre tractography on preoperative diffusion MRI to generate a structural white matter network, and postoperative T1-weighted MRI to retrospectively infer the impact of surgical resection on this network. We then applied graph theory and machine learning to investigate the properties of change between the preoperative and predicted postoperative networks.

Results: Temporal lobe surgery had a modest impact on global network efficiency, despite the disruption caused. This was due to alternative shortest paths in the network leading to widespread increases in betweenness centrality post-surgery. Measurements of network change could retrospectively predict seizure outcomes with 79% accuracy and 65% specificity, which is twice as high as the empirical distribution. Fifteen connections which changed due to surgery were identified as useful for prediction of outcome, eight of which connected to the ipsilateral temporal pole.

Conclusion: Our results suggest that the use of network change metrics may have clinical value for predicting seizure outcome. This approach could be used to prospectively predict outcomes given a suggested resection mask using preoperative data only.
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http://dx.doi.org/10.1016/j.nicl.2018.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987798PMC
February 2019

Computer-assisted planning for the insertion of stereoelectroencephalography electrodes for the investigation of drug-resistant focal epilepsy: an external validation study.

J Neurosurg 2018 Apr 1:1-10. Epub 2018 Apr 1.

1Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, and.

OBJECTIVEOne-third of cases of focal epilepsy are drug refractory, and surgery might provide a cure. Seizure-free outcome after surgery depends on the correct identification and resection of the epileptogenic zone. In patients with no visible abnormality on MRI, or in cases in which presurgical evaluation yields discordant data, invasive stereoelectroencephalography (SEEG) recordings might be necessary. SEEG is a procedure in which multiple electrodes are placed stereotactically in key targets within the brain to record interictal and ictal electrophysiological activity. Correlating this activity with seizure semiology enables identification of the seizure-onset zone and key structures within the ictal network. The main risk related to electrode placement is hemorrhage, which occurs in 1% of patients who undergo the procedure. Planning safe electrode placement for SEEG requires meticulous adherence to the following: 1) maximize the distance from cerebral vasculature, 2) avoid crossing sulcal pial boundaries (sulci), 3) maximize gray matter sampling, 4) minimize electrode length, 5) drill at an angle orthogonal to the skull, and 6) avoid critical neurological structures. The authors provide a validation of surgical strategizing and planning with EpiNav, a multimodal platform that enables automated computer-assisted planning (CAP) for electrode placement with user-defined regions of interest.METHODSThirteen consecutive patients who underwent implantation of a total 116 electrodes over a 15-month period were studied retrospectively. Models of the cortex, gray matter, and sulci were generated from patient-specific whole-brain parcellation, and vascular segmentation was performed on the basis of preoperative MR venography. Then, the multidisciplinary implantation strategy and precise trajectory planning were reconstructed using CAP and compared with the implemented manually determined plans. Paired results for safety metric comparisons were available for 104 electrodes. External validity of the suitability and safety of electrode entry points, trajectories, and target-point feasibility was sought from 5 independent, blinded experts from outside institutions.RESULTSCAP-generated electrode trajectories resulted in a statistically significant improvement in electrode length, drilling angle, gray matter-sampling ratio, minimum distance from segmented vasculature, and risk (p < 0.05). The blinded external raters had various opinions of trajectory feasibility that were not statistically significant, and they considered a mean of 69.4% of manually determined trajectories and 62.2% of CAP-generated trajectories feasible; 19.4% of the CAP-generated electrode-placement plans were deemed feasible when the manually determined plans were not, whereas 26.5% of the manually determined electrode-placement plans were rated feasible when CAP-determined plans were not (no significant difference).CONCLUSIONSCAP generates clinically feasible electrode-placement plans and results in statistically improved safety metrics. CAP is a useful tool for automating the placement of electrodes for SEEG; however, it requires the operating surgeon to review the results before implantation, because only 62% of electrode-placement plans were rated feasible, compared with 69% of the manually determined placement plans, mainly because of proximity of the electrodes to unsegmented vasculature. Improved vascular segmentation and sulcal modeling could lead to further improvements in the feasibility of CAP-generated trajectories.
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http://dx.doi.org/10.3171/2017.10.JNS171826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076995PMC
April 2018

Evaluation of prospective motion correction of high-resolution 3D-T2-FLAIR acquisitions in epilepsy patients.

