Responsive neurostimulation as a treatment for super-refractory focal status epilepticus: a systematic review and case series.

OBJECTIVE: Super-refractory status epilepticus (SRSE) has high rates of morbidity and mortality. Few published studies have investigated neurostimulation treatment options in the setting of SRSE. This systematic literature review and series of 10 cases investigated the safety and efficacy of implanting and activating the responsive neurostimulation (RNS) system acutely during SRSE and discusses the rationale for lead placement and selection of stimulation parameters. METHODS: Through a literature search (of databases and American Epilepsy Society abstracts that were last searched on March 1, 2023) and direct contact with the manufacturer of the RNS system, 10 total cases were identified that utilized RNS acutely during SE (9 SRSE cases and 1 case of refractory SE [RSE]). Nine centers obtained IRB approval for retrospective chart review and completed data collection forms. A tenth case had published data from a case report that were referenced in this study. Data from the collection forms and the published case report were compiled in Excel. RESULTS: All 10 cases presented with focal SE: 9 with SRSE and 1 with RSE. Etiology varied from known lesion (focal cortical dysplasia in 7 cases and recurrent meningioma in 1) to unknown (2 cases, with 1 presenting with new-onset refractory focal SE [NORSE]). Seven of 10 cases exited SRSE after RNS placement and activation, with a time frame ranging from 1 to 27 days. Two patients died of complications due to ongoing SRSE. Another patient's SE never resolved but was subclinical. One of 10 cases had a device-related significant adverse event (trace hemorrhage), which did not require intervention. There was 1 reported recurrence of SE after discharge among the cases in which SRSE resolved up to the defined endpoint. CONCLUSIONS: This case series offers preliminary evidence that RNS is a safe and potentially effective treatment option for SRSE in patients with 1-2 well-defined seizure-onset zone(s) who meet the eligibility criteria for RNS. The unique features of RNS offer multiple benefits in the SRSE setting, including real-time electrocorticography to supplement scalp EEG for monitoring SRSE progress and response to treatment, as well as numerous stimulation options. Further research is indicated to investigate the optimal stimulation settings in this unique clinical scenario.

Insights From Chronic ECoG by RNS.

SUMMARY: The NeuroPace responsive neurostimulation system (RNS) has revolutionized the care of patients suffering from focal epilepsy since its approval in 2014. One major advantage of this device is its innate ability to gather long-term electrocorticographic (ECoG) data that the device uses in its novel closed-loop treatment paradigm. Beyond the standard stimulation treatments, which have been demonstrated to be safe and well-tolerated, the data collected by the RNS provide valuable information, such as the long-term circadian and ultradian variations that affect seizure risk, obtained under naturalistic conditions. Additionally, these data inform future surgical procedures, supplementing clinically reported seizures by patients, assessing the response to newly added anti-seizure medications, helping to forecast the risk of future seizures, and understanding the mechanisms of certain long-term outcomes in patients with postsurgical epilepsy. By leveraging these data, the delivery of high-quality clinical care for patients with epilepsy can only be enhanced. Finally, these data open significant avenues of research, including machine learning and artificial intelligence algorithms, which may also translate to improved outcomes in patients who struggle with recurrent seizures.

Asymmetric coding of reward prediction errors in human insula and dorsomedial prefrontal cortex.

The signed value and unsigned salience of reward prediction errors (RPEs) are critical to understanding reinforcement learning (RL) and cognitive control. Dorsomedial prefrontal cortex (dMPFC) and insula (INS) are key regions for integrating reward and surprise information, but conflicting evidence for both signed and unsigned activity has led to multiple proposals for the nature of RPE representations in these brain areas. Recently developed RL models allow neurons to respond differently to positive and negative RPEs. Here, we use intracranially recorded high frequency activity (HFA) to test whether this flexible asymmetric coding strategy captures RPE coding diversity in human INS and dMPFC. At the region level, we found a bias towards positive RPEs in both areas which paralleled behavioral adaptation. At the local level, we found spatially interleaved neural populations responding to unsigned RPE salience and valence-specific positive and negative RPEs. Furthermore, directional connectivity estimates revealed a leading role of INS in communicating positive and unsigned RPEs to dMPFC. These findings support asymmetric coding across distinct but intermingled neural populations as a core principle of RPE processing and inform theories of the role of dMPFC and INS in RL and cognitive control.

A rapid theta network mechanism for flexible information encoding.

Flexible behavior requires gating mechanisms that encode only task-relevant information in working memory. Extant literature supports a theoretical division of labor whereby lateral frontoparietal interactions underlie information maintenance and the striatum enacts the gate. Here, we reveal neocortical gating mechanisms in intracranial EEG patients by identifying rapid, within-trial changes in regional and inter-regional activities that predict subsequent behavioral outputs. Results first demonstrate information accumulation mechanisms that extend prior fMRI (i.e., regional high-frequency activity) and EEG evidence (inter-regional theta synchrony) of distributed neocortical networks in working memory. Second, results demonstrate that rapid changes in theta synchrony, reflected in changing patterns of default mode network connectivity, support filtering. Graph theoretical analyses further linked filtering in task-relevant information and filtering out irrelevant information to dorsal and ventral attention networks, respectively. Results establish a rapid neocortical theta network mechanism for flexible information encoding, a role previously attributed to the striatum.

Left hemisphere dominance for bilateral kinematic encoding in the human brain.

Neurophysiological studies in humans and nonhuman primates have revealed movement representations in both the contralateral and ipsilateral hemispheres. Inspired by clinical observations, we ask if this bilateral representation differs for the left and right hemispheres. Electrocorticography was recorded in human participants during an instructed-delay reaching task, with movements produced with either the contralateral or ipsilateral arm. Using a cross-validated kinematic encoding model, we found stronger bilateral encoding in the left hemisphere, an effect that was present during preparation and was amplified during execution. Consistent with this asymmetry, we also observed better across-arm generalization in the left hemisphere, indicating similar neural representations for right and left arm movements. Notably, these left hemisphere electrodes were centered over premotor and parietal regions. The more extensive bilateral encoding in the left hemisphere adds a new perspective to the pervasive neuropsychological finding that the left hemisphere plays a dominant role in praxis.

The brain is split into two hemispheres, each playing the leading role in coordinating movement for the opposite side of the body: lesions on the left hemisphere therefore often result in difficulties moving the right arm or leg, and vice versa. In fact, very few anatomical connections exist between a given hemisphere and the body parts on the same (or 'ipsilateral') side. Yet, movements produced with only one limb still engage both sides of the brain, with the hemisphere which does not control the action production, still encoding the direction and speed of the movement. Previous evidence also indicate that the two hemispheres may not have equal roles when coordinating ipsilateral movements. Merrick et al. aimed to shed light on these processes; to do so, they measured electrical activity from the surface of the brain of six patients as they moved their arms to reach a screen. The results revealed that, while the right hemisphere only encoded information about the opposite arm, the left hemisphere contained information about both arms. Finer analyses showed that, for both hemispheres, moving the opposite arm was strongly associated with activity in the primary motor cortex, a region which helps to execute movements. However, in the left hemisphere, movements from the ipsilateral arm were related to activity in brain areas involved in planning and integrating different types of sensory information. These findings contribute to a better understanding of how the motor system works, which could ultimately help with the development of brain-machine interfaces for patients who need a neuroprosthetic limb.

Intracranial Recordings Demonstrate Both Cortical and Medial Temporal Lobe Engagement in Visual Search in Humans.

Visual search is a fundamental human behavior, providing a gateway to understanding other sensory domains as well as the role of search in higher-order cognition. Search has been proposed to include two component processes: inefficient search (Search) and efficient search (Pop-out). According to extant research, these two processes map onto two separable neural systems located in the frontal and parietal association cortices. In this study, we use intracranial recordings from 23 participants to delineate the neural correlates of Search and Pop-out with an unprecedented combination of spatiotemporal resolution and coverage across cortical and subcortical structures. First, we demonstrate a role for the medial temporal lobe in visual search, on par with engagement in frontal and parietal association cortex. Second, we show a gradient of increasing engagement over anatomical space from dorsal to ventral lateral frontal cortex. Third, we confirm previous intracranial work demonstrating nearly complete overlap in neural engagement across cortical regions in Search and Pop-out. We further demonstrate Pop-out selectivity, manifesting as activity increase in Pop-out as compared to Search, in a distributed set of sites including frontal cortex. This result is at odds with the view that Pop-out is implemented in low-level visual cortex or parietal cortex alone. Finally, we affirm a central role for the right lateral frontal cortex in Search.

Forecasting seizure risk in adults with focal epilepsy: a development and validation study.

BACKGROUND: People with epilepsy are burdened with the apparent unpredictability of seizures. In the past decade, converging evidence from studies using chronic EEG (cEEG) revealed that epileptic brain activity shows robust cycles, operating over hours (circadian) and days (multidien). We hypothesised that these cycles can be leveraged to estimate future seizure probability, and we tested the feasibility of forecasting seizures days in advance. METHODS: We did a feasibility study in distinct development and validation cohorts, involving retrospective analysis of cEEG data recorded with an implanted device in adults (age ≥18 years) with drug-resistant focal epilepsy followed at 35 centres across the USA between Jan 19, 2004, and May 18, 2018. Patients were required to have had 20 or more electrographic seizures (development cohort) or self-reported seizures (validation cohort). In all patients, the device recorded interictal epileptiform activity (IEA; ≥6 months of continuous hourly data), the fluctuations in which helped estimate varying seizure risk. Point process statistical models trained on initial portions of each patient's cEEG data (both cohorts) generated forecasts of seizure probability that were tested on subsequent unseen seizure data and evaluated against surrogate time-series. The primary outcome was the percentage of patients with forecasts showing improvement over chance (IoC). FINDINGS: We screened 72 and 256 patients, and included 18 and 157 patients in the development and validation cohorts, respectively. Models incorporating information about multidien IEA cycles alone generated daily seizure forecasts for the next calendar day with IoC in 15 (83%) patients in the development cohort and 103 (66%) patients in the validation cohort. The forecasting horizon could be extended up to 3 days while maintaining IoC in two (11%) of 18 patients and 61 (39%) of 157 patients. Forecasts with a shorter horizon of 1 h, possible only for electrographic seizures in the development cohort, showed IoC in all 18 (100%) patients. INTERPRETATION: This study shows that seizure probability can be forecasted days in advance by leveraging multidien IEA cycles recorded with an implanted device. This study will serve as a basis for prospective clinical trials to establish how people with epilepsy might benefit from seizure forecasting over long horizons. FUNDING: None. VIDEO ABSTRACT.

Burden of disease in patients with a history of status epilepticus and their caregivers.

OBJECTIVE: Status epilepticus (SE) is a life-threatening neurological emergency with the potential for wide-ranging impact on patients and caregivers. In this study, the burden of disease in patients with a history of SE and their caregivers was assessed. METHODS: Adult patients as well as caregivers of children, adolescents, and adults who had experienced ≥1 SE event in the past 24 months completed an online survey. Functional, social, emotional, and economic burden in patients and caregivers was assessed. Burden was measured through concept-targeted questionnaires, including the US Centers for Disease Control and Prevention (CDC) Health-Related Quality of Life 4 (HRQoL-4) and the Work Productivity and Activity Impairment (WPAI) instruments. RESULTS: The 198 respondents comprised 49 adult patients, 51 caregivers of children, 47 caregivers of adolescents, and 51 caregivers of adults. Most patients (93.9%) were diagnosed with epilepsy. Patients' daily activities were highly affected, and many respondents reported a substantial long-term physical and mental impact on patients. The mean CDC HRQoL-4 score for unhealthy days per month ranged from 11.1 for caregivers of adults to 16.9 for caregivers of children. WPAI scores demonstrated a substantial impact on the ability of adult patients and all caregivers to work. Among respondents, caregivers of children reported the highest absenteeism from work (20%) and the lowest employment rate (33%). Proportions of caregivers reporting that their daily social life was impacted at least 'some of the time' ranged from 80% to 92%, with nearly half (47%) of caregivers of children responding that their social life was impacted 'all the time'. CONCLUSIONS: Status epilepticus episodes place a high burden on patients and caregivers. Notably, the burden appeared high across a variety of domains. This study highlights that the burden of disease is pronounced and wide-reaching and goes beyond the immediate physical and medical impact of an SE episode.