Predictors of long-term memory and network connectivity 10 years after anterior temporal lobe resection.

OBJECTIVE: Anterior temporal lobe resection (ATLR) effectively controls seizures in medically refractory temporal lobe epilepsy but risks significant episodic memory decline. Beyond 1 year postoperatively, the influence of preoperative clinical factors on episodic memory and long-term network plasticity remain underexplored. Ten years post-ATLR, we aimed to determine biomarkers of successful memory network reorganization and establish presurgical features' lasting impact on memory function. METHODS: Twenty-five ATLR patients (12 left-sided) and 10 healthy controls underwent a memory-encoding functional magnetic resonance imaging paradigm alongside neuropsychometry 10 years postsurgery. Generalized psychophysiological interaction analyses modeled network functional connectivity of words/faces remembered, seeding from the medial temporal lobes (MTLs). Differences in successful memory connectivity were assessed between controls and left/right ATLR. Multivariate regressions and mixed-effect models probed preoperative phenotypes' effects on long-term memory outcomes. RESULTS: Ten years post-ATLR, lower baseline functioning (verbal and performance intelligence quotient) and a focal memory impairment preoperatively predicted worse long-term memory outcomes. Poorer verbal memory was significantly associated with longer epilepsy duration and earlier onset age. Relative to controls, successful word and face encoding involved increased functional connectivity from both or remnant MTL seeds and contralesional parahippocampus/hippocampus after left/right ATLR. Irrespective of surgical laterality, successful memory encoding correlated with increased MTL-seeded connectivity to frontal (bilateral insula, right anterior cingulate), right parahippocampal, and bilateral fusiform gyri. Ten years postsurgery, better memory performance was correlated with contralateral frontal plasticity, which was disrupted with longer epilepsy duration. SIGNIFICANCE: Our findings underscore the enduring nature of functional network reorganizations to provide long-term cognitive support. Ten years post-ATLR, successful memory formation featured stronger connections near resected areas and contralateral regions. Preoperative network disruption possibly influenced effectiveness of postoperative plasticity. These findings are crucial for enhancing long-term memory prediction and strategies for lasting memory rehabilitation.

Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy.

Cognitive impairment is a common comorbidity of epilepsy and adversely impacts people with both frontal lobe (FLE) and temporal lobe (TLE) epilepsy. While its neural substrates have been investigated extensively in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devised a multiscale approach to map brain activation and deactivation during cognition and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems; and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, as well as reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE are broadly similar to those in TLE, but some patterns are syndrome-specific: altered default-mode deactivation is more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands is more marked in TLE. Functional abnormalities in FLE and TLE appear overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies and sheds light on system behaviour that may be amenable to future remediation strategies.

Identification of different MRI atrophy progression trajectories in epilepsy by subtype and stage inference.

Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy.In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy.Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualized prognostics and targeted therapeutics.

Robotic assessment of sensorimotor and cognitive deficits in patients with temporal lobe epilepsy.

OBJECTIVE: Individuals with temporal lobe epilepsy (TLE) frequently demonstrate impairments in executive function, working memory, and/or declarative memory. It is recommended that screening for cognitive impairment is undertaken in all people newly diagnosed with epilepsy. However, standard neuropsychological assessments are a limited resource and thus not available to all. Our study investigated the use of robotic technology (the Kinarm robot) for cognitive screening. METHODS: 27 participants with TLE (17 left) underwent both a brief neuropsychological screening and a robotic (Kinarm) assessment. The degree of impairments and correlations between standardized scores from both approaches to assessments were analysed across different neurocognitive domains. Performance was compared between people with left and right TLE to look for laterality effects. Finally, the association between the duration of epilepsy and performance was assessed. RESULTS: Across the 6 neurocognitive domains (attention, executive function, language, memory, motor and visuospatial) assessed by our neuropsychological screening, all showed scores that significantly correlated with Kinarm tasks assessing the same cognitive domains except language and memory that were not adequately assessed with Kinarm. Participants with right TLE performed worse on most tasks than those with left TLE, including both visuospatial (typically considered right hemisphere), and verbal memory and language tasks (typically considered left hemisphere). No correlations were found between the duration of epilepsy and either the neuropsychological screening or Kinarm assessment. SIGNIFICANCE: Our findings suggest that Kinarm may be a useful tool in screening for neurocognitive impairment in people with TLE. Further development may facilitate an easier and more rapid screening of cognition in people with epilepsy and distinguishing patterns of cognitive impairment.

Canadian Practice and Recommendations on Functional MRI to Lateralize Language in Epilepsy.

BACKGROUND/OBJECTIVE: Identifying a patient's dominant language hemisphere is an important evaluation performed prior to epilepsy surgery and is commonly assessed using functional magnetic resonance imaging (fMRI). However, the lack of standardization and resultant heterogeneity of fMRI paradigms used in clinical practice limits the ability of cross-center comparisons to be made regarding language laterality results. METHODS: Through surveying Canadian Epilepsy Centres in combination with reviewing supporting literature, current fMRI language lateralization practices for the clinical evaluation of patients with epilepsy were assessed. To encourage standardization of this practice, we outlined a two-part paradigm series that demonstrates widespread acceptance, reliability and accessibility in lateralizing various aspects of language functioning in individuals with average or near-average IQ and normal literacy skills. RESULTS: The collected data confirm a lack of standardization in fMRI laterality assessments leading to clinical heterogeneity in stimulation and control tasks, paradigm design and timing, laterality index calculations, thresholding values and analysis software and technique. We suggest a Sentence Completion (SC) and Word Generation (WG) paradigm series as it was most commonly employed across Canada, demonstrated reliability in lateralizing both receptive and expressive language areas in supporting literature, and could be readily intelligible to an inclusive population. CONCLUSION: Through providing recommendations for a two-part paradigm series, we hope to contribute to the standardization of this practice across Canada to reduce clinical heterogeneity, encourage communicability between institutions, and enhance methodologies for the surgical treatment of epilepsy for the benefit of all individuals living with epilepsy in Canada.

Quantitative susceptibility mapping identifies hippocampal and other subcortical grey matter tissue composition changes in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is associated with widespread brain alterations. Using quantitative susceptibility mapping (QSM) alongside transverse relaxation rate ( R 2 * ), we investigated regional brain susceptibility changes in 36 patients with left-sided (LTLE) or right-sided TLE (RTLE) secondary to hippocampal sclerosis, and 27 healthy controls (HC). We compared three susceptibility calculation methods to ensure image quality. Correlations of susceptibility and R 2 * with age of epilepsy onset, frequency of focal-to-bilateral tonic-clonic seizures (FBTCS), and neuropsychological test scores were examined. Weak-harmonic QSM (WH-QSM) successfully reduced noise and removed residual background field artefacts. Significant susceptibility increases were identified in the left putamen in the RTLE group compared to the LTLE group, the right putamen and right thalamus in the RTLE group compared to HC, and a significant susceptibility decrease in the left hippocampus in LTLE versus HC. LTLE patients who underwent epilepsy surgery showed significantly lower left-versus-right hippocampal susceptibility. Significant R 2 * changes were found between TLE and HC groups in the amygdala, putamen, thalamus, and in the hippocampus. Specifically, decreased R2 * was found in the left and right hippocampus in LTLE and RTLE, respectively, compared to HC. Susceptibility and R 2 * were significantly correlated with cognitive test scores in the hippocampus, globus pallidus, and thalamus. FBTCS frequency correlated positively with ipsilateral thalamic and contralateral putamen susceptibility and with R 2 * in bilateral globi pallidi. Age of onset was correlated with susceptibility in the hippocampus and putamen, and with R 2 * in the caudate. Susceptibility and R 2 * changes observed in TLE groups suggest selective loss of low-myelinated neurons alongside iron redistribution in the hippocampi, predominantly ipsilaterally, indicating QSM's sensitivity to local pathology. Increased susceptibility and R 2 * in the thalamus and putamen suggest increased iron content and reflect disease severity.

Altered amygdala volumes and microstructure in focal epilepsy patients with tonic-clonic seizures, ictal, and post-convulsive central apnea.

OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal-to-bilateral tonic-clonic seizures (FBTCS) are a major risk factor, and centrally-mediated respiratory depression may increase the risk further. Here, we determined the volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by the presence or absence of FBTCS, ictal central apnea (ICA), and post-convulsive central apnea (PCCA). METHODS: Seventy-three patients with focal impaired awareness seizures without FBTC seizures (FBTCneg group) and 30 with FBTCS (FBTCpos group) recorded during video electroencephalography (VEEG) with respiratory monitoring were recruited prospectively during presurgical investigations. We acquired high-resolution T1-weighted anatomic and multi-shell diffusion images, and computed neurite orientation dispersion and density imaging (NODDI) metrics in all patients with epilepsy and 69 healthy controls. Amygdala volumetric and microstructure alterations were compared between three groups: healthy subjects, FBTCneg and FBTCpos groups. The FBTCpos group was further subdivided by the presence of ICA and PCCA, verified by VEEG. RESULTS: Bilateral amygdala volumes were significantly increased in the FBTCpos cohort compared to healthy controls and the FBTCneg group. Patients with recorded PCCA had the highest increase in bilateral amygdala volume of the FBTCpos cohort. Amygdala neurite density index (NDI) values were decreased significantly in both the FBTCneg and FBTCpos groups relative to healthy controls, with values in the FBTCpos group being the lowest of the two. The presence of PCCA was associated with significantly lower NDI values vs the non-apnea FBTCpos group (p = 0.004). SIGNIFICANCE: Individuals with FBTCpos and PCCA show significantly increased amygdala volumes and disrupted architecture bilaterally, with greater changes on the left side. The structural alterations reflected by NODDI and volume differences may be associated with inappropriate cardiorespiratory patterns mediated by the amygdala, particularly after FBTCS. Determination of amygdala volumetric and architectural changes may assist identification of individuals at risk.

Episodic memory network connectivity in temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) affects brain networks and is associated with impairment of episodic memory. Temporal and extratemporal reorganization of memory functions is described in functional magnetic resonance imaging (fMRI) studies. Functional reorganizations have been shown at the local activation level, but network-level alterations have been underinvestigated. We aim to investigate the functional anatomy of memory networks using memory fMRI and determine how this relates to memory function in TLE. METHODS: Ninety patients with unilateral TLE (43 left) and 29 controls performed a memory-encoding fMRI paradigm of faces and words with subsequent out-of-scanner recognition test. Subsequent memory event-related contrasts of words and faces remembered were generated. Psychophysiological interaction analysis investigated task-associated changes in functional connectivity seeding from the mesial temporal lobes (MTLs). Correlations between changes in functional connectivity and clinical memory scores, epilepsy duration, age at epilepsy onset, and seizure frequency were investigated, and between connectivity supportive of better memory and disease burden. Connectivity differences between controls and TLE, and between TLE with and without hippocampal sclerosis, were explored using these confounds as regressors of no interest. RESULTS: Compared to controls, TLE patients showed widespread decreased connectivity between bilateral MTLs and frontal lobes, and increased local connectivity between the anterior MTLs bilaterally. Increased intrinsic connectivity within the bilateral MTLs correlated with better out-of-scanner memory performance in both left and right TLE. Longer epilepsy duration and higher seizure frequency were associated with decreased connectivity between bilateral MTLs and left/right orbitofrontal cortex (OFC) and insula, connections supportive of memory functions. TLE due to hippocampal sclerosis was associated with greater connectivity disruption within the MTL and extratemporally. SIGNIFICANCE: Connectivity analyses showed that TLE is associated with temporal and extratemporal memory network reorganization. Increased bilateral functional connectivity within the MTL and connectivity to OFC and insula are efficient, and are disrupted by greater disease burden.

Multivariate white matter alterations are associated with epilepsy duration.

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.

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

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.

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

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.

Decoupling of functional and structural language networks in temporal lobe epilepsy.

OBJECTIVE: To identify functional and structural alterations in language networks of people with temporal lobe epilepsy (TLE), who frequently present with naming and word-finding difficulties. METHODS: Fifty-five patients with unilateral TLE (29 left) and 16 controls were studied with auditory and picture naming functional magnetic resonance imaging (fMRI) tasks. Activation maxima in the left posterobasal temporal lobe were used as seed regions for whole-brain functional connectivity analyses (psychophysiological interaction). White matter language pathways were investigated using diffusion tensor imaging and neurite orientation dispersion and density imaging metrics extracted along fiber bundles starting from fMRI-guided seeds. Regression analyses were performed to investigate the correlation of functional connectivity with diffusion MRI metrics. RESULTS: In the whole group of patients and controls, weaker functional connectivity from the left posterobasal temporal lobe (1) to the bilateral anterior temporal lobe, precentral gyrus, and lingual gyrus during auditory naming and (2) to the bilateral occipital cortex and right fusiform gyrus during picture naming was associated with decreased neurite orientation dispersion and higher free water fraction of white matter tracts. Compared to controls, TLE patients exhibited fewer structural connections and an impaired coupling of functional and structural metrics. SIGNIFICANCE: TLE is associated with an impairment and decoupling of functional and structural language networks. White matter damage, as evidenced by diffusion abnormalities, may contribute to impaired functional connectivity and language dysfunction in TLE.

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

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.

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

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, η2p = 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.

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

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.

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

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 (SpO2 ) 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.

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

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.

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

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.

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

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.

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.

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.