J Neuroradiol 2018 Oct 2;45(6):368-373. Epub 2018 Mar 2.

Epilepsy Society MRI Unit, Chalfont St Peter, United Kingdom; Wellcome/EPSRC Centre for Interventional and Surgical Sciences (WEISS), University College London, London, United Kingdom; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.

T2-FLAIR is the single most sensitive MRI contrast to detect lesions underlying focal epilepsies but 3D sequences used to obtain isotropic high-resolution images are susceptible to motion artefacts. Prospective motion correction (PMC) - demonstrated to improve 3D-T1 image quality in a pediatric population - was applied to high-resolution 3D-T2-FLAIR scans in adult epilepsy patients to evaluate its clinical benefit. Coronal 3D-T2-FLAIR scans were acquired with a 1mm isotropic resolution on a 3T MRI scanner. Two expert neuroradiologists reviewed 40 scans without PMC and 40 with navigator-based PMC. Visual assessment addressed six criteria of image quality (resolution, SNR, WM-GM contrast, intensity homogeneity, lesion conspicuity, diagnostic confidence) on a seven-point Likert scale (from non-diagnostic to outstanding). SNR was also objectively quantified within the white matter. PMC scans had near-identical scores on the criteria of image quality to non-PMC scans, with the notable exception that intensity homogeneity was generally worse. Using PMC, the percentage of scans with bad image quality was substantially lower than without PMC (3.25% vs. 12.5%) on the other five criteria. Quantitative SNR estimates revealed that PMC and non-PMC had no significant difference in SNR (P=0.07). Application of prospective motion correction to 3D-T2-FLAIR sequences decreased the percentage of low-quality scans, reducing the number of scans that need to be repeated to obtain clinically useful data.
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http://dx.doi.org/10.1016/j.neurad.2018.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180279PMC
October 2018

Voxel-based magnetic resonance image postprocessing in epilepsy.

Epilepsia 2017 09 26;58(9):1653-1664. Epub 2017 Jul 26.

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Objective: Although the general utility of voxel-based processing of structural magnetic resonance imaging (MRI) data for detecting occult lesions in focal epilepsy is established, many differences exist among studies, and it is unclear which processing method is preferable. The aim of this study was to compare the ability of commonly used methods to detect epileptogenic lesions in magnetic resonance MRI-positive and MRI-negative patients, and to estimate their diagnostic yield.

Methods: We identified 144 presurgical focal epilepsy patients, 15 of whom had a histopathologically proven and MRI-visible focal cortical dysplasia; 129 patients were MRI negative with a clinical hypothesis of seizure origin, 27 of whom had resections. We applied four types of voxel-based morphometry (VBM), three based on T1 images (gray matter volume, gray matter concentration, junction map [JM]) and one based on normalized fluid-attenuated inversion recovery (nFSI). Specificity was derived from analysis of 50 healthy controls.

Results: The four maps had different sensitivity and specificity profiles. All maps showed detection rates for focal cortical dysplasia patients (MRI positive and negative) of >30% at a strict threshold of p < 0.05 (family-wise error) and >60% with a liberal threshold of p < 0.0001 (uncorrected), except for gray matter volume (14% and 27% detection rate). All maps except nFSI showed poor specificity, with high rates of false-positive findings in controls. In the MRI-negative patients, absolute detection rates were lower. A concordant nFSI finding had a significant positive odds ratio of 7.33 for a favorable postsurgical outcome in the MRI-negative group. Spatial colocalization of JM and nFSI was rare, yet showed good specificity throughout the thresholds.

Significance: All VBM variants had specific diagnostic properties that need to be considered for an adequate interpretation of the results. Overall, structural postprocessing can be a useful tool in presurgical diagnostics, but the low specificity of some maps has to be taken into consideration.
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http://dx.doi.org/10.1111/epi.13851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601223PMC
September 2017

Automated T2 relaxometry of the hippocampus for temporal lobe epilepsy.

