Publications by authors named "Lorenzo Caciagli"

25 Publications

  • Page 1 of 1

Atypical neural topographies underpin dysfunctional pattern separation in temporal lobe epilepsy.

Brain 2021 Mar 17. Epub 2021 Mar 17.

Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.

Episodic memory is the ability to accurately remember events from our past. The process of pattern separation is hypothesized to underpin this ability and is defined as the ability to orthogonalize memory traces, to maximize the features that make them unique. Contemporary cognitive neuroscience suggests that pattern separation entails complex interactions between the hippocampus and the neocortex, where specific hippocampal subregions shape neural reinstatement in the neocortex. To test this hypothesis, the current work studied both healthy controls and patients with temporal lobe epilepsy (TLE) who present with hippocampal structural anomalies. In all participants, we measured neural activity using functional magnetic resonance imaging (fMRI) while they retrieved memorized items compared to lure items which share features with the target. Behaviorally, TLE patients were less able to exclude lures than controls, and showed a reduction in pattern separation. To assess the hypothesized relationship between neural patterns in the hippocampus and the neocortex, we identified topographic gradients of intrinsic connectivity along neocortical and hippocampal subfield surfaces and identified the topographic profile of the neural activity accompanying pattern separation. In healthy controls, pattern separation followed a graded pattern of neural activity, both along the hippocampal long axis (and peaked in anterior segments that are more heavily engaged in transmodal processing) and along the neocortical hierarchy running from unimodal to transmodal regions (peaking in transmodal default mode regions). In TLE patients, however, this concordance between task-based functional activations and topographic gradients was markedly reduced. Furthermore, person specific measures of concordance between task-related activity and connectivity gradients in patients and controls related to inter-individual differences in behavioral measures of pattern separation and episodic memory, highlighting the functional relevance of the observed topographic motifs. Our work is consistent with an emerging understanding that successful discrimination between memories with similar features entails a shift in the locus of neural activity away from sensory systems, a pattern that is mirrored along the hippocampal long axis and with respect to neocortical hierarchies. More broadly, our study establishes topographic profiling using intrinsic connectivity gradients captures the functional underpinnings of episodic memory processes in manner that is sensitive to their reorganization in pathology.
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http://dx.doi.org/10.1093/brain/awab121DOI Listing
March 2021

A Structure-Function Substrate of Memory for Spatial Configurations in Medial and Lateral Temporal Cortices.

Cereb Cortex 2021 Jun;31(7):3213-3225

McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada.

Prior research has shown a role of the medial temporal lobe, particularly the hippocampal-parahippocampal complex, in spatial cognition. Here, we developed a new paradigm, the conformational shift spatial task (CSST), which examines the ability to encode and retrieve spatial relations between unrelated items. This task is short, uses symbolic cues, incorporates two difficulty levels, and can be administered inside the scanner. A cohort of 48 healthy young adults underwent the CSST, together with a set of behavioral measures and multimodal magnetic resonance imaging (MRI). Inter-individual differences in CSST performance correlated with scores on an established spatial memory paradigm, but neither with episodic memory nor mnemonic discrimination, supporting specificity. Analyzing high-resolution structural MRI data, individuals with better spatial memory showed thicker medial and lateral temporal cortices. Functional relevance of these findings was supported by task-based functional MRI analysis in the same participants and ad hoc meta-analysis. Exploratory resting-state functional MRI analyses centered on clusters of morphological effects revealed additional modulation of intrinsic network integration, particularly between lateral and medial temporal structures. Our work presents a novel spatial memory paradigm and supports an integrated structure-function substrate in the human temporal lobe. Task paradigms are programmed in python and made open access.
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http://dx.doi.org/10.1093/cercor/bhab001DOI Listing
June 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

Impaired naming performance in temporal lobe epilepsy: language fMRI responses are modulated by disease characteristics.

J Neurol 2021 Jan 3;268(1):147-160. Epub 2020 Aug 3.

Epilepsy Society MRI Unit, Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0LR, UK.

Objective: To investigate alterations of language networks and their relation to impaired naming performance in temporal lobe epilepsy (TLE) using functional MRI.

Methods: Seventy-two adult TLE patients (41 left) and 36 controls were studied with overt auditory and picture naming fMRI tasks to assess temporal lobe language areas, and a covert verbal fluency task to probe frontal lobe language regions. Correlation of fMRI activation with clinical naming scores, and alteration of language network patterns in relation to epilepsy duration, age at onset and seizure frequency, were investigated with whole-brain multiple regression analyses.

