Worrell, Gregory A.

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.

Abstract BACKGROUND Subdural grids and strip electrodes provide wide coverage of the cerebral cortex, precise delineation of the extent of the seizure onset zone, and improved spatial sampling to perform functional mapping for eloquent cortex. OBJECTIVE To describe a novel device that allows for a minimally invasive approach to implantation of subdural grid and strip electrodes. METHODS A skull mounted device was created to allow for implantation of subdural electrodes through a keyhole craniotomy with direct visualization using the aid of a flexible neurovideoscope. The initial studies in preparation for grid development performed on cadaveric skulls were analyzed to determine the size of craniotomy required for deployment, maximal distance of strip electrode deployment from center of craniotomy, and visual inspection of the cortex was performed for any underlying damage. RESULTS The device allowed for the placement of subdural electrodes through a 40-mm craniotomy. Subdural electrodes were deployed in multiple directions to a distance of a 70-mm radius from the center of the craniotomy. There was no visual damage to the underlying cortex after the procedures were completed. CONCLUSION Large craniotomies are typically desired to provide direct visualization of the implantation of subdural electrodes, but can increase the risk of subdural hemorrhages and infections. This study describes a novel minimally invasive endoscopically assisted device for the implantation of subdural strip electrodes under direct visualization. With this device, we are able to limit the size of the craniotomy, avoid incision through the temporalis muscle, and implant subdural electrodes with visualization of the cortex.

AbstractMicroglial activation has been recognized as a major contributor to inflammation of the epileptic brain. Seizures are commonly accompanied by remarkable microgliosis and loss of neurons. In this study, we utilize the CX3CR1GFP/+ CCR2RFP/+ genetic mouse model, in which CX3CR1+ resident microglia and CCR2+ monocytes are labeled with GFP and RFP, respectively. Using a combination of time‐lapse two‐photon imaging and whole‐cell patch clamp recording, we determined the distinct morphological, dynamic, and electrophysiological characteristics of infiltrated monocytes and resident microglia, and the evolution of their behavior at different time points following kainic acid‐induced seizures. Seizure activated microglia presented enlarged somas with less ramified processes, whereas, infiltrated monocytes were smaller, highly motile cells that lacked processes. Moreover, resident microglia, but not infiltrated monocytes, proliferate locally in the hippocampus after seizure. Microglial proliferation was dependent on the colony‐stimulating factor 1 receptor (CSF‐1R) pathway. Pharmacological inhibition of CSF‐1R reduced seizure‐induced microglial proliferation, which correlated with attenuation of neuronal death without altering acute seizure behaviors. Taken together, we demonstrated that proliferation of activated resident microglia contributes to neuronal death in the hippocampus via CSF‐1R after status epilepticus, providing potential therapeutic targets for neuroprotection in epilepsy.

OBJECTIVEAlmost 30% of the patients with suspected temporal lobe epilepsy (TLE) have normal results on MRI. Success rates for resection of MRI-negative TLE are less favorable, ranging from 36% to 76%. Herein the authors describe the impact of intraoperative electrocorticography (ECoG) augmented by opioid activation and its effect on postoperative seizure outcome.METHODSAdult and pediatric patients with medically resistant MRI-negative TLE who underwent standardized ECoG at the time of their elective anterior temporal lobectomy (ATL) with amygdalohippocampectomy between 1990 and 2016 were included in this study. Seizure recurrence comprised the primary outcome of interest and was assessed using Kaplan-Meier and multivariable Cox regression analysis plots based on distribution of interictal epileptiform discharges (IEDs) recorded on scalp electroencephalography, baseline and opioid-induced IEDs on ECoG, and extent of resection.RESULTSOf the 1144 ATLs performed at the authors’ institution between 1990 and 2016, 127 (11.1%) patients (81 females) with MRI-negative TLE were eligible for this study. Patients with complete resection of tissue generating IED recorded on intraoperative ECoG were less likely to have seizure recurrence compared to those with incomplete resection on univariate analysis (p < 0.05). No difference was found in seizure recurrence between patients with bilateral independent IEDs and unilateral IEDs (p = 0.15), presence or absence of opioid-induced epileptiform activation (p = 0.61), or completeness of resection of tissue with opioid-induced IEDs on intraoperative ECoG (p = 0.41).CONCLUSIONSThe authors found that incomplete resection of IED-generating tissue on intraoperative ECoG was associated with an increased chance of seizure recurrence. However, they found that induction of epileptiform activity with intraoperative opioid activation did not provide useful intraoperative data predictive of improving operative results for temporal lobectomy in MRI-negative epilepsy.