Epilepsia 2017 09 12;58(9):1645-1652. Epub 2017 Jul 12.

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.

Objective: Hippocampal sclerosis (HS), the most common cause of refractory temporal lobe epilepsy, is associated with hippocampal volume loss and increased T2 signal. These can be identified on quantitative imaging with hippocampal volumetry and T2 relaxometry. Although hippocampal segmentation for volumetry has been automated, T2 relaxometry currently involves subjective and time-consuming manual delineation of regions of interest. In this work, we develop and validate an automated technique for hippocampal T2 relaxometry.

Methods: Fifty patients with unilateral or bilateral HS and 50 healthy controls underwent T -weighted and dual-echo fast recovery fast spin echo scans. Hippocampi were automatically segmented using a multi-atlas-based segmentation algorithm (STEPS) and a template database. Voxelwise T2 maps were determined using a monoexponential fit. The hippocampal segmentations were registered to the T2 maps and eroded to reduce partial volume effect. Voxels with T2 >170 msec excluded to minimize cerebrospinal fluid (CSF) contamination. Manual determination of T2 values was performed twice in each subject. Twenty controls underwent repeat scans to assess interscan reproducibility.

Results: Hippocampal T2 values were reliably determined using the automated method. There was a significant ipsilateral increase in T2 values in HS (p < 0.001), and a smaller but significant contralateral increase. The combination of hippocampal volumes and T2 values separated the groups well. There was a strong correlation between automated and manual methods for hippocampal T2 measurement (0.917 left, 0.896 right, both p < 0.001). Interscan reproducibility was superior for automated compared to manual measurements.

Significance: Automated hippocampal segmentation can be reliably extended to the determination of hippocampal T2 values, and a combination of hippocampal volumes and T2 values can separate subjects with HS from healthy controls. There is good agreement with manual measurements, and the technique is more reproducible on repeat scans than manual measurement. This protocol can be readily introduced into a clinical workflow for the assessment of patients with focal epilepsy.
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http://dx.doi.org/10.1111/epi.13843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599984PMC
September 2017

Brain imaging in the assessment for epilepsy surgery.

Lancet Neurol 2016 Apr 24;15(4):420-33. Epub 2016 Feb 24.

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK; Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK; National Hospital for Neurology and Neurosurgery, London, UK.

Brain imaging has a crucial role in the presurgical assessment of patients with epilepsy. Structural imaging reveals most cerebral lesions underlying focal epilepsy. Advances in MRI acquisitions including diffusion-weighted imaging, post-acquisition image processing techniques, and quantification of imaging data are increasing the accuracy of lesion detection. Functional MRI can be used to identify areas of the cortex that are essential for language, motor function, and memory, and tractography can reveal white matter tracts that are vital for these functions, thus reducing the risk of epilepsy surgery causing new morbidities. PET, SPECT, simultaneous EEG and functional MRI, and electrical and magnetic source imaging can be used to infer the localisation of epileptic foci and assist in the design of intracranial EEG recording strategies. Progress in semi-automated methods to register imaging data into a common space is enabling the creation of multimodal three-dimensional patient-specific datasets. These techniques show promise for the demonstration of the complex relations between normal and abnormal structural and functional data and could be used to direct precise intracranial navigation and surgery for individual patients.
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http://dx.doi.org/10.1016/S1474-4422(15)00383-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736670PMC
April 2016

Memory network plasticity after temporal lobe resection: a longitudinal functional imaging study.

Brain 2016 Feb 10;139(Pt 2):415-30. Epub 2016 Jan 10.

1 Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 2 Epilepsy Society MRI Unit, Chesham Lane, Chalfont St. Peter SL9 0RJ, Buckinghamshire, UK

Anterior temporal lobe resection can control seizures in up to 80% of patients with temporal lobe epilepsy. Memory decrements are the main neurocognitive complication. Preoperative functional reorganization has been described in memory networks, but less is known of postoperative reorganization. We investigated reorganization of memory-encoding networks preoperatively and 3 and 12 months after surgery. We studied 36 patients with unilateral medial temporal lobe epilepsy (19 right) before and 3 and 12 months after anterior temporal lobe resection. Fifteen healthy control subjects were studied at three equivalent time points. All subjects had neuropsychological testing at each of the three time points. A functional magnetic resonance imaging memory-encoding paradigm of words and faces was performed with subsequent out-of-scanner recognition assessments. Changes in activations across the time points in each patient group were compared to changes in the control group in a single flexible factorial analysis. Postoperative change in memory across the time points was correlated with postoperative activations to investigate the efficiency of reorganized networks. Left temporal lobe epilepsy patients showed increased right anterior hippocampal and frontal activation at both 3 and 12 months after surgery relative to preoperatively, for word and face encoding, with a concomitant reduction in left frontal activation 12 months postoperatively. Right anterior hippocampal activation 12 months postoperatively correlated significantly with improved verbal learning in patients with left temporal lobe epilepsy from preoperatively to 12 months postoperatively. Preoperatively, there was significant left posterior hippocampal activation that was sustained 3 months postoperatively at word encoding, and increased at face encoding. For both word and face encoding this was significantly reduced from 3 to 12 months postoperatively. Patients with right temporal lobe epilepsy showed increased left anterior hippocampal activation on word encoding from 3 to 12 months postoperatively compared to preoperatively. On face encoding, left anterior hippocampal activations were present preoperatively and 12 months postoperatively. Left anterior hippocampal and orbitofrontal cortex activations correlated with improvements in both design and verbal learning 12 months postoperatively. On face encoding, there were significantly increased left posterior hippocampal activations that reduced significantly from 3 to 12 months postoperatively. Postoperative changes occur in the memory-encoding network in both left and right temporal lobe epilepsy patients across both verbal and visual domains. Three months after surgery, compensatory posterior hippocampal reorganization that occurs is transient and inefficient. Engagement of the contralateral hippocampus 12 months after surgery represented efficient reorganization in both patient groups, suggesting that the contralateral hippocampus contributes to memory outcome 12 months after surgery.
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http://dx.doi.org/10.1093/brain/awv365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805088PMC
February 2016

Simulated field maps for susceptibility artefact correction in interventional MRI.

Int J Comput Assist Radiol Surg 2015 Sep 16;10(9):1405-16. Epub 2015 Jul 16.

Centre for Medical Image Computing, University College London, London, UK,

Purpose: Intraoperative MRI (iMRI) is a powerful modality for acquiring images of the brain to facilitate precise image-guided neurosurgery. Diffusion-weighted MRI (DW-MRI) provides critical information about location, orientation and structure of nerve fibre tracts, but suffers from the "susceptibility artefact" stemming from magnetic field perturbations due to the step change in magnetic susceptibility at air-tissue boundaries in the head. An existing approach to correcting the artefact is to acquire a field map by means of an additional MRI scan. However, to recover true field maps from the acquired field maps near air-tissue boundaries is challenging, and acquired field maps are unavailable in historical MRI data sets. This paper reports a detailed account of our method to simulate field maps from structural MRI scans that was first presented at IPCAI 2014 and provides a thorough experimental and analysis section to quantitatively validate our technique.

Methods: We perform automatic air-tissue segmentation of intraoperative MRI scans, feed the segmentation into a field map simulation step and apply the acquired and the simulated field maps to correct DW-MRI data sets.

Results: We report results for 12 patient data sets acquired during anterior temporal lobe resection surgery for the surgical management of focal epilepsy. We find a close agreement between acquired and simulated field maps and observe a statistically significant reduction in the susceptibility artefact in DW-MRI data sets corrected using simulated field maps in the vicinity of the resection. The artefact reduction obtained using acquired field maps remains better than that using the simulated field maps in all evaluated regions of the brain.

Conclusions: The proposed simulated field maps facilitate susceptibility artefact reduction near the resection. Accurate air-tissue segmentation is key to achieving accurate simulation. The proposed simulation approach is adaptable to different iMRI and neurosurgical applications.
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http://dx.doi.org/10.1007/s11548-015-1253-7DOI Listing
September 2015