Lundstrom, Brian N.

AbstractAlthough electricity has been used in medicine for thousands of years, bioelectronic medicine for treating epilepsy has become increasingly common in recent years. Invasive neurostimulation centers primarily around three approaches: vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS). These approaches differ by target (e.g., cranial nerve, cortex, or thalamus) and stimulation parameters (e.g., triggered stimulation or continuous stimulation). Although typically noncurative, these approaches can dramatically reduce the seizure burden and offer patients new treatment options. There remains much to be understood about optimal targets and individualized stimulation protocols. Objective markers of seizure burden and biomarkers that quickly quantify neural excitability are still needed. In the future, bioelectronic medicine could become a curative approach that remodels neural networks to reduce pathological activity.

AbstractObjectiveStereoelectroencephalography‐guided radiofrequency thermocoagulation (SEEG‐guided RFTC) has been increasingly used as diagnostic and therapeutic approach for drug‐resistant focal epilepsies (DREs). We aimed to describe seizure outcomes of RFTC before and after further neurosurgical intervention.MethodsRetrospective single‐institution case series of patients who underwent SEEG‐RFTC. The primary outcome was Engel class I–IV classification ([responders Engel I–III and non‐responders Engel IV]) at last follow‐up after RFTC and prior to further neurosurgical intervention (open surgical resection, laser ablation, and neuromodulation).ResultsTwenty‐five patients (median age 18.9 years) with DRE were included. The median follow‐up time after RFTC was 7.2 months, including 20 patients who underwent further intervention (median follow‐up time of 7.3 months) and 5 without intervention (median of 3.5 months). From the patients who had further intervention, 17 (85%) underwent surgical procedure (laser ablation 53%, open surgical resection 47%) (median 4.4 months) and 3 (15%) had responsive neurostimulators placed (median 6.9 months). Prior to further intervention (median follow‐up 3.5 months after RFTC), 12 (48%) patients were classified as responders (12% Engel class I, 16% class II, and 20% class III) and 13 (52%) as non‐responders. Following neurosurgical intervention, 17 (68%) patients were followed for a median time of 2.7 months and 3 were lost to follow‐up. Of eight initial RFTC responders, 87.5% and 12.5% had Engel classes I and III, respectively. Of nine who were non‐responders, 33% had Engel class I, 22% II and III, and 44% IV outcomes following further intervention. No neurologic complications were reported.SignificanceSEEG‐guided RFTC is a well‐tolerated procedure and a beneficial diagnostic approach prior to further neurosurgical interventions in patients with DRE.Plain Language SummarySEEG‐guided RFTC is a well‐tolerated procedure and in the patients who experienced initial seizure reduction (n = 8), subsequent neurosurgical intervention (surgery or neuromodulation) led to favorable seizure outcomes (87.5% seizure freedom and 12.5% worthwhile seizure improvement).

Abstract Temporal lobe epilepsy is a common neurological disease characterized by recurrent seizures that often originate within limbic networks involving amygdala and hippocampus. The limbic network is involved in crucial physiologic functions involving memory, emotion and sleep. Temporal lobe epilepsy is frequently drug-resistant, and people often experience comorbidities related to memory, mood and sleep. Deep brain stimulation targeting the anterior nucleus of the thalamus (ANT-DBS) is an established therapy for temporal lobe epilepsy. However, the optimal stimulation parameters and their impact on memory, mood and sleep comorbidities remain unclear. We used an investigational brain sensing-stimulation implanted device to accurately track seizures, interictal epileptiform spikes (IES), and memory, mood and sleep comorbidities in five ambulatory subjects. Wireless streaming of limbic network local field potentials (LFPs) and subject behaviour were captured on a mobile device integrated with a cloud environment. Automated algorithms applied to the continuous LFPs were used to accurately cataloged seizures, IES and sleep-wake brain state. Memory and mood assessments were remotely administered to densely sample cognitive and behavioural response during ANT-DBS in ambulatory subjects living in their natural home environment. We evaluated the effect of continuous low-frequency and duty cycle high-frequency ANT-DBS on epileptiform activity and memory, mood and sleep comorbidities. Both low-frequency and high-frequency ANT-DBS paradigms reduced seizures. However, continuous low-frequency ANT-DBS showed greater reductions in IES, electrographic seizures and better sleep and memory outcomes. These results highlight the potential of synchronized brain sensing and dense behavioural tracking during ANT-DBS for optimizing neuromodulation therapy. While studies with larger patient numbers are needed to validate the benefits of low-frequency ANT-DBS, these findings are potentially translatable to individuals currently implanted with ANT-DBS systems.

