Cholinergic and behavior-dependent beta and gamma waves are coupled between olfactory bulb and hippocampus.

Olfactory oscillations may enhance cognitive processing through coupling with beta (ß, 15-30 Hz) and gamma (γ, 30-160 Hz) activity in the hippocampus (HPC). We hypothesize that coupling between olfactory bulb (OB) and HPC oscillations is increased by cholinergic activation in control rats and is reduced in kainic-acid-treated epileptic rats, a model of temporal lobe epilepsy. OB γ2 (63-100 Hz) power was higher during walking and immobility-awake (IMM) compared to sleep, while γ1 (30-57 Hz) power was higher during grooming than other behavioral states. Muscarinic cholinergic agonist pilocarpine (25 mg/kg ip) with peripheral muscarinic blockade increased OB power and OB-HPC coherence at ß and γ1 frequency bands. A similar effect was found after physostigmine (0.5 mg/kg ip) but not scopolamine (10 mg/kg ip). Pilocarpine increased bicoherence and cross-frequency coherence (CFC) between OB slow waves (SW, 1-5 Hz) and hippocampal ß, γ1 and γ2 waves, with stronger coherence at CA1 alveus and CA3c than CA1 stratum radiatum. Bicoherence further revealed a nonlinear interaction of ß waves in OB with ß waves at the CA1-alveus. Beta and γ1 waves in OB or HPC were segregated at one phase of the OB-SW, opposite to the phase of γ2 and γ3 (100-160 Hz) waves, suggesting independent temporal processing of ß/γ1 versus γ2/γ3 waves. At CA1 radiatum, kainic-acid-treated epileptic rats compared to control rats showed decreased theta power, theta-ß and theta-γ2 CFC during baseline walking, decreased CFC of HPC SW with γ2 and γ3 waves during baseline IMM, and decreased coupling of OB SW with ß and γ2 waves at CA1 alveus after pilocarpine. It is concluded that ß and γ waves in the OB and HPC are modulated by a slow respiratory rhythm, in a cholinergic and behavior-dependent manner, and OB-HPC functional connectivity at ß and γ frequencies may enhance cognitive functions.

The use of automated and AI-driven algorithms for the detection of hippocampal sclerosis and focal cortical dysplasia.

In drug-resistant epilepsy, magnetic resonance imaging (MRI) plays a central role in detecting lesions as it offers unmatched spatial resolution and whole-brain coverage. In addition, the last decade has witnessed continued developments in MRI-based computer-aided machine-learning techniques for improved diagnosis and prognosis. In this review, we focus on automated algorithms for the detection of hippocampal sclerosis and focal cortical dysplasia, particularly in cases deemed as MRI negative, with an emphasis on studies with histologically validated data. In addition, we discuss imaging-derived prognostic markers, including response to anti-seizure medication, post-surgical seizure outcome, and cognitive reserves. We also highlight the advantages and limitations of these approaches and discuss future directions toward person-centered care.

Multimodal mapping of regional brain vulnerability to focal cortical dysplasia.

Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.

Decomposing MRI phenotypic heterogeneity in epilepsy: a step towards personalized classification.

In drug-resistant temporal lobe epilepsy, precise predictions of drug response, surgical outcome and cognitive dysfunction at an individual level remain challenging. A possible explanation may lie in the dominant 'one-size-fits-all' group-level analytical approaches that does not allow parsing interindividual variations along the disease spectrum. Conversely, analysing inter-patient heterogeneity is increasingly recognized as a step towards person-centred care. Here, we used unsupervised machine learning to estimate latent relations (or disease factors) from 3 T multimodal MRI features [cortical thickness, hippocampal volume, fluid-attenuated inversion recovery (FLAIR), T1/FLAIR, diffusion parameters] representing whole-brain patterns of structural pathology in 82 patients with temporal lobe epilepsy. We assessed the specificity of our approach against age- and sex-matched healthy individuals and a cohort of frontal lobe epilepsy patients with histologically verified focal cortical dysplasia. We identified four latent disease factors variably co-expressed within each patient and characterized by ipsilateral hippocampal microstructural alterations, loss of myelin and atrophy (Factor 1), bilateral paralimbic and hippocampal gliosis (Factor 2), bilateral neocortical atrophy (Factor 3) and bilateral white matter microstructural alterations (Factor 4). Bootstrap analysis and parameter variations supported high stability and robustness of these factors. Moreover, they were not expressed in healthy controls and only negligibly in disease controls, supporting specificity. Supervised classifiers trained on latent disease factors could predict patient-specific drug response in 76 ± 3% and postsurgical seizure outcome in 88 ± 2%, outperforming classifiers that did not operate on latent factor information. Latent factor models predicted inter-patient variability in cognitive dysfunction (verbal IQ: r = 0.40 ± 0.03; memory: r = 0.35 ± 0.03; sequential motor tapping: r = 0.36 ± 0.04), again outperforming baseline learners. Data-driven analysis of disease factors provides a novel appraisal of the continuum of interindividual variability, which is probably determined by multiple interacting pathological processes. Incorporating interindividual variability is likely to improve clinical prognostics.