Results: Auditory and picture naming fMRI activated the left posterior temporal lobe, and stronger activation correlated with better clinical naming scores. Verbal fluency MRI mainly activated frontal lobe regions. In left and right TLE, a later age of epilepsy onset related to stronger temporal lobe activations, while earlier age of onset was associated with impaired deactivation of extratemporal regions. In left TLE patients, longer disease duration and higher seizure frequency were associated with reduced deactivation. Frontal lobe language networks were unaffected by disease characteristics.

Conclusions: While frontal lobe language regions appear spared, temporal lobe language areas are susceptible to dysfunction and reorganisation, particularly in left TLE. Early onset and long duration of epilepsy, and high seizure frequency, were associated with compromised activation and deactivation patterns of task-associated regions, which might account for impaired naming performance in individuals with TLE.
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http://dx.doi.org/10.1007/s00415-020-10116-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815622PMC
January 2021

Noise removal in resting-state and task fMRI: functional connectivity and activation maps.

J Neural Eng 2020 08 19;17(4):046040. Epub 2020 Aug 19.

Department of Medical Physics and Bioengineering, University College London, London, United Kingdom. Author to whom any correspondence should be addressed.

Objective: Blood-oxygenated-level dependent (BOLD)-based functional magnetic resonance imaging (fMRI) is a widely used non-invasive tool for mapping brain function and connectivity. However, the BOLD signal is highly affected by non-neuronal contributions arising from head motion, physiological noise and scanner artefacts. Therefore, it is necessary to recover the signal of interest from the other noise-related fluctuations to obtain reliable functional connectivity (FC) results. Several pre-processing pipelines have been developed, mainly based on nuisance regression and independent component analysis (ICA). The aim of this work was to investigate the impact of seven widely used denoising methods on both resting-state and task fMRI.

Approach: Task fMRI can provide some ground truth given that the task administered has well established brain activations. The resulting cleaned data were compared using a wide range of measures: motion evaluation and data quality, resting-state networks and task activations, FC.

Main Results: Improved signal quality and reduced motion artefacts were obtained with all advanced pipelines, compared to the minimally pre-processed data. Larger variability was observed in the case of brain activation and FC estimates, with ICA-based pipelines generally achieving more reliable and accurate results.

Significance: This work provides an evidence-based reference for investigators to choose the most appropriate method for their study and data.
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http://dx.doi.org/10.1088/1741-2552/aba5ccDOI Listing
August 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

Macroscale and microcircuit dissociation of focal and generalized human epilepsies.

Commun Biol 2020 05 18;3(1):244. Epub 2020 May 18.

McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, 3801 University Street, Montreal, QC, H3A2B4, Canada.

Thalamo-cortical pathology plays key roles in both generalized and focal epilepsies, but there is little work directly comparing these syndromes at the level of whole-brain mechanisms. Using multimodal imaging, connectomics, and computational simulations, we examined thalamo-cortical and cortico-cortical signatures and underlying microcircuits in 96 genetic generalized (GE) and 107 temporal lobe epilepsy (TLE) patients, along with 65 healthy controls. Structural and functional network profiling highlighted extensive atrophy, microstructural disruptions and decreased thalamo-cortical connectivity in TLE, while GE showed only subtle structural anomalies paralleled by enhanced thalamo-cortical connectivity. Connectome-informed biophysical simulations indicated modest increases in subcortical drive contributing to cortical dynamics in GE, while TLE presented with reduced subcortical drive and imbalanced excitation-inhibition within limbic and somatomotor microcircuits. Multiple sensitivity analyses supported robustness. Our multiscale analyses differentiate human focal and generalized epilepsy at the systems-level, showing paradoxically more severe microcircuit and macroscale imbalances in the former.
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http://dx.doi.org/10.1038/s42003-020-0958-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234993PMC
May 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

Cognitive Function in Genetic Generalized Epilepsies: Insights From Neuropsychology and Neuroimaging.

Front Neurol 2020 10;11:144. Epub 2020 Mar 10.

