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.

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.

Optimal Surgical Extent for Memory and Seizure Outcome in Temporal Lobe Epilepsy.

OBJECTIVE: Postoperative memory decline is an important consequence of anterior temporal lobe resection (ATLR) for temporal lobe epilepsy (TLE), and the extent of resection may be a modifiable factor. This study aimed to define optimal resection margins for cognitive outcome while maintaining a high rate of postoperative seizure freedom. METHODS: This cohort study evaluated the resection extent on postoperative structural MRI using automated voxel-based methods and manual measurements in 142 consecutive patients with unilateral drug refractory TLE (74 left, 68 right TLE) who underwent standard ATLR. RESULTS: Voxel-wise analyses revealed that postsurgical verbal memory decline correlated with resections of the posterior hippocampus and inferior temporal gyrus, whereas larger resections of the fusiform gyrus were associated with worsening of visual memory in left TLE. Limiting the posterior extent of left hippocampal resection to 55% reduced the odds of significant postoperative verbal memory decline by a factor of 8.1 (95% CI 1.5-44.4, p = 0.02). Seizure freedom was not related to posterior resection extent, but to the piriform cortex removal after left ATLR. In right TLE, variability of the posterior extent of resection was not associated with verbal and visual memory decline or seizures after surgery. INTERPRETATION: The extent of surgical resection is an independent and modifiable risk factor for cognitive decline and seizures after left ATLR. Adapting the posterior extent of left ATLR might optimize postoperative outcome, with reduced risk of memory impairment while maintaining comparable seizure-freedom rates. The current, more lenient, approach might be appropriate for right ATLR. ANN NEUROL 2022;91:131-144.

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.

Diffusion MRI of the facial-vestibulocochlear nerve complex: a prospective clinical validation study.

OBJECTIVES: Surgical planning of vestibular schwannoma surgery would benefit greatly from a robust method of delineating the facial-vestibulocochlear nerve complex with respect to the tumour. This study aimed to optimise a multi-shell readout-segmented diffusion-weighted imaging (rs-DWI) protocol and develop a novel post-processing pipeline to delineate the facial-vestibulocochlear complex within the skull base region, evaluating its accuracy intraoperatively using neuronavigation and tracked electrophysiological recordings. METHODS: In a prospective study of five healthy volunteers and five patients who underwent vestibular schwannoma surgery, rs-DWI was performed and colour tissue maps (CTM) and probabilistic tractography of the cranial nerves were generated. In patients, the average symmetric surface distance (ASSD) and 95% Hausdorff distance (HD-95) were calculated with reference to the neuroradiologist-approved facial nerve segmentation. The accuracy of patient results was assessed intraoperatively using neuronavigation and tracked electrophysiological recordings. RESULTS: Using CTM alone, the facial-vestibulocochlear complex of healthy volunteer subjects was visualised on 9/10 sides. CTM were generated in all 5 patients with vestibular schwannoma enabling the facial nerve to be accurately identified preoperatively. The mean ASSD between the annotators' two segmentations was 1.11 mm (SD 0.40) and the mean HD-95 was 4.62 mm (SD 1.78). The median distance from the nerve segmentation to a positive stimulation point was 1.21 mm (IQR 0.81-3.27 mm) and 2.03 mm (IQR 0.99-3.84 mm) for the two annotators, respectively. CONCLUSIONS: rs-DWI may be used to acquire dMRI data of the cranial nerves within the posterior fossa. CLINICAL RELEVANCE STATEMENT: Readout-segmented diffusion-weighted imaging and colour tissue mapping provide 1-2 mm spatially accurate imaging of the facial-vestibulocochlear nerve complex, enabling accurate preoperative localisation of the facial nerve. This study evaluated the technique in 5 healthy volunteers and 5 patients with vestibular schwannoma. KEY POINTS: • Readout-segmented diffusion-weighted imaging (rs-DWI) with colour tissue mapping (CTM) visualised the facial-vestibulocochlear nerve complex on 9/10 sides in 5 healthy volunteer subjects. • Using rs-DWI and CTM, the facial nerve was visualised in all 5 patients with vestibular schwannoma and within 1.21-2.03 mm of the nerve's true intraoperative location. • Reproducible results were obtained on different scanners.

Normative brain mapping of interictal intracranial EEG to localize epileptogenic tissue.

The identification of abnormal electrographic activity is important in a wide range of neurological disorders, including epilepsy for localizing epileptogenic tissue. However, this identification may be challenging during non-seizure (interictal) periods, especially if abnormalities are subtle compared to the repertoire of possible healthy brain dynamics. Here, we investigate if such interictal abnormalities become more salient by quantitatively accounting for the range of healthy brain dynamics in a location-specific manner. To this end, we constructed a normative map of brain dynamics, in terms of relative band power, from interictal intracranial recordings from 234 participants (21 598 electrode contacts). We then compared interictal recordings from 62 patients with epilepsy to the normative map to identify abnormal regions. We proposed that if the most abnormal regions were spared by surgery, then patients would be more likely to experience continued seizures postoperatively. We first confirmed that the spatial variations of band power in the normative map across brain regions were consistent with healthy variations reported in the literature. Second, when accounting for the normative variations, regions that were spared by surgery were more abnormal than those resected only in patients with persistent postoperative seizures (t = -3.6, P = 0.0003), confirming our hypothesis. Third, we found that this effect discriminated patient outcomes (area under curve 0.75 P = 0.0003). Normative mapping is a well-established practice in neuroscientific research. Our study suggests that this approach is feasible to detect interictal abnormalities in intracranial EEG, and of potential clinical value to identify pathological tissue in epilepsy. Finally, we make our normative intracranial map publicly available to facilitate future investigations in epilepsy and beyond.

