Abstract Dynamic functional connectivity (FC) analyses of resting-state functional magnetic resonance imaging (fMRI) commonly apply k-means clustering to time-resolved whole-brain connectivity matrices to identify recurring “brain states” presumed to reflect shared neural dynamics. However, whether this approach reliably identifies group-level states in relatively small and heterogeneous clinical cohorts remains unclear. Here, we systematically evaluated k-means clustering in temporal lobe epilepsy (TLE) subgroups (bilateral, left, and right TLE) and healthy controls by incrementally increasing the number of clusters (k) from two to the number of participants in each group. Across all groups, clustering solutions converged toward participant-specific rather than shared group-level FC patterns. Identified FC states increasingly resembled participants’ static FC matrices, with higher k values approaching near one-to-one correspondence between states and participants. Elbow and silhouette analyses failed to identify a consistent optimal k and generally favored larger clustering solutions, consistent with increasing participant-specific structure. State occupancy analyses further showed prolonged residence within a single dominant state, providing limited evidence for shared dynamic transitions. These findings persisted under a leave-same-participant-out condition designed to reduce participant-specific influence. Together, these findings suggest that whole-brain k-means clustering in small clinical cohorts may primarily capture interindividual FC differences rather than reproducible group-level dynamic brain states.

Infants aged 1-24 months with new onset epilepsy frequently present with structural brain abnormalities, yet no updated evidence-based magnetic resonance imaging (MRI) guidelines exist for this population. The International League Against Epilepsy (ILAE) Neuroimaging Task Force developed evidence-based recommendations for structural brain MRI in infants with a first afebrile seizure or new onset epilepsy. A multidisciplinary panel defined three PICO (patients, intervention, comparison group, outcome under consideration) questions, conducted a systematic review (PROSPERO [Prospective Register of Systematic Reviews] CRD42024592653), and reported the results in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines. Risk of bias was evaluated using the JBI (Joanna Briggs Institute) checklist. GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology was used to assess certainty of evidence and formulate recommendations for the following: (1) the effectiveness of MRI in identifying underlying etiologies, (2) clinical predictors of MRI abnormalities, and (3) MRI protocols. Seventeen studies (n = 1209) were included. Among 753 infants who underwent MRI, 438 (58.2%) had abnormal findings. Despite heterogeneity in MRI protocols and reporting, the evidence supports the utility of MRI in this population. Specific clinical features (focal seizure semiology, abnormal neurological examination, seizure duration > 5 min, focal electroencephalographic abnormalities, developmental delay, and perinatal complications) were associated with abnormal MRI findings, although methodological limitations reduce certainty. Only six studies provided data on MRI sequences; however, none reported findings specifically in relation to the diagnostic accuracy or yield of individual protocols, precluding the development of evidence-based recommendations on MRI protocol selection. MRI is conditionally recommended in all infants with a first afebrile seizure or new onset epilepsy. MRI could be prioritized in those with specific clinical features indicative of higher likelihood of abnormal findings. Recommendations are based on very low certainty of evidence. These are the first ILAE-endorsed, evidence-based recommendations for MRI in infants with first afebrile seizure or new onset epilepsy. Further prospective studies with standardized protocols are needed to refine MRI indications and optimize diagnostic yield in this age group.

Purpose A methodological challenge in using CT perfusion (CTP) to assess blood-brain barrier (BBB) integrity is that the permeability–surface area product (PS) can be influenced by cerebral perfusion, making it difficult to distinguish genuine BBB opening from perfusion-driven signal. Methods We examined PS–perfusion coupling in 24 adults with focal epilepsy (16 non-lesional, 8 lesional) who underwent paired baseline and postictal CTP, fitting three linear mixed models (LMMs) to test whether PS–cerebral blood flow (CBF), PS–cerebral blood volume (CBV), and CBF–CBV coupling differed between groups. Results PS–perfusion coupling differed between groups in both PS-coupling models (CBF × Group: Estimate = + 0.0143, p = 0.004, semi-partial R 2 = 0.043; CBV × Group: Estimate = + 0.2159, p = 0.002, semi-partial R 2 = 0.053). Within-group slopes were near zero in non-lesional participants (PS–CBF Estimate = + 0.002, p = 0.67; PS–CBV Estimate = + 0.031, p = 0.72) and larger in lesional participants (PS–CBF Estimate = + 0.016, p = 0.016; PS–CBV Estimate = + 0.174, p = 0.055). CBF–CBV coupling was uniformly strong in both groups (within-subject slopes 14.9 and 12.5; both p < 0.001), with no group difference (p = 0.37) and a small postictal attenuation (CBV × Condition Estimate = − 1.46, p = 0.021). Conclusions Postictal PS–perfusion coupling differs by lesion status, suggesting that postictal PS variation in non-lesional focal epilepsy is largely perfusion-independent and that an LMM-based coupling analysis can help separate perfusion-driven from permeability-specific signal in CTP-based BBB assessment more broadly.

Introduction:Combined electroencephalography and functional magnetic resonance imaging (EEG-fMRI) identifies regions of neural activity in response to interictal epileptiform discharges (IEDs). While positive BOLD responses have historically been used to localize epileptogenic tissue, negative BOLD responses remain poorly understood. This study examined the spatial relationship between positive and negative BOLD responses to IEDs and their associations with epileptogenic tissue and the default mode network (DMN) using intracranial EEG-fMRI. Methods:70 adult participants (57 met inclusion criteria), with drug-resistant focal epilepsy, underwent intracranial EEG-fMRI during presurgical monitoring. BOLD response maps were generated and maximum positive and negative clusters identified. Linear mixed models examined distances between BOLD clusters and both IED-generating contacts and contacts closest to clinically-defined seizure onset zone. A subset of 38 participants were assessed for spatial overlap and functional connectivity with the DMN. Results:Maximum positive BOLD clusters were significantly closer to both IED-generating contacts (estimate = -30.0, 95% CI [-55.5, -4.37]) and seizure onset zone contacts (estimate = -32.7, 95% CI [-57.5, -8.43]) compared to maximum negative clusters, when the absolute maximum is positive. Negative BOLD clusters demonstrated significantly greater spatial overlap with the DMN than positive clusters (22.5% vs 10.0%, p = 0.04). Conclusions:Positive BOLD responses provide superior localization of epileptogenic tissue compared to negative responses in intracranial EEG-fMRI. In contrast, negative BOLD clusters show greater spatial overlap with the DMN, suggesting they may reflect network deactivation at the time of IED events. These findings support prioritizing positive BOLD responses for clinical decision-making in presurgical epilepsy evaluation.

OBJECTIVE:Meditation has widely recognized psychological and neuromodulatory benefits, yet its effects on epileptiform activity remain unclear. This study examined whether novice meditation modulates interictal epileptiform discharges (IEDs) in patients with drug-resistant epilepsy using intracranial electroencephalography (iEEG). METHODS:Twenty-seven meditation-naïve patients undergoing iEEG monitoring performed two meditation conditions, focused attention meditation (FAM) and open monitoring meditation (OMM), as well as two control conditions, story listening (STL) and classical music listening (CMM). IEDs were visually identified across the brain and manually labeled by an experienced neurologist. Linear mixed-effects models were applied to assess the effect of meditation on IED density (IEDs/min). Subjective meditative depth was evaluated using the Meditation Depth Questionnaire (MEDEQ), and associations between IED density and subjective experiences were examined. RESULTS:Both focused attention (p = .027) and open monitoring (p = .041) meditation increased IED density relative to the non-meditative STL control condition, whereas no differences were observed relative to the CMM control condition. Although both meditation conditions produced numerically comparable IED increases relative to STL control at the individual level, there was notable inter-individual variability depending on type of meditation. Subjects overall reported higher meditation depth scores during meditation than the STL control, and perceived depth increased with progressive meditative levels. Crucially, the relationship between IED density and perceived meditation depth changed across levels (p < .01), suggesting a dynamic interplay between neural excitability in the context of epilepsy and the subjective ease of meditative engagement. SIGNIFICANCE:This exploratory study provides direct intracranial evidence that meditation modulates interictal epileptiform activity in meditation-naïve epilepsy patients. Increased IED density during meditation suggests that these internally directed cognitive states can transiently influence epileptic network dynamics. These preliminary findings indicate a functional coupling between meditative states and cortical excitability in epilepsy, offering crucial insights into the clinical relevance of meditation in epilepsy.

The ILAE Neuroimaging Task Force publishes educational case reports that highlight basic aspects of neuroimaging in epilepsy consistent with the ILAE's educational mission. Tuberous sclerosis complex (TSC) is a rare, complex, and multisystem autosomal dominant genetic disorder that arises from variations in the TSC1 or TSC2 genes. While characterized by a wide range of clinical manifestations, TSC commonly presents with epilepsy, which is a clinically challenging feature of the condition. Neuroimaging plays a pivotal role in the early diagnosis, screening, and long-term monitoring of TSC patients. CT serves as the first-line imaging tool in emergency settings; yet MRI is the primary diagnostic modality for TSC. In this report, we present two patients with TSC-related epilepsy and analyze their neuroimaging findings. We also address the diagnostic and therapeutic challenges faced by TSC patients with epilepsy.

The ILAE Neuroimaging Task Force publishes educational case reports that highlight basic aspects of neuroimaging in epilepsy, consistent with ILAE's educational mission. In patients with drug-resistant focal epilepsy who are candidates for surgical intervention, the identification of structural abnormalities is a strong predictor of favorable postoperative seizure outcomes. When conventional imaging is insufficient, the integration of multimodal neuroimaging data with structural, metabolic, and functional imaging modalities is often helpful. The following two illustrative cases from two different centers highlight the challenges and needs to integrate the information from multiple imaging modalities for a more accurate diagnosis and resection planning of drug-resistant focal epilepsies. This approach can increase the number of patients eligible for surgery while minimizing the risk of postoperative deficits.

The ILAE Neuroimaging Task Force aims to publish educational case reports that highlight basic aspects of neuroimaging in epilepsy consistent with the ILAE's educational mission. Here, we describe a case series of three neonates with focal cortical dysplasia (FCD)-related drug-resistant epilepsy who underwent surgical intervention. The purpose of this series is to demonstrate the difficulties of identifying FCD in this age group and to highlight the potential added value of arterial spin labeling MRI for delineation of the epileptogenic zone. This series also supports the importance of the 2019 ILAE recommendations for structural imaging in epilepsy, the 2009 ILAE recommendations on imaging infants and children with recent-onset epilepsy, and the 2022 ILAE consensus classification of FCD.

BACKGROUND:There is growing interest in using Hadamard Encoding and Reconstruction for MEGA-Edited Spectroscopy (HERMES) within the mesial temporal lobe (MTL). For cross-sectional group comparisons and longitudinal repeated measures designs, an understanding of the internal and test-retest validity of γ-aminobutyric acid (GABA+) and glutathione (GSH) is critical. We therefore evaluated the reproducibility of the consensus recommended semi-localization by adiabatic selective refocusing (sLASER) localization for edited-MRS acquisitions in a challenging region, the MTL. NEW METHOD:Data were acquired in 15 participants. Single voxel HERMES was collected in the left MTL (two acquisitions) and the right MTL (one acquisition). Participants were repositioned between the two left HERMES acquisitions. An ANOVA was used to assess differences between acquisitions. To assess measurement variation in the repeated left of GABA+ and GSH measures within the left MTL difference values and coefficients of variation (CVs) were calculated. RESULTS:There were no significant differences in metabolite values between any of the acquisitions. The mean difference between the metabolite measures from the repeated left acquisitions centred close to zero, and the average CVs were 14.09 % for GABA+ and 18.94 % for GSH. COMPARISON WITH EXISTING METHODS:The CVs of GABA+ and GSH in the MTL obtained from a HERMES acquisition were comparable to GABA+ or GSH-edited acquisitions in this region, and to data from cortical voxels using HERMES acquisitions. CONCLUSIONS:This supports the use of HERMES in the MTL, a challenging region for MRS. However, larger samples and caution in interpretation may be required in repeated-measures designs.

