Spatial and temporal properties of intra-operatively recorded spikes and high frequency oscillations in focal cortical dysplasia.

OBJECTIVE: Focal cortical dysplasias (FCD) are characterized by distinct interictal spike patterns and high frequency oscillations (HFOs; ripples: 80-250 Hz; fast ripples: 250-500 Hz) in the intra-operative electrocorticogram (ioECoG). We studied the temporal relation between intra-operative spikes and HFOs and their relation to resected tissue in people with FCD with a favorable outcome. METHODS: We included patients who underwent ioECoG-tailored epilepsy surgery with pathology confirmed FCD and long-term Engel 1A outcome. Spikes and HFOs were automatically detected and visually checked in 1-minute pre-resection-ioECoG. Channels covering resected and non-resected tissue were compared using a logistic mixed model, assessing event numbers, co-occurrence ratios, and time-based properties. RESULTS: We found pre-resection spikes, ripples in respectively 21 and 20 out of 22 patients. Channels covering resected tissue showed high numbers of spikes and HFOs, and high ratios of co-occurring events. Spikes, especially with ripples, have a relatively sharp rising flank with a long descending flank and early ripple onset over resected tissue. CONCLUSIONS: A combined analysis of event numbers, ratios, and temporal relationships between spikes and HFOs may aid identifying epileptic tissue in epilepsy surgery. SIGNIFICANCE: This study shows a promising method for clinically relevant properties of events, closely associated with FCD.

Why did my seizures start now? Influences of lesion connectivity and genetic etiology on age at seizure onset in focal epilepsy.

OBJECTIVE: Patients with focal, lesional epilepsy present with seizures at variable ages. Larger lesion size and overlap with sensorimotor or default mode network (DMN) have been associated with younger age at seizure onset in cohorts with mixed types of focal cortical dysplasia (FCD). Here, we studied determinants of age at seizure onset in patients with bottom-of-sulcus dysplasia (BOSD), a discrete type of FCD with highly localized epileptogenicity. METHODS: Eighty-four patients (77% operated) with BOSD were studied. Demographic, histopathologic, and genetic findings were recorded. BOSD volume and anatomical, primary versus association, rostral versus caudal, and functional network locations were determined. Normative functional connectivity analyses were performed using each BOSD as a region of interest in resting-state functional magnetic resonance imaging data of healthy children. Variables were correlated with age at seizure onset. RESULTS: Median age at seizure onset was 5.4 (interquartile range = 2-7.9) years. Of 50 tested patients, 22 had somatic and nine had germline pathogenic mammalian target of rapamycin (mTOR) pathway variants. Younger age at seizure onset was associated with greater BOSD volume (p = .002), presence of a germline pathogenic variant (p = .04), DMN overlap (p = .04), and increased functional connectivity with the DMN (p < .05, false discovery rate corrected). Location within sensorimotor cortex and networks was not associated with younger age at seizure onset in our relatively small but homogenous cohort. SIGNIFICANCE: Greater lesion size, pathogenic mTOR pathway germline variants, and DMN connectivity are associated with younger age at seizure onset in small FCD. Our findings strengthen the suggested role of DMN connectivity in the onset of FCD-related focal epilepsy and reveal novel contributions of genetic etiology.

Intraoperative ECoG in bottom-of-the-sulcus syndrome using a novel flexible strip electrode.

The recording of epileptiform discharges from bottom-of-sulcus focal cortical dysplasia (BOSD) is often difficult during intraoperative electrocorticography (ECoG) due to the deep localization. We describe the use in this scenario of a new-generation electrode strip with high flexibility, easily adapted to cortical gyri and sulci. A right-handed 20-year-old male with drug-resistant focal epilepsy due to BOSD of the inferior frontal gyrus and daily focal aware seizures was evaluated for epilepsy surgery. Based on electroclinical and neuroimaging results, a focal cortectomy guided by ECoG was proposed. ECoG recordings were performed with new-generation cortical strips (Wise Cortical Strip; WCS®) and standard cortical strips. ECoG, performed on the convexity of the frontal cortical surface, recorded only sporadic spikes with both types of strips. Then, after microsurgical trans-sulcal dissection, WCS was molded along the sulcal surface of the suspected BOSD based on 3D-imaging reconstruction, showing continuous/subcontinuous 3-4-Hz rhythmic spike activity from the deepest electrode. Registration after resection of the BOSD did not show any epileptiform activity. Pathology showed dysmorphic neurons and gliosis. No surgical complications occurred. The patient is seizure-free after 12 months. This single case experience shows that highly flexible electrode strips with adaptability to cortical gyrations can identify IEDs originating from deep location and could therefore be useful in cases of bottom of the sulcus dysplasia.