Structure and function of language networks in temporal lobe epilepsy.

Individuals with temporal lobe epilepsy (TLE) may have significant language deficits. Language capabilities may further decline following temporal lobe resections. The language network, comprising dispersed gray matter regions interconnected with white matter fibers, may be atypical in individuals with TLE. This review explores the structural changes to the language network and the functional reorganization of language abilities in TLE. We discuss the importance of detailed reporting of patient's characteristics, such as, left- and right-sided focal epilepsies as well as lesional and nonlesional pathological subtypes. These factors can affect the healthy functioning of gray and/or white matter. Dysfunction of white matter and displacement of gray matter function could concurrently impact their ability, in turn, producing an interactive effect on typical language organization and function. Surgical intervention can result in impairment of function if the resection includes parts of this structure-function network that are critical to language. In addition, impairment may occur if language function has been reorganized and is included in a resection. Conversely, resection of an epileptogenic zone may be associated with recovery of cortical function and thus improvement in language function. We explore the abnormality of functional regions in a clinically applicable framework and highlight the differences in the underlying language network. Avoidance of language decline following surgical intervention may depend on tailored resections to avoid critical areas of gray matter and their white matter connections. Further work is required to elucidate the plasticity of the language network in TLE and to identify sub-types of language representation, both of which will be useful in planning surgery to spare language function.

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.

Event-based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data.

OBJECTIVE: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. METHODS: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. RESULTS: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI. SIGNIFICANCE: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.

Independent components of human brain morphology.

Quantification of brain morphology has become an important cornerstone in understanding brain structure. Measures of cortical morphology such as thickness and surface area are frequently used to compare groups of subjects or characterise longitudinal changes. However, such measures are often treated as independent from each other. A recently described scaling law, derived from a statistical physics model of cortical folding, demonstrates that there is a tight covariance between three commonly used cortical morphology measures: cortical thickness, total surface area, and exposed surface area. We show that assuming the independence of cortical morphology measures can hide features and potentially lead to misinterpretations. Using the scaling law, we account for the covariance between cortical morphology measures and derive novel independent measures of cortical morphology. By applying these new measures, we show that new information can be gained; in our example we show that distinct morphological alterations underlie healthy ageing compared to temporal lobe epilepsy, even on the coarse level of a whole hemisphere. We thus provide a conceptual framework for characterising cortical morphology in a statistically valid and interpretable manner, based on theoretical reasoning about the shape of the cortex.

Tractography dissection variability: What happens when 42 groups dissect 14 white matter bundles on the same dataset?

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.

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.

Automated quantitative MRI volumetry reports support diagnostic interpretation in dementia: a multi-rater, clinical accuracy study.

OBJECTIVES: We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists' accuracy and confidence in detecting volume loss, and in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone. METHODS: Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52-81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, 'non-clinical image analysts') assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as 'normal' or 'abnormal' and if 'abnormal' as 'AD' or 'FTD'. RESULTS: The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group's accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters' agreement (Cohen's κ) with the 'gold standard' was not significantly affected by the QReport; only the consultant group improved significantly (κs 0.41➔0.55, p = 0.04*). Cronbach's alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from 'good' to 'excellent'. CONCLUSION: Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses. KEY POINTS: • The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone. • Consultant neuroradiologists' assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports. • First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.

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.

Resective surgery prevents progressive cortical thinning in temporal lobe epilepsy.

Focal epilepsy in adults is associated with progressive atrophy of the cortex at a rate more than double that of normal ageing. We aimed to determine whether successful epilepsy surgery interrupts progressive cortical thinning. In this longitudinal case-control neuroimaging study, we included subjects with unilateral temporal lobe epilepsy (TLE) before (n = 29) or after (n = 56) anterior temporal lobe resection and healthy volunteers (n = 124) comparable regarding age and sex. We measured cortical thickness on paired structural MRI scans in all participants and compared progressive thinning between groups using linear mixed effects models. Compared to ageing-related cortical thinning in healthy subjects, we found progressive cortical atrophy on vertex-wise analysis in TLE before surgery that was bilateral and localized beyond the ipsilateral temporal lobe. In these regions, we observed accelerated annualized thinning in left (left TLE 0.0192 ± 0.0014 versus healthy volunteers 0.0032 ± 0.0013 mm/year, P < 0.0001) and right (right TLE 0.0198 ± 0.0016 versus healthy volunteers 0.0037 ± 0.0016 mm/year, P < 0.0001) presurgical TLE cases. Cortical thinning in these areas was reduced after surgical resection of the left (0.0074 ± 0.0016 mm/year, P = 0.0006) or right (0.0052 ± 0.0020 mm/year, P = 0.0006) anterior temporal lobe. Directly comparing the post- versus presurgical TLE groups on vertex-wise analysis, the areas of postoperatively reduced thinning were in both hemispheres, particularly, but not exclusively, in regions that were affected preoperatively. Participants who remained completely seizure-free after surgery had no more progressive thinning than that observed during normal ageing. Those with postoperative seizures had small areas of continued accelerated thinning after surgery. Thus, successful epilepsy surgery prevents progressive cortical atrophy that is observed in TLE and may be potentially neuroprotective. This effect was more pronounced in those who remained seizure-free after temporal lobe resection, normalizing the rate of atrophy to that of normal ageing. These results provide evidence of epilepsy surgery preventing further cerebral damage and provide incentives for offering early surgery in refractory TLE.