Frontal lobe epilepsy (FLE), marked by recurrent seizures arising from the frontal lobes, can significantly impair cognitive and motor function, reducing quality of life. Recent studies suggest that epilepsies can involve functional networks throughout the brain that can be identified using resting-state functional magnetic resonance imaging (fMRI). In this study, we aimed to determine whether FLE is associated with a distinct functional network brain states. Using dynamic functional connectivity analysis in combination with k-means clustering, we investigated dynamic connectivity patterns of the somatomotor network (SMN) and default mode network (DMN) of ten right-hemisphere and six left-hemisphere FLE patients, as well as nine healthy controls. We found two distinct states of rest for both the SMN and DMN: a high connectivity state and a lower, more variable connectivity state that was often specific to individual patients. Both FLE groups showed reduced overall connectivity compared to controls, with the greatest differences emerging during the low connectivity state. Right FLE patients and controls exhibited relatively uniform reductions, whereas left FLE patients showed spatially specific disruptions, including reduced lateral-to-medial SMN connectivity and decreased connectivity in posterior and left-lateralized DMN regions. Our findings suggest that dynamic connectivity analysis can uncover the temporal complexity and patient-specific nature of brain network disruption in FLE, supporting the development of personalized diagnostic and treatment strategies. Further research with larger cohorts is necessary to validate these results and explore additional factors affecting brain functional connectivity.

OBJECTIVE:To use intracranial electroencephalography (EEG) to characterize functional magnetic resonance imaging (fMRI) activation maps associated with high-frequency oscillations (HFOs) (80-250 Hz) and examine their proximity to HFO- and seizure-generating tissue. METHODS:Forty-five patients implanted with intracranial depth electrodes underwent a simultaneous EEG-fMRI study at 3 T. HFOs were detected algorithmically from cleaned EEG and visually confirmed by an experienced electroencephalographer. HFOs that co-occurred with interictal epileptiform discharges (IEDs) were subsequently identified. fMRI activation maps associated with HFOs were generated that occurred either independently of IEDs or within ±200 ms of an IED. For all significant analyses, the Maximum, Second Maximum, and Closest activation clusters were identified, and distances were measured to both the electrodes where the HFOs were observed and the electrodes involved in seizure onset. RESULTS:We identified 108 distinct groups of HFOs from 45 patients. We found that HFOs with IEDs produced fMRI clusters that were closer to the local field potentials of the corresponding HFOs observed within the EEG than HFOs without IEDs. In addition to the fMRI clusters being closer to the location of the EEG correlate, HFOs with IEDs generated Maximum clusters with greater z-scores and larger volumes than HFOs without IEDs. We also observed that HFOs with IEDs resulted in more discrete activation maps. SIGNIFICANCE:Intracranial EEG-fMRI can be used to probe the hemodynamic response to HFOs. The hemodynamic response associated with HFOs that co-occur with IEDs better identifies known epileptic tissue than HFOs that occur independently.

SUMMARY:Stereo-EEG is a widely used method to improve the diagnostic precision of presurgical workup in patients with refractory epilepsy. Its ability to detect epileptic activity and identify epileptic networks largely depends on the chosen implantation strategy. Even in an ideal situation, electrodes record activity generated in <10% of the brain and contacts only record from brain tissue in their immediate proximity. In this article, the authors discuss how recording stereo-EEG simultaneously with other diagnostic methods can improve its diagnostic value in clinical and research settings. It can help overcome the limited spatial coverage of intracranial recording and better understand the sources of epileptic activity. Simultaneous scalp EEG is the most widely available method, often used to understand large epileptic networks, seizure propagation, and EEG activity occurring on the contralateral hemisphere. Simultaneous magnetoencephalography allows for more precise source localization and identification of deep sources outside the stereo-EEG coverage. Finally, simultaneous functional MRI can highlight metabolic changes following epileptic activity and help understand the widespread network changes associated with interictal activity. This overview highlights advantages and methodological challenges for all these methods. Clinical use and research applications are presented for each approach.

Various subjective and objective methods have been proposed to identify which interictal epileptiform discharge (IED)-related EEG-functional MRI (fMRI) results are more likely to delineate seizure-generating tissue in patients with drug-resistant focal epilepsy for the purposes of surgical planning. In this intracranial EEG-fMRI study, we evaluated the utility of these methods to localize clinically relevant regions preoperatively and compared the extent of resection of these areas to postoperative outcome.Seventy patients admitted for intracranial video-EEG monitoring were recruited for a simultaneous intracranial EEG-fMRI study. For all analyses of blood oxygen level-dependent responses associated with IEDs, an experienced epileptologist identified the most clinically relevant brain activation cluster using available clinical information. The maximum cluster (the cluster with the highest z-score) was also identified for all analyses and assigned to one of three confidence levels (low, medium or high) based on the difference of the peak z-scores between the maximum and second maximum cluster (the cluster with the second highest peak z-value). The distance was measured and compared between the peak voxel of the aforementioned clusters and the electrode contacts where the interictal discharge and seizure onset were recorded. In patients who subsequently underwent epilepsy surgery, the spatial concordance between the aforementioned clusters and the area of resection was determined and compared to postoperative outcome.We evaluated 106 different IEDs in 70 patients. Both subjective (identification of the clinically relevant cluster) and objective (maximum cluster much more significant than the second maximum cluster) methods of culling non-localizing EEG-fMRI activation maps increased the spatial concordance between these clusters and the corresponding IED or seizure onset zone contacts. However, only the objective methods of identifying medium and high confidence maps resulted in a significant association between resection of the peak voxel of the maximum cluster and postoperative outcome. Resection of this area was associated with good postoperative outcomes but was not sufficient for seizure freedom. On the other hand, we found that failure to resect the medium and high confidence maximum clusters was associated with a poor post-surgical outcome (negative predictive value = 1.0, sensitivity = 1.0).Methods to identify higher confidence EEG-fMRI results are needed to localize areas necessary for good postoperative outcomes. However, resection of the peak voxel within higher confidence maximum clusters is not sufficient for good outcomes. Conversely, failure to resect the peak voxel in these clusters is associated with a poor post-surgical outcome. Wilson et al. evaluate the utility of intracranial EEG-fMRI as a tool to help predict outcomes in epilepsy surgery. Removal of the brain area where peak activation (as revealed by fMRI) is associated with brief seizure discharges is necessary, but not sufficient, for good post-surgical outcomes.

The ILAE Neuroimaging Task Force publishes educational case reports that highlight basic aspects of neuroimaging in epilepsy consistent with the ILAE's educational mission. Subcortical laminar heterotopia, also known as subcortical band heterotopia (SBH) or "double cortex," is an intriguing and rare congenital malformation of cortical development. SBH lesions are part of a continuum best designated as agyria-pachygyria-band-spectrum. The malformation is associated with epilepsy that is often refractory, as well as variable degrees of developmental delay. Moreover, in an increasing proportion of cases, a distinct molecular-genetic background can be found. Diagnosing SBH can be a major challenge for many reasons, including more subtle lesions, and "non-classic" or unusual MRI-appearances. By presenting an illustrative case, we address the challenges and needs of diagnosing and treating SBH patients in epilepsy, especially the value of high-resolution imaging and specialized MRI-protocols.

OBJECTIVE:Temporal lobe epilepsy (TLE) has a high probability of becoming drug resistant and is frequently considered for surgical intervention. However, 30% of TLE cases have nonlesional magnetic resonance imaging (MRI) scans, which is associated with worse surgical outcomes. Characterizing interactions between temporal and extratemporal structures in these patients may help understand these poor outcomes. Simultaneous intracranial electroencephalography-functional MRI (iEEG-fMRI) can measure the hemodynamic changes associated with interictal epileptiform discharges (IEDs) recorded directly from the brain. This study was designed to characterize the whole brain patterns of IED-associated fMRI activation recorded exclusively from the mesial temporal lobes of patients with nonlesional TLE. METHODS:Eighteen patients with nonlesional TLE undergoing iEEG monitoring with mesial temporal IEDs underwent simultaneous iEEG-fMRI at 3 T. IEDs were marked, and statistically significant clusters of fMRI activation were identified. The locations of IED-associated fMRI activation for each patient were determined, and patients were grouped based on the location and pattern of fMRI activation. RESULTS:Two patterns of IED-associated fMRI activation emerged: primarily localized (n = 7), where activation was primarily located within the ipsilateral temporal lobe, and primarily diffuse (n = 11), where widespread bilateral extratemporal activation was detected. The primarily diffuse group reported significantly fewer focal to bilateral tonic-clonic seizures and had better postsurgical outcomes. SIGNIFICANCE:Simultaneous iEEG-fMRI can measure the hemodynamic changes associated with focal IEDs not visible on scalp EEG, such as those arising from the mesial temporal lobe. Significant fMRI activation associated with these IEDs was observed in all patients. Two distinct patterns of IED-associated activation were seen: primarily localized to the ipsilateral temporal lobe and more widespread, bilateral activation. Patients with widespread IED associated-activation had fewer focal to bilateral tonic-clonic seizures and better postsurgical outcome, which may suggest a neuroprotective mechanism limiting the spread of ictal events.

Objective: N/A Background: Chronic granulomatous herpes simplex encephalitis (CGHSE) is a rare complication following infantile and pediatric herpes simplex virus encephalitis (HSVE). Clinically, it follows a biphasic course, with acute HSVE later followed by drug-resistant seizures and progressive neurologic deterioration. Convincing evidence is lacking for whether CGHSE occurs due to virus reactivation versus post-infectious inflammatory sequelae. Design/Methods: The neuropathologic findings of two patients who underwent epilepsy surgery following remote infectious encephalitis are herein discussed. The first case is previously unreported and confirmed to be associated with HSV-I, and the second case, newly re-examined, is previously reported and of presumed HSV-I encephalitis. Results: The histological findings in the current cases were consistent with chronic, ongoing inflammation, both of which harboured parenchymal HSV-I DNA by PCR. There were no HSV antigens detected via immunohistochemistry nor viral inclusions seen on the H&E sections. A novel finding, shared by both cases, is the identification of cytoplasmic phosphorylated tau-immunopositive components: neurofibrillary tangles, pretangles and neuropil threads. These were demonstrated within regions of inflammation as well as seemingly uninvolved areas. Conclusions: Tau hyperphosphorylation has been reported following other infections, such as post-measles subacute sclerosing panencephalitis and HIV-associated neurocognitive disorders. HSV-I infection has been postulated to promote tau protein hyperphosphorylation. HSV-I primary infection and reactivation have been associated with phosphorylated tau accumulation in murine models. HSV-I in vitro infection models exposed to acyclovir treatment demonstrate dose-dependent reductions in phosphorylated tau accumulation. While in vitro murine, monkey and human experimental data have demonstrated hyperphosphorylated tau accumulates following HSV-I infection, to our knowledge, this may represent the first patient report of abnormal phosphorylated tau accumulation associated with neuropathologic chronic granulomatous HSVE. Further investigation into the possibility that tau accumulation contributes to long-term neurologic sequelae among HSVE survivors may be warranted. Disclosure: Dr. Sjonnesen has nothing to disclose. Dr. Appendino has nothing to disclose. Walter J. Hader, MD has nothing to disclose. Dr. Xu has nothing to disclose. The institution of Prof. Jacobs has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. Prof. Jacobs has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Epilog. Prof. Jacobs has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Prof. Jacobs has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pendopharm. Prof. Jacobs has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wiley. Prof. Jacobs has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Prof. Jacobs has received research support from Alberta Childrens Hospital Foundation. Dr. Federico has nothing to disclose. Dr. Langdon has nothing to disclose.

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