Atypical functional connectome hierarchy impacts cognition in temporal lobe epilepsy.

OBJECTIVE: Drug-resistant temporal lobe epilepsy (TLE) is typically associated with hippocampal pathology. However, widespread network alterations are increasingly recognized and suggested to perturb cognitive function in multiple domains. Here we tested (1) whether TLE shows atypical cortical hierarchical organization, differentiating sensory and higher order systems; and (2) whether atypical hierarchy predicts cognitive impairment. METHODS: We studied 72 well-characterized drug-resistant TLE patients and 41 healthy controls, statistically matched for age and sex, using multimodal magnetic resonance imaging analysis and cognitive testing. To model cortical hierarchical organization in vivo, we used a bidirectional stepwise functional connectivity analysis tapping into the differentiation between sensory/unimodal and paralimbic/transmodal cortices. Linear models compared patients to controls. Finally, we assessed associations of functional anomalies to cortical atrophy and microstructural anomalies, as well as clinical and cognitive parameters. RESULTS: Compared to controls, TLE presented with bidirectional disruptions of sensory-paralimbic functional organization. Stepwise connectivity remained segregated within paralimbic and salience networks at the top of the hierarchy, and sensorimotor and dorsal attention at the bottom. Whereas paralimbic segregation was associated with atypical cortical myeloarchitecture and hippocampal atrophy, dysconnectivity of sensorimotor cortices reflected diffuse cortical thinning. The degree of abnormal hierarchical organization in sensory-petal streams covaried, with broad cognitive impairments spanning sensorimotor, attention, fluency, and visuoconstructional ability and memory, and was more marked in patients with longer disease duration and Engel I outcome. SIGNIFICANCE: Our findings show atypical functional integration between paralimbic/transmodal and sensory/unimodal systems in TLE. Differential associations with paralimbic microstructure and sensorimotor atrophy suggest that system-level imbalance likely reflects complementary structural processes, but ultimately accounts for a broad spectrum of cognitive impairments. Hierarchical contextualization of cognitive deficits promises to open new avenues for personalized counseling in TLE.

A connectome-based mechanistic model of focal cortical dysplasia.

Neuroimaging studies have consistently shown distributed brain anomalies in epilepsy syndromes associated with a focal structural lesion, particularly mesiotemporal sclerosis. Conversely, a system-level approach to focal cortical dysplasia has been rarely considered, likely due to methodological difficulties in addressing variable location and topography. Given the known heterogeneity in focal cortical dysplasia histopathology, we hypothesized that lesional connectivity consists of subtypes with distinct structural signatures. Furthermore, in light of mounting evidence for focal anomalies impacting whole-brain systems, we postulated that patterns of focal cortical dysplasia connectivity may exert differential downstream effects on global network topology. We studied a cohort of patients with histologically verified focal cortical dysplasia type II (n = 27), and age- and sex-matched healthy controls (n = 34). We subdivided each lesion into similarly sized parcels and computed their connectivity to large-scale canonical functional networks (or communities). We then dichotomized connectivity profiles of lesional parcels into those belonging to the same functional community as the focal cortical dysplasia (intra-community) and those adhering to other communities (inter-community). Applying hierarchical clustering to community-reconfigured connectome profiles identified three lesional classes with distinct patterns of functional connectivity: decreased intra- and inter-community connectivity, a selective decrease in intra-community connectivity, and increased intra- as well as inter-community connectivity. Hypo-connectivity classes were mainly composed of focal cortical dysplasia type IIB, while the hyperconnected lesions were type IIA. With respect to whole-brain networks, patients with hypoconnected focal cortical dysplasia and marked structural damage showed only mild imbalances, while those with hyperconnected subtle lesions had more pronounced topological alterations. Correcting for interictal epileptic discharges did not impact connectivity patterns. Multivariate structural equation analysis provided a mechanistic model of such complex, diverging interactions, whereby the focal cortical dysplasia structural makeup shapes its functional connectivity, which in turn modulates whole-brain network topology.

Recommendations for the use of structural magnetic resonance imaging in the care of patients with epilepsy: A consensus report from the International League Against Epilepsy Neuroimaging Task Force.

Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and treatment of epilepsy, particularly when surgery is being considered. Despite previous recommendations and guidelines, practices for the use of MRI are variable worldwide and may not harness the full potential of recent technological advances for the benefit of people with epilepsy. The International League Against Epilepsy Diagnostic Methods Commission has thus charged the 2013-2017 Neuroimaging Task Force to develop a set of recommendations addressing the following questions: (1) Who should have an MRI? (2) What are the minimum requirements for an MRI epilepsy protocol? (3) How should magnetic resonance (MR) images be evaluated? (4) How to optimize lesion detection? These recommendations target clinicians in established epilepsy centers and neurologists in general/district hospitals. They endorse routine structural imaging in new onset generalized and focal epilepsy alike and describe the range of situations when detailed assessment is indicated. The Neuroimaging Task Force identified a set of sequences, with three-dimensional acquisitions at its core, the harmonized neuroimaging of epilepsy structural sequences-HARNESS-MRI protocol. As these sequences are available on most MR scanners, the HARNESS-MRI protocol is generalizable, regardless of the clinical setting and country. The Neuroimaging Task Force also endorses the use of computer-aided image postprocessing methods to provide an objective account of an individual's brain anatomy and pathology. By discussing the breadth and depth of scope of MRI, this report emphasizes the unique role of this noninvasive investigation in the care of people with epilepsy.

The spectrum of structural and functional network alterations in malformations of cortical development.

Neuroimaging studies of malformations of cortical development have mainly focused on the characterization of the primary lesional substrate, while whole-brain investigations remain scarce. Our purpose was to assess large-scale brain organization in prevalent cortical malformations. Based on experimental evidence suggesting that distributed effects of focal insults are modulated by stages of brain development, we postulated differential patterns of network anomalies across subtypes of malformations. We studied a cohort of patients with focal cortical dysplasia type II (n = 63), subcortical nodular heterotopia (n = 44), and polymicrogyria (n = 34), and compared them to 82 age- and sex-matched controls. Graph theoretical analysis of structural covariance networks indicated a consistent rearrangement towards a regularized architecture characterized by increased path length and clustering, as well as disrupted rich-club topology, overall suggestive of inefficient global and excessive local connectivity. Notably, we observed a gradual shift in network reconfigurations across subgroups, with only subtle changes in focal cortical dysplasia type II, moderate effects in heterotopia and maximal effects in polymicrogyria. Analysis of resting state functional connectivity also revealed gradual network changes, with most marked rearrangement in polymicrogyria; contrary to findings in the structural domain, however, functional architecture was characterized by decreases in both local and global parameters. Diverging results in the structural and functional domain were supported by formal structure-function coupling analysis. Our findings support the concept that time of insult during corticogenesis impacts the severity of topological network reconfiguration. Specifically, late-stage malformations, typified by polymicrogyria, may selectively disrupt the formation of large-scale cortico-cortical networks and thus lead to a more profound impact on whole-brain organization than early stage disturbances of predominantly radial migration patterns observed in cortical dysplasia type II, which likely affect a relatively confined cortical territory.

MRI-Based Machine Learning Prediction Framework to Lateralize Hippocampal Sclerosis in Patients With Temporal Lobe Epilepsy.

