Faculty Bibliography

Magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE) may be a distinct syndrome from TLE with mesial temporal sclerosis (TLE-MTS). Imaging and neuropsychological features of TLE-MTS are well-known; yet, these features are only beginning to be described in MRI-negative TLE. This study examined whether a quantitative measure of cortical gray and white matter blurring (GWB) was elevated in the temporal lobes ipsilateral to the seizure onset zone of individuals with MRI-negative TLE relative to TLE-MTS and healthy controls (HCs) and whether GWB elevations were associated with neuropsychological comorbidity. Gray-white matter blurring from 34 cortical regions and hippocampal volumes were quantified and compared across 28 people with MRI-negative TLE, 15 people with TLE-MTS, and 51 HCs. Declarative memory was assessed with standard neuropsychological tests and the intracarotid amobarbital procedure (IAP). In the group with MRI-negative TLE (left and right onsets combined), hippocampal volumes were within normal range but GWB was elevated, relative to HCs, across several mesial and lateral temporal lobe regions ipsilateral to the seizure onset zone. Gray-white matter blurring did not differ between the groups with TLE-MTS and HC or between the groups with TLE-MTS and MRI-negative TLE. The group with MRI-negative TLE could not be distinguished from the group with TLE-MTS on any of the standard neuropsychological tests; however, ipsilateral hippocampal volumes and IAP memory scores were lower in the group with TLE-MTS than in the group with MRI-negative TLE. The group with left MRI-negative TLE had lower general cognitive abilities and verbal fluency relative to the HC group, which adds to the characterization of neuropsychological comorbidities in left MRI-negative TLE. In addition, ipsilateral IAP memory performance was reduced relative to contralateral memory performance in MRI-negative TLE, indicating some degree of ipsilateral memory dysfunction. There was no relationship between hippocampal volume and IAP memory scores in MRI-negative TLE; however, decreased ipsilateral IAP memory scores were correlated with elevated GWB in the ipsilateral superior temporal sulcus of people with left MRI-negative TLE. In sum, GWB elevations in the ipsilateral temporal lobe of people with MRI-negative TLE suggest that GWB may serve as a marker for reduced structural integrity in regions in or near the seizure onset zone. Although mesial temporal abnormalities might be the major driver of memory dysfunction in TLE-MTS, a loss of structural integrity in lateral temporal lobe regions may contribute to IAP memory dysfunction in MRI-negative TLE.

Electrical stimulation in the anterior nucleus of the thalamus (ANT) has previously been found to be efficacious for reducing seizure frequency in patients with epilepsy. Bilateral deep brain stimulation (DBS) of the ANT is an open-loop system that can be used in the management of treatment-resistant epilepsy. In contrast, the responsive neurostimulation (RNS) system is a closed-loop device that delivers treatment in response to prespecified electrocorticographic triggers. The efficacy and safety of RNS targeting the ANT is unknown. We describe 3 patients with treatment-resistant multifocal epilepsy who were implanted with an RNS system, which included unilateral stimulation of the ANT. After >33 months of follow-up, there were no adverse effects on mood, memory or behavior. Two patients had ≥50% reduction in disabling seizures and one patient had a 50% reduction compared to pretreatment baseline. Although reduction in seizure frequency has been modest to date, these findings support responsive neurostimulation of the ANT as feasible, safe, and well-tolerated. Further studies are needed to determine optimal stimulation parameters.

OBJECTIVE:Current brain-computer interface (BCI) studies demonstrate the potential to decode neural signals obtained from structured and trial-based tasks to drive actuators with high performance within the context of these tasks. Ideally, to maximize utility, such systems will be applied to a wide range of behavioral settings or contexts. Thus, we explore the potential to augment such systems with the ability to decode abstract behavioral contextual states from neural activity. APPROACH/METHODS:To demonstrate the feasibility of such context decoding, we used electrocorticography (ECoG) and stereo-electroencephalography (sEEG) data recorded from the cortical surface and deeper brain structures, respectively, continuously across multiple days from three subjects. During this time, the subjects were engaged in a range of naturalistic behaviors in a hospital environment. Behavioral contexts were labeled manually from video and audio recordings; four states were considered: engaging in dialogue, rest, using electronics, and watching television. We decode these behaviors using a factor analysis and support vector machine (SVM) approach. MAIN RESULTS/RESULTS:We demonstrate that these general behaviors can be decoded with high accuracies of 73% for a four-class classifier for one subject and 71% and 62% for a three-class classifier for two subjects. SIGNIFICANCE/CONCLUSIONS:To our knowledge, this is the first demonstration of the potential to disambiguate abstract naturalistic behavioral contexts from neural activity recorded throughout the day from implanted electrodes. This work motivates further study of context decoding for BCI applications using continuously recorded naturalistic activity in the clinical setting.

Direct recordings from the human brain have historically involved epilepsy patients undergoing invasive electroencephalography (iEEG) for surgery. However, these measurements are temporally limited and affected by clinical variables. The RNS System (NeuroPace, Inc.) is a chronic, closed-loop electrographic seizure detection and stimulation system. When adapted by investigators for research, it facilitates cognitive testing in a controlled ambulatory setting, with measurements collected over months to years. We utilized an associative learning paradigm in 5 patients with traditional iEEG and 3 patients with chronic iEEG, and found increased hippocampal gamma (60-100 Hz) sustained at 1.3-1.5 seconds during encoding in successful versus failed trials in surgical patients, with similar results in our RNS System patients (1.4-1.6 seconds). Our findings replicate other studies demonstrating that sustained hippocampal gamma supports encoding. Importantly, we have validated the RNS System to make sensitive measurements of hippocampal dynamics during cognitive tasks in a chronic ambulatory research setting.

There are no functional imaging based biomarkers for pharmacological treatment response in temporal lobe epilepsy (TLE). In this study, we investigated whether there is an association between resting state functional brain connectivity (RsFC) and seizure control in TLE. We screened a large database containing resting state functional magnetic resonance imaging (Rs-fMRI) data from 286 epilepsy patients. Patient medical records were screened for seizure characterization, EEG reports for lateralization and location of seizure foci to establish uniformity of seizure localization within patient groups. Rs-fMRI data from patients with well-controlled left TLE, patients with treatment-resistant left TLE, and healthy controls were analyzed. Healthy controls and cTLE showed similar functional connectivity patterns, whereas trTLE exhibited a significant bilateral decrease in thalamo-hippocampal functional connectivity. This work is the first to demonstrate differences in neural network connectivity between well-controlled and treatment-resistant TLE. These differences are spatially highly focused and suggest sites for the etiology and possibly treatment of TLE. Altered thalamo-hippocampal RsFC thus is a potential new biomarker for TLE treatment resistance.

The running-down phenomenon refers to 2 analogous but distinct entities that may be seen after epilepsy surgery. The first is clinical, and denotes a progressive diminution in seizures after epilepsy surgery in which the epileptogenic zone could not be completely removed (Modern Problems of Psychopharmacology 1970;4:306, Brain 1996:989). The second is electrographic, and refers to a progressive deactivation of a secondary seizure focus after removal of the primary epileptogenic zone. This progressive decrease in epileptiform activity may represent a reversal of secondary epileptogenesis, where a primary epileptogenic zone is postulated to activate epileptiform discharges at a second site and may become independent.³ The electrographic running-down phenomenon has been reported in only limited numbers of patients, using serial postoperative routine scalp electroencephalography (EEG) (Arch Neurol 1985;42:318). We present what is, to our knowledge, the most detailed demonstration of the electrographic running-down phenomenon in humans, made possible by chronic electrocorticography (ECoG). Our patient's left temporal seizure focus overlapped with language areas, limiting the resection to a portion of the epileptogenic zone, followed by implantation of a direct brain-responsive neurostimulator (RNS System, NeuroPace Inc.) to treat residual epileptogenic tissue. Despite the limited extent of the resection, the patient remains seizure-free more than 2 years after surgery, with the RNS System recording ECoG without delivering stimulation. We reviewed the chronic recordings with automated spike detection and inspection of electrographic episodes marked by the neurostimulator. These recordings demonstrate progressive diminution in spiking and rhythmic discharges, consistent with an electrographic running-down phenomenon.