Categorizing cortical dysplasia lesions for surgical outcome using network functional connectivity.

OBJECTIVE: Focal cortical dysplasia (FCD) is often associated with drug-resistant epilepsy, leading to a recommendation to surgically remove the seizure focus. Predicting outcome for resection of FCD is challenging, requiring a new approach. Lesion-symptom mapping is a powerful and broadly applicable method for linking neurological symptoms or outcomes to damage to particular brain regions. In this work, the authors applied lesion network mapping, an expansion of the traditional approach, to search for the association of lesion network connectivity with surgical outcomes. They hypothesized that connectivity of lesion volumes, preoperatively identified by MRI, would associate with seizure outcomes after surgery in a pediatric cohort with FCD. METHODS: This retrospective study included 21 patients spanning the ages of 3 months to 17.7 years with FCD lesions who underwent surgery for drug-resistant epilepsy. The mean brain-wide functional connectivity map of each lesion volume was assessed across a database of resting-state functional MRI data from healthy children (spanning approximately 2.9 to 18.9 years old) compiled at the authors' institution. Lesion connectivity maps were averaged across age and sex groupings from the database and matched to each patient. The authors sought to associate voxel-wise differences in these maps with subject-specific surgical outcome (seizure free vs persistent seizures). RESULTS: Lesion volumes with persistent seizures after surgery tended to have stronger connectivity to attention and motor networks and weaker connectivity to the default mode network compared with lesion volumes with seizure-free surgical outcome. CONCLUSIONS: Network connectivity-based lesion-outcome mapping may offer new insight for determining the impact of lesion volumes discerned according to both size and specific location. The results of this pilot study could be validated with a larger set of data, with the ultimate goal of allowing examination of lesions in patients with FCD and predicting their surgical outcomes.

Reduced risk aversion and impaired short-term memory in juvenile rats with malformation of cortical development.

Malformation of cortical developments (MCDs) is currently an incurable disease and is associated with significant neuropsychological problems, such as intellectual disability, epilepsy, and anxiety disorders from a young age. Development of a suitable animal model and pathophysiological study is therefore necessary to better understand and treat MCDs from being an incurable disease. The Y-maze, open field, and fear conditioning studies were performed at postnatal days 40-44 to validate the behavioral phenotypes of the existing rat model of MCD with prenatal methylazoxymethanol exposure at their developmental period. The study results show that juvenile rats with MCD spent significantly less time inside the novel arms in Y-maze and less time in the peripheral zones of the open field. Additionally, the rats with MCDs showed attenuated freezing behavior to sound and light cues as well as to context after fear conditioning. This comprehensive behavioral analysis of rats with MCDs at the juvenile period indicate a lack of spatial memory, decreased anxiety, and learning disability in these rats, which is compatible with the human behavioral phenotype of MCDs and can be used as the behavioral biomarkers for future translational research.

Non-Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia.

OBJECTIVE: Low-level somatic mosaicism in the brain has been shown to be a major genetic cause of intractable focal epilepsy. However, how a relatively few mutation-carrying neurons are able to induce epileptogenesis at the local network level remains poorly understood. METHODS: To probe the origin of epileptogenesis, we measured the excitability of neurons with MTOR mutation and nearby nonmutated neurons recorded by whole-cell patch-clamp and array-based electrodes comparing the topographic distribution of mutation. Computational simulation is used to understand neural network-level changes based on electrophysiological properties. To examine the underlying mechanism, we measured inhibitory and excitatory synaptic inputs in mutated neurons and nearby neurons by electrophysiological and histological methods using the mouse model and postoperative human brain tissue for cortical dysplasia. To explain non-cell-autonomous hyperexcitability, an inhibitor of adenosine kinase was injected into mice to enhance adenosine signaling and to mitigate hyperactivity of nearby nonmutated neurons. RESULTS: We generated mice with a low-level somatic mutation in MTOR presenting spontaneous seizures. The seizure-triggering hyperexcitability originated from nonmutated neurons near mutation-carrying neurons, which proved to be less excitable than nonmutated neurons. Interestingly, the net balance between excitatory and inhibitory synaptic inputs onto mutated neurons remained unchanged. Additionally, we found that inhibition of adenosine kinase, which affects adenosine metabolism and neuronal excitability, reduced the hyperexcitability of nonmutated neurons. INTERPRETATION: This study shows that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non-cell-autonomous hyperexcitability of nearby nonmutated neurons. ANN NEUROL 2021;90:285-299.

Ictal gamma-band interactions localize ictogenic nodes of the epileptic network in focal cortical dysplasia.

OBJECTIVE: Epilepsy surgery fails in > 30% of patients with focal cortical dysplasia (FCD). The seizure persistence after surgery can be attributed to the inability to precisely localize the tissue with an endogenous potential to generate seizures. In this study, we aimed to identify the critical components of the epileptic network that were actively involved in seizure genesis. METHODS: The directed transfer function was applied to intracranial EEG recordings and the effective connectivity was determined with a high temporal and frequency resolution. Pre-ictal network properties were compared with ictal epochs to identify regions actively generating ictal activity and discriminate them from the areas of propagation. RESULTS: Analysis of 276 seizures from 30 patients revealed the existence of a seizure-related network reconfiguration in the gamma-band (25-170 Hz; p < 0.005) - ictogenic nodes. Unlike seizure onset zone, resecting the majority of ictogenic nodes correlated with favorable outcomes (p < 0.012). CONCLUSION: The prerequisite to successful epilepsy surgery is the accurate identification of brain areas from which seizures arise. We show that in FCD-related epilepsy, gamma-band network markers can reliably identify and distinguish ictogenic areas in macroelectrode recordings, improve intracranial EEG interpretation and better delineate the epileptogenic zone. SIGNIFICANCE: Ictogenic nodes localize the critical parts of the epileptogenic tissue and increase the diagnostic yield of intracranial evaluation.

External validation of automated focal cortical dysplasia detection using morphometric analysis.

OBJECTIVE: Focal cortical dysplasias (FCDs) are a common cause of drug-resistant focal epilepsy but frequently remain undetected by conventional magnetic resonance imaging (MRI) assessment. The visual detection can be facilitated by morphometric analysis of T1-weighted images, for example, using the Morphometric Analysis Program (v2018; MAP18), which was introduced in 2005, independently validated for its clinical benefits, and successfully integrated in standard presurgical workflows of numerous epilepsy centers worldwide. Here we aimed to develop an artificial neural network (ANN) classifier for robust automated detection of FCDs based on these morphometric maps and probe its generalization performance in a large, independent data set. METHODS: In this retrospective study, we created a feed-forward ANN for FCD detection based on the morphometric output maps of MAP18. The ANN was trained and cross-validated on 113 patients (62 female, mean age ± SD =29.5 ± 13.6 years) with manually segmented FCDs and 362 healthy controls (161 female, mean age ± SD =30.2 ± 9.6 years) acquired on 13 different scanners. In addition, we validated the performance of the trained ANN on an independent, unseen data set of 60 FCD patients (28 female, mean age ± SD =30 ± 15.26 years) and 70 healthy controls (42 females, mean age ± SD = 40.0 ± 12.54 years). RESULTS: In the cross-validation, the ANN achieved a sensitivity of 87.4% at a specificity of 85.4% on the training data set. On the independent validation data set, our method still reached a sensitivity of 81.0% at a comparably high specificity of 84.3%. SIGNIFICANCE: Our method shows a robust automated detection of FCDs and performance generalizability, largely independent of scanning site or MR-sequence parameters. Taken together with the minimal input requirements of a standard T1 image, our approach constitutes a clinically viable and useful tool in the presurgical diagnostic routine for drug-resistant focal epilepsy.

Improvement of brain function after surgery in infants with posterior quadrant cortical dysplasia.

OBJECTIVE: To reveal whether neurodevelopmental outcome of infants after epilepsy surgery can be quantitatively assessed by electroencephalography (EEG) functional connectivity analysis. METHODS: We enrolled 13 infants with posterior quadrant dysplasia aged <2 years who were treated using posterior quadrantectomy and 21 age-matched infants. EEG was performed both before and one year after surgery. Developmental quotient (DQ) was assessed both before and 3 years after surgery. The phase lag index (PLI) of three different pairs of electrodes in the nonsurgical hemisphere, i.e., the anterior short distance (ASD), posterior short distance (PSD), and long distance (LD) pairs, were calculated as indices of brain connectivity. The relationship between the PLI and DQ was evaluated. RESULTS: Overall, 77% infants experienced seizure freedom after surgery. The beta- and gamma- range PLI of PSD pairs increased preoperatively. All these pairs normalized postoperatively. Simple linear regression analysis revealed a significant relationship between the postoperative DQ and the postoperative beta-band PLI of ASD pairs. CONCLUSION: Preoperative abnormal hyper-connectivity was normalized to the control level after surgery. The postoperative hyperconnectivity was associated with long-term neurodevelopmental improvement. SIGNIFICANCE: PLI quantifies neurodevelopmental improvements after posterior quadrantectomy.

Excitatory/Inhibitory Synaptic Ratios in Polymicrogyria and Down Syndrome Help Explain Epileptogenesis in Malformations.

BACKGROUND: The ratio between excitatory (glutamatergic) and inhibitory (GABAergic) inputs into maturing individual cortical neurons influences their epileptic potential. Structural factors during development that alter synaptic inputs can be demonstrated neuropathologically. Increased mitochondrial activity identifies neurons with excessive discharge rates. METHODS: This study focuses on the neuropathological examinaion of surgical resections for epilepsy and at autopsy, in fetuses, infants, and children, using immunocytochemical markers, and electron microscopy in selected cases. Polymicrogyria and Down syndrome are highlighted. RESULTS: Factors influencing afferent synaptic ratios include the following: (1) synaptic short-circuitry in fused molecular zones of adjacent gyri (polymicrogyria); (2) impaired development of dendritic spines decreasing excitation (Down syndrome); (3) extracellular keratan sulfate proteoglycan binding to somatic membranes but not dendritic spines may be focally diminished (cerebral atrophy, schizencephaly, lissencephaly, polymicrogyria) or augmented, ensheathing individual axons (holoprosencephaly), or acting as a barrier to axonal passage in the U-fiber layer. If keratan is diminished, glutamate receptors on the neuronal soma enable ectopic axosomatic excitatory synapses to form; (4) dysplastic, megalocytic neurons and balloon cells in mammalian target of rapamycin disorders; (5) satellitosis of glial cells displacing axosomatic synapses; (6) peri-neuronal inflammation (tuberous sclerosis) and heat-shock proteins. CONCLUSIONS: Synaptic ratio of excitatory/inhibitory afferents is a major fundamental basis of epileptogenesis at the neuronal level. Neuropathology can demonstrate subcellular changes that help explain either epilepsy or lack of seizures in immature brains. Synaptic ratios in malformations influence postnatal epileptogenesis. Single neurons can be hypermetabolic and potentially epileptogenic.

GABAergic Interneuron and Neurotransmission Are mTOR-Dependently Disturbed in Experimental Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is a major cause for drug-resistant epilepsies. The molecular and cellular mechanisms of epileptogenesis in FCD are still poorly understood. Some studies have suggested that deficiencies of γ-aminobutyric acid (GABA) system may play an important role in type II FCD, but it remains controversial. In order to examine whether and how GABAergic interneurons and synaptic function are affected, we generated a somatic mTOR hyperactivation-based mouse model of type II FCD by in utero electroporation, quantified densities of interneurons in the malformed cortices, and recorded miniature inhibitory postsynaptic currents in dysmorphic neurons. We detected 20-25% reduction of GABAergic interneurons within malformed cortices, independent of cortical regions and cell subtypes but proportionate to the decrease of global neuron counts. GABAergic synaptic transmission from interneurons to mTOR hyperactivated dysmorphic neurons was dramatically disrupted, outweighing the decrease of interneuron counts. Postnatal mTOR inhibition partially rescued these alterations of GABAergic system. We also quantified the expression of GABAA receptor, GABA transporter, and chloridion transporter encoding genes and found that their expression was relatively intact within the malformed cortices. Taken together, these results confirmed that GABAergic interneuron and synapse transmission are disturbed profoundly in an mTOR-dependent manner in type II FCD. Our study suggests that postsynaptic mechanisms independent of interneuron reduction or altered expression of GABA synapse genes might be accountable for the impaired GABAergic neurotransmission in type II FCD as well as other mTOR-related epilepsies.

Connectome biomarkers of drug-resistant epilepsy.

Drug-resistant epilepsy (DRE) considerably affects patient health, cognition, and well-being, and disproportionally contributes to the overall burden of epilepsy. The most common DRE syndromes are temporal lobe epilepsy related to mesiotemporal sclerosis and extratemporal epilepsy related to cortical malformations. Both syndromes have been traditionally considered as "focal," and most patients benefit from brain surgery for long-term seizure control. However, increasing evidence indicates that many DRE patients also present with widespread structural and functional network disruptions. These anomalies have been suggested to relate to cognitive impairment and prognosis, highlighting their importance for patient management. The advent of multimodal neuroimaging and formal methods to quantify complex systems has offered unprecedented ability to profile structural and functional brain networks in DRE patients. Here, we performed a systematic review on existing DRE network biomarker candidates and their contribution to three key application areas: (1) modeling of cognitive impairments, (2) localization of the surgical target, and (3) prediction of clinical and cognitive outcomes after surgery. Although network biomarkers hold promise for a range of clinical applications, translation of neuroimaging biomarkers to the patient's bedside has been challenged by a lack of clinical and prospective studies. We therefore close by highlighting conceptual and methodological strategies to improve the evaluation and accessibility of network biomarkers, and ultimately guide clinically actionable decisions.

Bilateral polymicrogyria associated with dystonia: A new neurogenetic syndrome?

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.

Continuous epileptiform discharges during sleep as an evolutionary pattern in patients with congenital Zika virus syndrome.

Congenital Zika virus syndrome (CZVS) is associated with severe neurological deficits. Clinical characteristics of epilepsy and the electroencephalographic (EEG) pattern in CZVS were documented in infancy. In this study, we aimed to describe the EEG findings observed during the follow-up of children with CZVS. Seventy-six EEGs of 55 children (60% female; mean age = 50 months) with confirmed CZVS were analyzed, considering the background, interictal, and ictal epileptiform discharges. Continuous (or almost continuous) epileptiform discharges during non-rapid eye movement sleep were identified in 22 (40%) patients. In 20 (90.1%) patients, the pattern was symmetrical, with an anterior predominance of the epileptiform activity. All patients with this pattern had epilepsy, which was severe in 15 (68.2%) and demanded polytherapy in 19 (86.4%). Subcortical calcifications (77.3%) and multifocal EEGs (72.8%) in earlier ages occurred more often in patients with this pattern. Other unspecific interictal EEG patterns were focal epileptiform discharges in 23 (41.8%) and multifocal activity in six (10.9%). In CZVS, continuous (or almost continuous) epileptiform discharges during sleep emerge as a pattern after the second year of life. This was associated with severe and drug-resistant epilepsy, but not necessarily with an apparent regression. Subcortical calcifications and multifocal epileptiform discharges in infancy are associated with this pattern.