BACKGROUND AND OBJECTIVES: MRI fails to reveal hippocampal pathology in 30% to 50% of temporal lobe epilepsy (TLE) surgical candidates. To address this clinical challenge, we developed an automated MRI-based classifier that lateralizes the side of covert hippocampal pathology in TLE. METHODS: We trained a surface-based linear discriminant classifier that uses T1-weighted (morphology) and T2-weighted and fluid-attenuated inversion recovery (FLAIR)/T1 (intensity) features. The classifier was trained on 60 patients with TLE (mean age 35.6 years, 58% female) with histologically verified hippocampal sclerosis (HS). Images were deemed to be MRI negative in 42% of cases on the basis of neuroradiologic reading (40% based on hippocampal volumetry). The predictive model automatically labeled patients as having left or right TLE. Lateralization accuracy was compared to electroclinical data, including side of surgery. Accuracy of the classifier was further assessed in 2 independent TLE cohorts with similar demographics and electroclinical characteristics (n = 57, 58% MRI negative). RESULTS: The overall lateralization accuracy was 93% (95% confidence interval 92%-94%), regardless of HS visibility. In MRI-negative TLE, the combination of T2 and FLAIR/T1 intensities provided the highest accuracy in both the training (84%, area under the curve [AUC] 0.95 ± 0.02) and validation (cohort 1 90%, AUC 0.99; cohort 2 76%, AUC 0.94) cohorts. DISCUSSION: This prediction model for TLE lateralization operates on readily available conventional MRI contrasts and offers gain in accuracy over visual radiologic assessment. The combined contribution of decreased T1- and increased T2-weighted intensities makes the synthetic FLAIR/T1 contrast particularly effective in MRI-negative HS, setting the basis for broad clinical translation. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with TLE and MRI-negative HS, an automated MRI-based classifier accurately determines the side of pathology.

Multicenter Validation of a Deep Learning Detection Algorithm for Focal Cortical Dysplasia.

BACKGROUND AND OBJECTIVE: To test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD). METHODS: We used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2-55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity. RESULTS: Overall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls. DISCUSSION: This first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.

Unsupervised machine learning reveals lesional variability in focal cortical dysplasia at mesoscopic scale.

OBJECTIVE: Focal cortical dysplasia (FCD) is the most common epileptogenic developmental malformation and a prevalent cause of surgically amenable epilepsy. While cellular and molecular biology data suggest that FCD lesional characteristics lie along a spectrum, this notion remains to be verified in vivo. We tested the hypothesis that machine learning applied to MRI captures FCD lesional variability at a mesoscopic scale. METHODS: We studied 46 patients with histologically verified FCD Type II and 35 age- and sex-matched healthy controls. We applied consensus clustering, an unsupervised learning technique that identifies stable clusters based on bootstrap-aggregation, to 3 T multicontrast MRI (T1-weighted MRI and FLAIR) features of FCD normalized with respect to distributions in controls. RESULTS: Lesions were parcellated into four classes with distinct structural profiles variably expressed within and across patients: Class-1 with isolated white matter (WM) damage; Class-2 combining grey matter (GM) and WM alterations; Class-3 with isolated GM damage; Class-4 with GM-WM interface anomalies. Class membership was replicated in two independent datasets. Classes with GM anomalies impacted local function (resting-state fMRI derived ALFF), while those with abnormal WM affected large-scale connectivity (assessed by degree centrality). Overall, MRI classes reflected typical histopathological FCD characteristics: Class-1 was associated with severe WM gliosis and interface blurring, Class-2 with severe GM dyslamination and moderate WM gliosis, Class-3 with moderate GM gliosis, Class-4 with mild interface blurring. A detection algorithm trained on class-informed data outperformed a class-naïve paradigm. SIGNIFICANCE: Machine learning applied to widely available MRI contrasts uncovers FCD Type II variability at a mesoscopic scale and identifies tissue classes with distinct structural dimensions, functional and histopathological profiles. Integrating in vivo staging of FCD traits with automated lesion detection is likely to inform the development of novel personalized treatments.

Resting state functional network disruptions in a kainic acid model of temporal lobe epilepsy.

We studied the graph topological properties of brain networks derived from resting-state functional magnetic resonance imaging in a kainic acid induced model of temporal lobe epilepsy (TLE) in rats. Functional connectivity was determined by temporal correlation of the resting-state Blood Oxygen Level Dependent (BOLD) signals between two brain regions during 1.5% and 2% isoflurane, and analyzed as networks in epileptic and control rats. Graph theoretical analysis revealed a significant increase in functional connectivity between brain areas in epileptic than control rats, and the connected brain areas could be categorized as a limbic network and a default mode network (DMN). The limbic network includes the hippocampus, amygdala, piriform cortex, nucleus accumbens, and mediodorsal thalamus, whereas DMN involves the medial prefrontal cortex, anterior and posterior cingulate cortex, auditory and temporal association cortex, and posterior parietal cortex. The TLE model manifested a higher clustering coefficient, increased global and local efficiency, and increased small-worldness as compared to controls, despite having a similar characteristic path length. These results suggest extensive disruptions in the functional brain networks, which may be the basis of altered cognitive, emotional and psychiatric symptoms in TLE.