Jobst, Barbara C.

Abstract Neuromodulation is a key therapeutic tool for clinicians managing patients with drug‐resistant epilepsy. Multiple devices are available with long‐term follow‐up and real‐world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS‐ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow‐up for all modalities, albeit in uncontrolled follow‐up or retrospective studies. A significant number of patients experience seizure‐free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved—DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

Coronavirus 19 (COVID-19) has infected over 400 million people worldwide. Although COVID-19 causes predominantly respiratory symptoms, it can affect other organs including the brain, producing neurological symptoms. People with epilepsy (PWE) have been particularly impacted during the pandemic with decreased access to care, increased stress, and worsening seizures in up to 22% of them probably due to multiple factors. COVID-19 vaccines were produced in a record short time and have yielded outstanding protection with very rare serious side effects. Studies have found that COVID-19 vaccination does not increase seizures in the majority of PWE. COVID-19 does not produce a pathognomonic EEG or seizure phenotype, but rather 1 that can be seen in other types of encephalopathy. COVID-19 infection and its complications can lead to seizures, status epilepticus and post-COVID inflammatory syndrome with potential multi-organ damage in people without pre-existing epilepsy. The lack of access to care during the pandemic has forced patients and doctors to rapidly implement telemedicine. The use of phone videos and smart telemedicine are helping to treat patients during this pandemic and are becoming standard of care. Investment in infrastructure is important to make sure patients can have access to care even during a pandemic.

Abstract Scientists debate where, when, and how different visual, orthographic, lexical, and semantic features are involved in visual word recognition. In this study, we investigate intracranial neurophysiology data from 151 patients engaged in reading single words. Using representational similarity analysis, we characterize the neural representation of a hierarchy of word features across the entire cerebral cortex. We find evidence of both feed-forward and feedback processing, with early representation of visual and lexical information in lingual gyrus followed by lexical representation in fusiform gyrus and semantic sensitivity in inferior frontal gyrus, with letter representation emerging later in fusiform gyrus. Furthermore, we observed a variety of anatomically heterogeneous temporal response shapes, and these functional populations had significant feature sensitivity. Taken together, our results demonstrate the early influence of lexical, phonological, and semantic features in visual word recognition and reveal feed-forward, feed-back, and anatomically distributed processing mechanisms that contribute to visual word recognition.

Intracranial electroencephalography (iEEG) has been the mainstay of identifying the seizure onset zone (SOZ), a key diagnostic procedure in addition to neuroimaging when considering epilepsy surgery. In many patients, iEEG has been the basis for resective epilepsy surgery, to date still the most successful treatment for drug-resistant epilepsy. Intracranial EEG determines the location and resectability of the SOZ. Advances in recording and implantation of iEEG provide multiple options in the 21st century. This not only includes the choice between subdural electrodes (SDE) and stereoelectroencephalography (SEEG) but also includes the implantation and recordings from microelectrodes. Before iEEG implantation, especially in magnetic resonance imaging -negative epilepsy, a clear hypothesis for seizure generation and propagation should be based on noninvasive methods. Intracranial EEG implantation should be planned by a multidisciplinary team considering epileptic networks. Recordings from SDE and SEEG have both their advantages and disadvantages. Stereo-EEG seems to have a lower rate of complications that are clinically significant, but has limitations in spatial sampling of the cortical surface. Stereo-EEG can sample deeper areas of the brain including deep sulci and hard to reach areas such as the insula. To determine the epileptogenic zone, interictal and ictal information should be taken into consideration. Interictal spiking, low frequency slowing, as well as high frequency oscillations may inform about the epileptogenic zone. Ictally, high frequency onsets in the beta/gamma range are usually associated with the SOZ, but specialized recordings with combined macro and microelectrodes may in the future educate us about onset in higher frequency bands. Stimulation of intracranial electrodes triggering habitual seizures can assist in identifying the SOZ. Advanced computational methods such as determining the epileptogenicity index and similar measures may enhance standard clinical interpretation. Improved techniques to record and interpret iEEG may in the future lead to a greater proportion of patients being seizure free after epilepsy surgery.

Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of mesial temporal lobe (MTL) brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of mesial temporal lobe origin.MethodsSubjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.ResultsThere were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy‐six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow‐up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty‐nine percent of subjects experienced at least one seizure‐free period of 6 months or longer, and 15% experienced at least one seizure‐free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device‐related adverse event was soft tissue implant‐site infection (overall rate, including events categorized as device‐related, uncertain, or not device‐related: 0.03 per implant year, which is not greater than with other neurostimulation devices).SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of neocortical origin.MethodsPatients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset.ResultsThere were 126 patients with seizures of neocortical onset. The average follow‐up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty‐six percent of patients experienced at least one seizure‐free period of 6 months or longer and 14% experienced at least one seizure‐free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices.SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.