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

Genetic generalized epilepsies (GGE), previously called idiopathic generalized epilepsies, constitute about 20% of all epilepsies, and include childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone (CAE, JAE, JME, and GGE-GTCS, respectively). GGE are characterized by high heritability, likely underlain by polygenetic mechanisms, which may relate to atypical neurodevelopmental trajectories. Age of onset ranges from pre-school years, for CAE, to early adulthood for GGE-GTCS. Traditionally, GGE have been considered benign, a belief contrary to evidence from neuropsychology studies conducted over the last two decades. In JME, deficits in executive and social functioning are common findings and relate to impaired frontal lobe function. Studies using neuropsychological measures and cognitive imaging paradigms provide evidence for hyperconnectivity between prefrontal and motor cortices, aberrant fronto-thalamo-cortical connectivity, and reduced fronto-cortical and subcortical gray matter volumes, which are associated with altered cognitive performance. Recent research has also identified associations between abnormal hippocampal morphometry and fronto-temporal activation during episodic memory. Longitudinal studies on individuals with newly diagnosed JME have observed cortical dysmaturation, which is paralleled by delayed cognitive development compared to the patients' peers. Comorbidities and cognitive deficits observed in other GGE subtypes, such as visuo-spatial and language deficits in both CAE and JAE, have also been correlated with atypical neurodevelopment. Although it remains unclear whether cognitive impairment profiles differ amongst GGE subtypes, effects may become more pronounced with disease duration, particularly in absence epilepsies. Finally, there is substantial evidence that patients with JME and their unaffected siblings share patterns of cognitive deficits, which is indicative of an underlying genetic etiology (endophenotype), independent of seizures and anti-epileptic medication.
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http://dx.doi.org/10.3389/fneur.2020.00144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076110PMC
March 2020

Preoperative language mapping using navigated TMS compared with extra-operative direct cortical stimulation using intracranial electrodes: A case report.

Seizure 2020 Feb 8;76:96-99. Epub 2020 Feb 8.

Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, United Kingdom; Department of Clinical & Experimental Epilepsy, UCL, Queen Square Institute of Neurology, United Kingdom.

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http://dx.doi.org/10.1016/j.seizure.2020.01.019DOI Listing
February 2020

Disrupted basal ganglia-thalamocortical loops in focal to bilateral tonic-clonic seizures.

Brain 2020 01;143(1):175-190

Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Focal to bilateral tonic-clonic seizures are associated with lower quality of life, higher risk of seizure-related injuries, increased chance of sudden unexpected death, and unfavourable treatment outcomes. Achieving greater understanding of their underlying circuitry offers better opportunity to control these seizures. Towards this goal, we provide a network science perspective of the interactive pathways among basal ganglia, thalamus and cortex, to explore the imprinting of secondary seizure generalization on the mesoscale brain network in temporal lobe epilepsy. Specifically, we parameterized the functional organization of both the thalamocortical network and the basal ganglia-thalamus network with resting state functional MRI in three groups of patients with different focal to bilateral tonic-clonic seizure histories. Using the participation coefficient to describe the pattern of thalamocortical connections among different cortical networks, we showed that, compared to patients with no previous history, those with positive histories of focal to bilateral tonic-clonic seizures, including both remote (none for >1 year) and current (within the past year) histories, presented more uniform distribution patterns of thalamocortical connections in the ipsilateral medial-dorsal thalamic nuclei. As a sign of greater thalamus-mediated cortico-cortical communication, this result comports with greater susceptibility to secondary seizure generalization from the epileptogenic temporal lobe to broader brain networks in these patients. Using interregional integration to characterize the functional interaction between basal ganglia and thalamus, we demonstrated that patients with current history presented increased interaction between putamen and globus pallidus internus, and decreased interaction between the latter and the thalamus, compared to the other two patient groups. Importantly, through a series of 'disconnection' simulations, we showed that these changes in interactive profiles of the basal ganglia-thalamus network in the current history group mainly depended upon the direct but not the indirect basal ganglia pathway. It is intuitively plausible that such disruption in the striatum-modulated tonic inhibition of the thalamus from the globus pallidus internus could lead to an under-suppressed thalamus, which in turn may account for their greater vulnerability to secondary seizure generalization. Collectively, these findings suggest that the broken balance between basal ganglia inhibition and thalamus synchronization can inform the presence and effective control of focal to bilateral tonic-clonic seizures. The mechanistic underpinnings we uncover may shed light on the development of new treatment strategies for patients with temporal lobe epilepsy.
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http://dx.doi.org/10.1093/brain/awz361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954388PMC
January 2020

Naming fMRI predicts the effect of temporal lobe resection on language decline.

Ann Clin Transl Neurol 2019 11 2;6(11):2186-2196. Epub 2019 Oct 2.

Epilepsy Society MRI Unit, Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0LR, United Kingdom.

Objective: To develop language functional MRI (fMRI) methods that accurately predict postsurgical naming decline in temporal lobe epilepsy (TLE).