Summary: The lack of reliable seizure detection remains a significant challenge for epilepsy care. A clinical deep brain stimulation (DBS) system provides constrained ambulatory brain recordings; however, limited data exist on the use of DBS recordings for seizure detection and lateralization. We present the case of an 18-year-old patient with drug-resistant focal epilepsy, who had seizure detection and lateralization by DBS recordings. Prior stereotactic-EEG, including a thalamus lead, identified independent left orbitofrontal and mesial temporal onset seizures. Notably, low-frequency thalamic ictal power was significantly elevated relative to baseline awake and sleep states. The patient was subsequently implanted with an anterior nucleus of the thalamus DBS system. Postimplantation, low-frequency power-in-band (5.3–10.3 Hz) recordings were initiated. Nursing staff identified four typical clinical seizures during the inpatient DBS recording period. Thalamic DBS trends contained relative peaks that were coincident with each nurse-reported seizure. Peri-ictal power was uniformly maximal ipsilateral to the seizure network. This case demonstrates the feasibility of seizure detection and lateralization by a thalamic DBS system for some individuals, and suggests DBS sensing parameter selection may be guided by thalamic stereotactic EEG. Further research is necessary to assess the generalizability of DBS seizure detection across individuals and diverse seizure networks.

Abstract There are limited treatment options for individuals with drug‐resistant idiopathic generalized epilepsy (IGE). Small, limited case series suggest that centromedian thalamus deep brain stimulation (CM‐DBS) may be an effective treatment option. The optimal CM‐DBS target for IGE is underexamined. Here, we present a retrospective analysis of CM‐DBS targeting and efficacy for five patients with drug‐resistant IGE. Volume of tissue activated (VTA) overlap with CM nucleus was performed using an open‐source toolbox. Median follow‐up time was 13 months. Median convulsive seizure frequency reduction was 66%. One patient had only absence seizures, with >99% reduction in absence seizure frequency. Four patients had electrode contacts positioned within the CM nucleus target, all of whom had >50% reduction in primary semiology seizure, with 85% median seizure reduction ( p = .004, paired‐sample t test). Volumetric “sweet‐spot” mapping revealed that best outcomes were correlated with stimulation of the middle ventral CM nucleus. Connectivity strength between the sweet‐spot region and central peri‐Rolandic cortex was increased significantly relative to other cortical regions ( p = 8.6 × 10 −4 , Mann–Whitney U test). Our findings indicate that CM‐DBS can be an effective treatment for patients with IGE, highlight the importance of accurate targeting and targeting analysis, and within the context of prior work, suggest that ideal CM‐DBS targets may be syndrome specific.

AbstractObjectiveNeuromodulation is a viable option for patients with drug‐resistant epilepsies. We reviewed the management of patients with two deep brain neurostimulators. In addition, patients implanted with a device targeting the centromedian‐parafascicular (CM‐Pf) nuclear complex supplements this report to provide an illustrative case to implantation and programming a patient with three active devices.MethodsA narrative review using PubMed and Embase identified patients with drug‐resistant epilepsy implanted with more than one neurostimulator was performed. Combinations of vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) were identified. We provide a background of a newly reported case of an adult with a triple implant eventually responding to CM‐Pf DBS as the third implant following suboptimal benefit from VNS and RNS.ResultsIn review of the literature, dual‐device therapy is increasing in reports of use with combinations of VNS, RNS, and DBS to treat patients with drug‐resistant epilepsy. We review dual‐device implants with thalamic DBS device combinations, functional neural networks, and programming patients with dual devices. CM‐Pf is a new target for DBS and has shown a variable response in focal epilepsy. We report the unique case of 28‐year‐old male with drug‐resistant focal epilepsy who experienced a 75% seizure reduction with CM‐Pf DBS as his third device after suboptimal responses to VNS and RNS. After 9 months, he also experienced seizure freedom from recurrent focal to bilateral tonic–clonic seizures. No medical or surgical complications or safety issues were encountered.ConclusionWe demonstrate safety and feasibility in an adult combining active VNS, RNS, and CM‐Pf DBS. Patients with dual‐device therapy who experience a suboptimal response to initial device use at optimized settings should not be considered a neuromodulation “failure.” Strategies to combine devices require a working knowledge of brain networks.

Neurostimulation is an increasingly common treatment option for medically intractable epilepsy. SANTE (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) and Responsive Neurostimulation (RNS) System are landmark neurostimulation trials that utilized either duty cycle or a responsive stimulation paradigm. A seizure-free outcome is rarely observed with responsive and duty cycle neurostimulation devices. Chronic subthreshold cortical stimulation (CSCS) is a promising treatment for adult drug-resistant epilepsy involving eloquent cortex and has demonstrated safety and efficacy. Herein, the authors describe the surgical technique as well as details of stimulation programming involved in CSCS placement to facilitate the adoption of this promising treatment. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2422

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ /K V 7 potassium channel cause gating pore currents (I gp ) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A /Na V 1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of Na V 1.2 caused I gp in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective I gp . These potentially pathogenic I gp were exacerbated by the absence of the extracellular Mg 2+ and Ca 2+ . In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward I gp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD.