Raman Sankar

Neuromodulation targeting thalamic nuclei is increasingly used to treat drug-resistant focal epilepsy, yet human intracranial EEG studies describing how thalamocortical interactions evolve across seizures remain limited. We aimed to define frequency-specific thalamocortical network dynamics from seizure onset to termination, compare thalamocortical and cortico-cortical network activation, and test whether thalamic EEG features can classify seizure state to inform closed-loop or adaptive thalamic stimulation strategies. We retrospectively analyzed chronic stereo-EEG recordings from 19 patients with pediatric-onset, drug-resistant focal epilepsy (6 females; age at thalamic recording 1.0–28.1 years, median 16.9) with cortical and thalamic sampling. Sixty-six focal seizures were included. Spectral power, imaginary coherence, and spectral Granger causality were computed in non-overlapping two-second windows across slow (1–12 Hz), beta (13–30 Hz), and gamma (30–70 Hz) bands and compared with an interictal baseline. Random forest classifiers were trained using thalamic spectral power and thalamocortical connectivity features to distinguish ictal from non-ictal states using leave-one-patient-out cross-validation, with Shapley additive explanations used for feature attribution. Visual analysis identified thalamic ictal involvement at seizure onset in 82/101 thalamic contacts (81.2%), increasing to near-universal involvement by seizure termination, with onset-to-termination patterns dominated by low-voltage fast activity at onset and rhythmic spike or rhythmic slow-wave patterns at termination. The thalamus and cortical seizure onset zone exhibited broadband power increases at seizure onset that attenuated toward termination, while slow- and beta-band thalamocortical connectivity increased throughout seizures and peaked around the end-of-seizure epoch. Directed connectivity demonstrated bidirectional thalamocortical coupling, with slow-frequency thalamus-to-seizure onset zone outflow exceeding propagation-zone-to-seizure onset zone cortico-cortical outflow during both ictal and end-of-seizure epochs (anterior nucleus: p = 9.06 × 10L ³ and p = 8.80 × 10L ³ ; centromedian nucleus: p = 3.30 × 10L ³ and p = 5.70 × 10L ³ ). Seizure state was classifiable from thalamic spectral power and thalamocortical network features, achieving an area under the receiver operating characteristic curve of 0.825 ± 0.163 (anterior nucleus model) and 0.839 ± 0.149 (centromedian nucleus model), with thalamic broadband power plus slow-frequency thalamus-to-cortex outflow and beta-frequency cortex-to-thalamus inflow among the most informative features. Leveraging human intracranial EEG data, we define coordinated, frequency- and direction-specific thalamocortical and cortico-cortical network dynamics that evolve from seizure onset to termination. These findings establish a mechanistic basis and identify actionable thalamocortical EEG targets—particularly slow- and beta-band interactions—to inform individualized, adaptive, closed-loop neuromodulation aimed at optimizing seizure outcomes.

Thalamic neuromodulation is an emerging therapeutic strategy for patients in whom resection of the epileptogenic zone is not feasible. Yet the mechanisms by which thalamic stimulation modulates epileptogenic network dynamics remain unclear. We designed this study to test whether brief thalamic stimulation transiently modulates cortico-cortical activity and coupling within patient-specific epileptic networks. We studied 10 patients undergoing stereo-EEG with sampling of the anterior or centromedian thalamic nuclei. During wakefulness, we delivered low-frequency single pulse stimulations at 1 Hz and compared post-stimulation epochs (15–900 ms) with a pre-stimulation baseline. We quantified band-limited spectral power and Granger causality between bipolar cortical contacts, focusing on slow (3.0–13.9 Hz) and fast (14.0–79.9 Hz) activity. Contacts were grouped as seizure onset zone, early-propagating regions, or other regions, emphasizing the hemisphere ipsilateral to the stimulated nucleus. Thalamic stimulation produced a rapid, distributed modulation of cortical dynamics. Across patients, power in early-propagating regions decreased consistently in both slow and fast bands, whereas seizure onset zone and other regions showed smaller and less consistent changes, indicating reduced recruitment of cortical regions that often participate in seizure propagation. Directed interactions measured by Granger causality increased modestly at the network level, with the most consistent change between the seizure onset zone and other regions, and a significant increase in influence directed toward the seizure onset zone. These effects were observed with both nuclei despite heterogeneous implant strategies, suggesting a conserved, thalamus-initiated rebalancing of cortico-cortical coupling. Notably, when the anterior nucleus was stimulated in patients with limbic seizure onset zone, the power decrease in early-propagating regions and the increase in directed influence between the seizure onset zone and other regions were prominent, consistent with anterior thalamic projections to the limbic network. Taken together, these findings point to a rapid, nucleus-specific modulation that engages thalamic nodes while recruiting broader cortico-cortical influence toward the seizure onset zone. The sub-second markers—characterized by reduced power in early-propagating regions and selective increases in directed influence between seizure onset zone and other regions— support a model in which thalamic input modulates cortico-cortical coupling to limit propagation of epileptic activity from seizure onset zone to early-propagating regions. By characterizing network effects on the timescale of therapeutic stimulations, this work identifies mechanistic markers for network-informed neuromodulation, where transient EEG responses can guide nucleus selection and parameter titration. Prospective studies that link these markers to long-term seizure outcomes and stratify by thalamocortical anatomy are warranted.

Cerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1 complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy. In a phase 2-3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of six major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score. A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in the long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem-cell transplantation and did not have MDS at the most recent follow-up. At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.).

Early onset epilepsies occur in newborns and infants, and to date, genetic aberrations and variants have been identified in approximately one quarter of all patients. With technological sequencing advances and ongoing research, the genetic diagnostic yield for specific seizure disorders and epilepsies is expected to increase. Genetic variants associated with epilepsy include chromosomal abnormalities and rearrangements of various sizes as well as single gene variants. Among these variants, a distinction can be made between germline and somatic, with the latter being increasingly identified in epilepsies with focal cortical malformations in recent years. The identification of the underlying genetic mechanisms of epilepsy syndromes not only revolutionizes the diagnostic schemes but also leads to a better understanding of the diseases and their interrelationships, ultimately providing new opportunities for therapeutic targeting. At the XVI Workshop on Neurobiology of Epilepsy (WONOEP 2022, Talloires, France, July 2022), various etiologies, research models, and mechanisms of genetic early onset epilepsies were presented and discussed.

Objective: Interictal high-frequency oscillations (HFOs) are a promising neurophysiological biomarker of the epileptogenic zone (EZ). However, objective criteria for distinguishing pathological from physiological HFOs remain elusive, hindering clinical application. We investigated whether the distinct mechanisms underlying pathological and physiological HFOs are encapsulated in their signal morphology in intracranial EEG (iEEG) recordings and whether this mechanism-driven distinction could be simulated by a deep generative model. Methods: In a retrospective cohort of 185 epilepsy patients who underwent iEEG monitoring, we analyzed 686,410 HFOs across 18,265 brain contacts. To learn morphological characteristics, each event was transformed into a time-frequency plot and input into a variational autoencoder. We characterized latent space clusters containing morphologically defined putative pathological HFOs (mpHFOs) using interpretability analysis, including latent space disentanglement and time-domain perturbation. Results: mpHFOs showed strong associations with expert-defined spikes and were predominantly located within the seizure onset zone (SOZ). Discovered novel pathological features included high power in the gamma (30–80 Hz) and ripple (>80 Hz) bands centered on the event. These characteristics were consistent across multiple variables, including institution, electrode type, and patient demographics. Predicting 12-month postoperative seizure outcomes using the resection ratio of mpHFOs outperformed unclassified HFOs (F1=0.72 vs. 0.68) and matched current clinical standards using SOZ resection (F1=0.74). Combining mpHFO data with demographic and SOZ resection status further improved prediction accuracy (F1=0.83). Interpretation: Our data-driven approach yielded a novel, explainable definition of pathological HFOs, which has the potential to further enhance the clinical use of HFOs for EZ delineation.

Neuromodulation therapies offer an efficacious treatment alternative for patients with drug‐resistant epilepsy (DRE), particularly those unlikely to benefit from surgical resection. Here we present our retrospective single‐center case series of patients with pediatric‐onset DRE who underwent responsive neurostimulation (RNS) depth electrode implantation targeting the bilateral centromedian nucleus (CM) of the thalamus between October 2020 and October 2022. Sixteen patients were identified; seizure outcomes, programming parameters, and complications at follow‐up were reviewed. The median age at implantation was 13 years (range 3.6–22). Six patients (38%) were younger than 12 years of age at the time of implantation. Ictal electroencephalography (EEG) patterns during patients’ most disabling seizures were reliably detected. Ten patients (62%) achieved 50% or greater reduction in seizure frequency at a median 1.3 years (range 0.6–2.6) of follow‐up. Eight patients (50%) experienced sensorimotor side effects, and three patients (19%) had superficial pocket infection, prompting the removal of the RNS device. Side effects of stimulation were experienced mostly in monopolar‐cathodal configuration and alleviated with programming change to bipolar configuration or low‐frequency stimulation. Closed‐loop neurostimulation using RNS targeting bilateral CM is a feasible and useful therapy for patients with pediatric‐onset DRE.