Methods: Forty-six patients with TLE (25 left) and 19 controls underwent two overt fMRI paradigms (auditory naming and picture naming, both with active baseline conditions) and one covert task (verbal fluency). Clinical naming performance was assessed preoperatively and 4 months following anterior temporal lobe resection. Preoperative fMRI activations were correlated with postoperative naming decline. Individual laterality indices (LI) were calculated for temporal (auditory and picture naming) and frontal regions (verbal fluency) and were considered as predictors of naming decline in multiple regression models, along with other clinical variables (age at onset of seizures, preoperative naming scores, hippocampal volume, age).

Results: In left TLE patients, activation of the left posterior inferior temporal gyrus during auditory naming and activation of left fusiform gyrus during picture naming were related to greater postoperative naming decline. Activation LI were the best individual predictors of naming decline in a multivariate regression model. For picture naming, an LI of higher than 0.34 gave 100% sensitivity and 92% specificity (positive predictive value (PPV) 91.6%). For auditory naming, a temporal lobe LI higher than 0.18 identified all patients with a clinically significant naming decline with 100% sensitivity and 58% specificity (PPV: 58.3%). No effect was seen for verbal fluency.

Interpretation: Auditory and picture naming fMRI are clinically applicable to predict postoperative naming decline after left temporal lobe resection in individual patients, with picture naming being more specific.
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http://dx.doi.org/10.1002/acn3.50911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856622PMC
November 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

Progressive Cortical Thinning in Patients With Focal Epilepsy.

JAMA Neurol 2019 Oct;76(10):1230-1239

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

Importance: It is controversial whether epilepsy is a static or progressive disease. Evidence of progressive gray matter loss in epilepsy would support early diagnosis, rapid treatment, and early referral for surgical interventions.

Objective: To demonstrate progressive cortical thinning in patients with focal epilepsy distinct from cortical thinning associated with normal aging.

Design, Setting, And Participants: A case-control neuroimaging study was conducted from August 3, 2004, to January 26, 2016, among 190 patients with focal epilepsy at a tertiary epilepsy referral center (epilepsy data) and 3 independent comparison cohorts matched for age and sex (healthy volunteer data; n = 141).

Exposures: Two or more high-resolution T1-weighted magnetic resonance imaging scans at least 6 months apart (mean [SD] interval, 2.5 [1.6] years).

Main Outcomes And Measures: Global and vertexwise rate of progressive cortical thinning.

Results: A total of 190 people with focal epilepsy (99 women and 91 men; mean [SD] age, 36 [11] years; 396 magnetic resonance imaging scans) were compared with 141 healthy volunteers (76 women and 65 men; mean [SD] age, 35 [17] years; 282 magnetic resonance imaging scans). Widespread highly significant progressive cortical thinning exceeding normal aging effects, mainly involving the bilateral temporal lobes, medial parietal and occipital cortices, pericentral gyri, and opercula, was seen in 146 individuals with epilepsy (76.8%; 95% CI, 58%-95%). The mean (SD) annualized rate of global cortical thinning in patients with epilepsy was twice the rate of age-associated thinning observed in healthy volunteers (0.024 [0.061] vs 0.011 [0.029] mm/y; P = .01). Progression was most pronounced in adults older than 55 years and during the first 5 years after the onset of seizures. Areas of accelerated cortical thinning were detected in patients with early onset of epilepsy and in patients with hippocampal sclerosis. Accelerated thinning was not associated with seizure frequency, history of generalized seizures, or antiepileptic drug load and did not differ between patients with or without ongoing seizures. Progressive atrophy in temporal (n = 101) and frontal (n = 28) lobe epilepsy was most pronounced ipsilaterally to the epileptic focus but also affected a widespread area extending beyond the focus and commonly affected the contralateral hemisphere. For patients with temporal lobe epilepsy, accelerated cortical thinning was observed within areas structurally connected with the ipsilateral hippocampus.

Conclusions And Relevance: Widespread progressive cortical thinning exceeding that seen with normal aging may occur in patients with focal epilepsy. These findings appear to highlight the need to develop epilepsy disease-modifying treatments to disrupt or slow ongoing atrophy. Longitudinal cortical thickness measurements may have the potential to serve as biomarkers for such studies.
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http://dx.doi.org/10.1001/jamaneurol.2019.1708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604082PMC
October 2019

WONOEP appraisal: Network concept from an imaging perspective.

Epilepsia 2019 07 9;60(7):1293-1305. Epub 2019 Jun 9.

Neuroimaging of Epilepsy Laboratory, Department of Neurosciences and McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Neuroimaging techniques applied to a variety of organisms-from zebrafish, to rodents to humans-can offer valuable insights into neuronal network properties and their dysfunction in epilepsy. A wide range of imaging methods used to monitor neuronal circuits and networks during evoked seizures in animal models and advances in functional magnetic resonance imaging (fMRI) applied to patients with epilepsy were discussed during the XIV Workshop on Neurobiology of Epilepsy (XIV WONOEP) organized in 2017 by the Neurobiology Commission of the International League Against Epilepsy (ILAE). We review the growing number of technological approaches developed, as well as the current state of knowledge gained from studies applying these advanced imaging approaches to epilepsy research.
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http://dx.doi.org/10.1111/epi.16067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667743PMC
July 2019

Social cognition in idiopathic generalized epilepsies and potential neuroanatomical correlates.

Epilepsy Behav 2019 11 27;100(Pt B):106118. Epub 2019 Feb 27.

Neurology Unit, Pisa University Hospital, Pisa, Italy. Electronic address:

Social cognition allows us to elaborate mental representations of social relationships and use them appropriately in a social environment. One of its main attributes is the so-called Theory of Mind (ToM), which consists of the ability to attribute beliefs, intentions, emotions, and feelings to self and others. Investigating social cognition may help understand the poor social outcome often experienced by persons with Idiopathic Generalized Epilepsies (IGE), who otherwise present with normal intelligence. In recent years, several studies have addressed social cognition in subjects with focal epilepsies, while literature on social cognition in IGE is scarce, and findings are often conflicting. Some studies on samples of patients with mixed IGE showed difficulties in emotion attribution tasks, which were not replicated in a homogeneous population of patients with Juvenile Myoclonic Epilepsy alone. Impairment of higher order social skills, such as those assessed by Strange Stories Test and Faux Pas Tasks, were consistently found by different studies on mixed IGE, suggesting that this may be a more distinctive IGE-associated trait, irrespective of the specific syndrome subtype. Though an interplay between social cognition and executive functions (EF) was suggested by several authors, and their simultaneous impairment was shown in several epilepsy syndromes including IGE, no formal correlations among the two domains were identified in most studies. People with IGE exhibit subtle brain structural alterations in areas potentially involved in sociocognitive functional networks, including mesial prefrontal and temporoparietal cortices, which may relate to impairment in social cognition. Heterogeneity in patient samples, mostly consisting of groups with mixed IGE, and lack of analyses in specific IGE subsyndromes, represent evident limitations of the current literature. Larger studies, focusing on specific subsyndromes and implementing standardized test batteries, will improve our understanding of sociocognitive processing in IGE. Concomitant high-resolution structural and functional neuroimaging may aid the identification of its neural correlates. This article is part of the Special Issue "Epilepsy and social cognition across the lifespan".
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http://dx.doi.org/10.1016/j.yebeh.2019.01.003DOI Listing
November 2019

Left temporal lobe language network connectivity in temporal lobe epilepsy.

Brain 2018 08;141(8):2406-2418

Epilepsy Society MRI Unit, Epilepsy Society, Chalfont St Peter, SL9 0LR, UK.

Impairment of naming function is a critical problem for temporal lobe epilepsy patients, yet the neural correlates of the disruption of temporal lobe language networks are poorly understood. Using functional MRI, we investigated the activation and task-related functional connectivity of left temporal lobe language networks and their relation to clinical naming performance and disease characteristics. We studied 59 adult patients with temporal lobe epilepsy (35 left temporal lobe epilepsy) and 32 healthy controls with auditory and visual naming functional MRI tasks. Time series of activation maxima in the left posterior inferior temporal lobe were extracted to create a psychophysiological interaction regressor for subsequent seed-based whole-brain task-related functional connectivity analyses. Correlational analyses were performed to assess the association of functional MRI activation and functional connectivity with clinical naming scores, age of onset of epilepsy, and duration of epilepsy. Auditory naming elicited activation in the left posterior inferior temporal gyrus and visual naming in the left fusiform gyrus across all groups. Activations in the left inferior temporal gyrus, left thalamus and left supplementary motor region during auditory naming as well as left fusiform activations during picture naming correlated with better clinical naming performance. Functional connectivity analyses indicated coupling of left posterior inferior temporal regions to bilateral anterior and posterior temporal lobe regions and the bilateral inferior precentral gyrus as well as contralateral occipital cortex. Stronger functional connectivity was associated with better clinical naming performance in all groups. In patients with left temporal lobe epilepsy only, functional connectivity increased with later age of onset of epilepsy and shorter disease duration. This suggests that onset of seizures early in life and prolonged disease duration lead to disrupted recruitment of temporal lobe networks ipsilateral to the seizure focus, which might account for naming deficits in temporal lobe epilepsy.
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http://dx.doi.org/10.1093/brain/awy164DOI Listing
August 2018

Effects of carbamazepine and lamotrigine on functional magnetic resonance imaging cognitive networks.

Epilepsia 2018 07 13;59(7):1362-1371. Epub 2018 Jun 13.

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

Objective: To investigate the effects of sodium channel-blocking antiepileptic drugs (AEDs) on functional magnetic resonance imaging (fMRI) language network activations in patients with focal epilepsy.

Methods: In a retrospective study, we identified patients who were treated at the time of language fMRI scanning with either carbamazepine (CBZ; n = 42) or lamotrigine (LTG; n = 42), but not another sodium channel-blocking AED. We propensity-matched 42 patients taking levetiracetam (LEV) as "patient-controls" and included further 42 age- and gender-matched healthy controls. After controlling for age, age at onset of epilepsy, gender, and antiepileptic comedications, we compared verbal fluency fMRI activations between groups and out-of-scanner psychometric measures of verbal fluency.

Results: Patients on CBZ performed less well on a verbal fluency tests than those taking LTG or LEV. Compared to either LEV-treated patients or controls, patients taking CBZ showed decreased activations in left inferior frontal gyrus and patients on LTG showed abnormal deactivations in frontal and parietal default mode areas. All patient groups showed fewer activations in the putamen bilaterally compared to controls. In a post hoc analysis, out-of-scanner fluency scores correlated positively with left putamen activation.

Significance: Our study provides evidence of AED effects on the functional neuroanatomy of language, which might explain subtle language deficits in patients taking otherwise well-tolerated sodium channel-blocking agents. Patients on CBZ showed dysfunctional frontal activation and more pronounced impairment of performance than patients taking LTG, which was associated only with failure to deactivate task-negative networks. As previously shown for working memory, LEV treatment did not affect functional language networks.
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http://dx.doi.org/10.1111/epi.14448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216427PMC
July 2018

Imaging Biomarkers of Anti-Epileptic Drug Action: Insights from Magnetic Resonance Imaging.

Curr Pharm Des 2017 ;23(37):5727-5739

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

Background: Approximately one third of patients with epilepsy are refractory to medical treatment. Adverse effects associated with Anti-Epileptic Drugs (AEDs) are considered to affect quality of life often more than seizures themselves. Neuroimaging techniques, particularly Magnetic Resonance Imaging (MRI), have proven instrumental in clinical decision making in relation to epilepsy surgery, but may also provide further insights into the mechanisms underlying treatment response and side effects associated with AEDs.

Objective And Method: We searched PubMed and Scopus databases for original articles and reviews published in the last two decades, which addressed the effects of AEDs on structural MRI, functional MRI and Magnetic Resonance Spectroscopy (MRS) measures.

Results: The majority of investigations implemented task-based fMRI, and probed the influence of widely used anti-epileptic drugs on tasks assessing language, executive functions and emotion recognition. Collectively, MRI allows detecting reproducible AED-related effects on regions and networks relevant to disease pathomechanisms, thus elucidating the anatomo-functional substrates of cognitive side effects. MRS analyses shed light on the molecular correlates of AED action, and may provide indicators of treatment response.

Conclusion: MRI techniques have considerably improved our understanding of the effects of AEDs at a regional and network level, and provide biomarkers with potential to improve routine clinical decision making in epilepsy.
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http://dx.doi.org/10.2174/1381612823666170809113636DOI Listing
July 2019

A meta-analysis on progressive atrophy in intractable temporal lobe epilepsy: Time is brain?

Neurology 2017 Aug 7;89(5):506-516. Epub 2017 Jul 7.

From the Neuroimaging of Epilepsy Laboratory (L.C., A.B., N.B., B.C.B.) and Multimodal Imaging and Connectome Analysis Laboratory (B.C.B.), Montreal Neurological Institute and Hospital, McGill University; Department of Clinical Neurosciences (S.W.), University of Calgary, Canada; and Department of Clinical and Experimental Epilepsy (L.C., M.J.K.), UCL Institute of Neurology, London, UK.

Objective: It remains unclear whether drug-resistant temporal lobe epilepsy (TLE) is associated with cumulative brain damage, with no expert consensus and no quantitative syntheses of the available evidence.

Methods: We conducted a systematic review and meta-analysis of MRI studies on progressive atrophy, searching PubMed and Ovid MEDLINE databases for cross-sectional and longitudinal quantitative MRI studies on drug-resistant TLE.

Results: We screened 2,976 records and assessed eligibility of 248 full-text articles. Forty-two articles met the inclusion criteria for quantitative evaluation. We observed a predominance of cross-sectional studies, use of different clinical indices of progression, and high heterogeneity in age-control procedures. Meta-analysis of 18/1 cross-sectional/longitudinal studies on hippocampal atrophy (n = 979 patients) yielded a pooled effect size of = -0.42 for ipsilateral atrophy related to epilepsy duration (95% confidence interval [CI] -0.51 to -0.32; < 0.0001; = 65.22%) and = -0.35 related to seizure frequency (95% CI -0.47 to -0.22; < 0.0001; = 61.97%). Sensitivity analyses did not change the results. Narrative synthesis of 25/3 cross-sectional/longitudinal studies on whole brain atrophy (n = 1,504 patients) indicated that >80% of articles reported duration-related progression in extratemporal cortical and subcortical regions. Detailed analysis of study design features yielded low to moderate levels of evidence for progressive atrophy across studies, mainly due to dominance of cross-sectional over longitudinal investigations, use of diverse measures of seizure estimates, and absence of consistent age control procedures.

Conclusions: While the neuroimaging literature is overall suggestive of progressive atrophy in drug-resistant TLE, published studies have employed rather weak designs to directly demonstrate it. Longitudinal multicohort studies are needed to unequivocally differentiate aging from disease progression.
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http://dx.doi.org/10.1212/WNL.0000000000004176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539734PMC
August 2017

Cyclic alternating pattern and interictal epileptiform discharges during morning sleep after sleep deprivation in temporal lobe epilepsy.

Epilepsy Behav 2017 08 18;73:131-136. Epub 2017 Jul 18.

Department of Clinical and Experimental Medicine, Section of Neurology, University of Pisa and Pisa University Hospital, Pisa, Italy.

Purpose: Sleep deprivation (SD) increases the occurrence of interictal epileptiform discharges (IED) compared to basal EEG in temporal lobe epilepsy (TLE). In adults, EEG after SD is usually performed in the morning after SD. We aimed to evaluate whether morning sleep after SD bears additional IED-inducing effects compared with nocturnal physiological sleep, and whether changes in sleep stability (described by the cyclic alternating pattern-CAP) play a significant role.

Methods: Adult patients with TLE underwent in-lab night polysomnography (n-PSG) and, within 7days from n-PSG, they underwent also a morning EEG after night SD (SD-EEG). We included only TLE patients in which both recordings showed IED. SD-EEG consisted of waking up patients at 2:00 AM and performing video EEG at 8:00 AM. For both recordings, we obtained the following markers for the first sleep cycle: IED/h (Spike Index, SI), sleep macrostructure, microstructure (NREM CAP rate; A1, A2 and A3 Indices), and SI association with CAP variables.

Results: The macrostructure of the first sleep cycle was similar in n-PSG and morning SD-EEG, whereas CAP rate and SI were significantly higher in SD-EEG. SI increase was selectively associated with CAP phases.

Conclusions: SD increases the instability of morning recovery sleep compared with n-PSG, and particularly enhances CAP A1 phases, which are associated with the majority of IED. Thus, higher instability of morning recovery sleep may account at least in part for the increased IED yield in SD-EEG in TLE patients.
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http://dx.doi.org/10.1016/j.yebeh.2017.05.005DOI Listing
August 2017

Social cognition in Juvenile Myoclonic Epilepsy.

Epilepsy Res 2016 12 26;128:61-67. Epub 2016 Oct 26.

Neurology Unit, Department of Clinical and Experimental Medicine and University Hospital, University of Pisa, Pisa, Italy.

Objective: Juvenile Myoclonic Epilepsy (JME) is a common genetic generalized epilepsy syndrome. Several studies have detailed cognitive and imaging abnormalities pointing to frontal lobe dysfunction, as well as disadvantageous behavioral traits and poor social outcome, challenging the commonly held view of JME being a benign disorder. Social cognition is the ability to elaborate mental representations of social interactions and to use them correctly in social contexts, and includes Theory of Mind (ToM), which pertains to the attribution of cognitive and affective mental states to self and others and seems to rely on complex fronto-temporal interactions. ToM has been recently assessed in focal epilepsy syndromes, but little is available for generalized epilepsies. We performed a cross-sectional study to assess social cognition, with an emphasis on ToM, as well as standard cognitive functions in patients with JME.

Method: We recruited twenty JME patients and twenty matched controls. Tests used to assess social cognition and ToM included the Emotion Attribution Task, Strange Stories Task (SST), Faux Pas Task (FPT), Reading the Mind in the Eyes Task and Social Situation Task. Subjects were also assessed via an extensive neuropsychological battery.

Results: Patients exhibited worse performance in the SST and in several scores of the FPT. They also showed widespread cognitive impairment, involving executive functions, psychomotor speed, verbal and visuo-spatial memory.

Conclusions: In addition to cognitive impairment for fronto-temporal tasks, some features of social cognition are also altered in JME. The latter deficit may underlie the poor social outcome previously described for these patients, and might also relate to imaging findings of frontal lobe dysfunction.
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http://dx.doi.org/10.1016/j.eplepsyres.2016.10.017DOI Listing
December 2016

Reflex seizures, traits, and epilepsies: from physiology to pathology.

Lancet Neurol 2016 Jan 28;15(1):92-105. Epub 2015 Nov 28.

Department of Clinical Neurophysiology, Danish Epilepsy Centre, Dianalund, Denmark; Department of Clinical Neurophysiology, Aarhus University, Aarhus, Denmark.

Epileptic seizures are generally unpredictable and arise spontaneously. Patients often report non-specific triggers such as stress or sleep deprivation, but only rarely do seizures occur as a reflex event, in which they are objectively and consistently modulated, precipitated, or inhibited by external sensory stimuli or specific cognitive processes. The seizures triggered by such stimuli and processes in susceptible individuals can have different latencies. Once seizure-suppressing mechanisms fail and a critical mass (the so-called tipping point) of cortical activation is reached, reflex seizures stereotypically manifest with common motor features independent of the physiological network involved. The complexity of stimuli increases from simple sensory to complex cognitive-emotional with increasing age of onset. The topography of physiological networks involved follows the posterior-to-anterior trajectory of brain development, reflecting age-related changes in brain excitability. Reflex seizures and traits probably represent the extremes of a continuum, and understanding of their underlying mechanisms might help to elucidate the transition of normal physiological function to paroxysmal epileptic activity.
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http://dx.doi.org/10.1016/S1474-4422(15)00219-7DOI Listing
January 2016

Functional network alterations and their structural substrate in drug-resistant epilepsy.

Front Neurosci 2014 11;8:411. Epub 2014 Dec 11.

Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Center, Montreal Neurological Institute and Hospital, McGill University Montreal, QC, Canada.

The advent of MRI has revolutionized the evaluation and management of drug-resistant epilepsy by allowing the detection of the lesion associated with the region that gives rise to seizures. Recent evidence indicates marked chronic alterations in the functional organization of lesional tissue and large-scale cortico-subcortical networks. In this review, we focus on recent methodological developments in functional MRI (fMRI) analysis techniques and their application to the two most common drug-resistant focal epilepsies, i.e., temporal lobe epilepsy related to mesial temporal sclerosis and extra-temporal lobe epilepsy related to focal cortical dysplasia. We put particular emphasis on methodological developments in the analysis of task-free or "resting-state" fMRI to probe the integrity of intrinsic networks on a regional, inter-regional, and connectome-wide level. In temporal lobe epilepsy, these techniques have revealed disrupted connectivity of the ipsilateral mesiotemporal lobe, together with contralateral compensatory reorganization and striking reconfigurations of large-scale networks. In cortical dysplasia, initial observations indicate functional alterations in lesional, peri-lesional, and remote neocortical regions. While future research is needed to critically evaluate the reliability, sensitivity, and specificity, fMRI mapping promises to lend distinct biomarkers for diagnosis, presurgical planning, and outcome prediction.
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http://dx.doi.org/10.3389/fnins.2014.00411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263093PMC
January 2015

What is the role for EEG after sleep deprivation in the diagnosis of epilepsy? Issues, controversies, and future directions.

Neurosci Biobehav Rev 2014 Nov;47:533-48

In patients with a first seizure, the identification of early sensitive and specific biomarkers for formulating a diagnosis of epilepsy is fundamental. Sleep deprivation (SD) has long been used as a means of enhancing EEG sensitivity in the diagnostic process. However, huge methodological differences among the studies addressing this topic have led to highly variable results and often confusing assumptions. Here, we provide a detailed description of the correlations between SD and epilepsy, along with their putative mechanistic explanations derived from experimental studies in animals and humans. We also outline the clinical studies evaluating the role of SD EEG and discuss them critically in terms of: (a) study design and SD EEG methodology; (b) EEG sensitivity and specificity; (c) the role of drug-induced sleep EEG and EEG during spontaneously occurring sleep; and (d) the relevance of patient features, syndromes, and subsyndromes, as well as their correlations with neuroimaging details. Finally, we propose specific studies that might increase the role of SD EEG in the diagnosis and prognosis of epilepsy.
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http://dx.doi.org/10.1016/j.neubiorev.2014.10.005DOI Listing
November 2014