SummaryObjectiveWe aimed to determine the frequency of probable obstructive sleep apnea (pOSA) in refractory epilepsy monitoring unit inpatients and clinical features associated with pOSA, including risk for sudden unexpected death in epilepsy (SUDEP).MethodsWe prospectively recruited 49 consecutive adult patients admitted to the Mayo Clinic Epilepsy Monitoring Unit with focal, generalized, or unclassified epilepsy syndromes. pOSA was identified using oximetric oxyhemoglobin desaturation index (ODI) and the Sleep Apnea–Sleep Disorders Questionnaire (SA‐SDQ) and STOP‐BAG screening tools. Revised SUDEP Risk Inventory (rSUDEP‐7) scores were calculated, and epilepsy patients with and without pOSA were compared with Wilcoxon signed‐rank tests. Correlation and regression analyses were utilized to determine relationships between pOSA and rSUDEP‐7 scores.ResultsThirty‐five percent of patients had pOSA, with a mean ODI of 11.3 ± 5.1/h (range = 5.1‐22.8). Patients with pOSA were older and heavier, and more frequently had a focal epilepsy syndrome and longer epilepsy duration, with higher SA‐SDQ and STOP‐BAG scores (all P < 0.05). Median rSUDEP‐7 score was 3 ± 1.4 (range = 0‐6). Higher rSUDEP‐7 scores were positively correlated with higher ODI (P = 0.036). rSUDEP‐7 score ≥ 5 was associated with pOSA by ODI, SA‐SDQ, and STOP‐BAG questionnaire criteria (P < 0.05).SignificanceOur pilot study identified a high frequency of pOSA in refractory epilepsy monitoring patients, finding that pOSA patients were older and heavier, with higher screening symptoms for sleep apnea and more frequent focal seizures with a longer epilepsy duration. We also found a possible association between OSA and SUDEP risk. Identification and treatment of OSA in patients with epilepsy could conceivably provide a novel approach toward preventing the risk of SUDEP. Future studies with polysomnography are needed to confirm predictive features for OSA in epilepsy populations, and to determine whether OSA is associated with SUDEP risk.

Abstract Objective This study investigates high‐frequency oscillations ( HFO s; 65–600 Hz) as a biomarker of epileptogenic brain and explores three barriers to their clinical translation: (1) Distinguishing pathological HFO s (path HFO ) from physiological HFO s (phys HFO ). (2) Classifying tissue under individual electrodes as epileptogenic (3) Reproducing results across laboratories. Methods We recorded HFO s using intracranial EEG ( iEEG ) in 90 patients with focal epilepsy and 11 patients without epilepsy. In nine patients with epilepsy putative phys HFO s were induced by cognitive or motor tasks. HFO s were identified using validated detectors. A support vector machine ( SVM ) using HFO features was developed to classify tissue under individual electrodes as normal or epileptogenic. Results There was significant overlap in the amplitude, frequency, and duration distributions for spontaneous phys HFO , task induced phys HFO , and path HFO , but the amplitudes of the path HFO were higher ( P < 0.0001). High gamma path HFO had the strongest association with seizure onset zone ( SOZ ), and were elevated on SOZ electrodes in 70% of epilepsy patients ( P < 0.0001). Failure to resect tissue generating high gamma path HFO was associated with poor outcomes ( P < 0.0001). A SVM classified individual electrodes as epileptogenic with 63.9% sensitivity and 73.7% specificity using SOZ as the target. Interpretation A broader range of interictal path HFO (65–600 Hz) than previously recognized are biomarkers of epileptogenic brain, and are associated with SOZ and surgical outcome. Classification of HFO s into physiological or pathological remains challenging. Classification of tissue under individual electrodes was demonstrated to be feasible. The open source data and algorithms provide a resource for future studies.

OBJECTIVE Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising therapy for refractory epilepsy. Unfortunately, the variability in outcomes from ANT DBS is not fully understood. In this pilot study, the authors assess potential differences in functional connectivity related to the volume of tissue activated (VTA) in ANT DBS responders and nonresponders as a means for better understanding the mechanism of action and potentially improving DBS targeting. METHODS This retrospective analysis consisted of 6 patients who underwent ANT DBS for refractory epilepsy. Patients were classified as responders (n = 3) if their seizure frequency decreased by at least 50%. The DBS electrodes were localized postoperatively and VTAs were computationally generated based on DBS programming settings. VTAs were used as seed points for resting-state functional MRI connectivity analysis performed using a control dataset. Differences in cortical connectivity to the VTA were assessed between the responder and nonresponder groups. RESULTS The ANT DBS responders showed greater positive connectivity with the default mode network compared to nonresponders, including the posterior cingulate cortex, medial prefrontal cortex, inferior parietal lobule, and precuneus. Interestingly, there was also a consistent anticorrelation with the hippocampus seen in responders that was not present in nonresponders. CONCLUSIONS Based on their pilot study, the authors observed that successful ANT DBS in patients with epilepsy produces increased connectivity in the default mode network, which the authors hypothesize increases the threshold for seizure propagation. Additionally, an inhibitory effect on the hippocampus mediated through increased hippocampal γ-aminobutyric acid (GABA) concentration may contribute to seizure suppression. Future studies are planned to confirm these findings.

When medically intractable epilepsy is multifocal or focal but poorly localized, neuromodulation can be useful therapy. One such technique is deep brain stimulation (DBS) targeting the anterior nucleus of the thalamus (ANT). Unfortunately, the ANT is difficult to visualize in standard MRI sequences and its indirect targeting is difficult because of thalamic variability and atrophy in patients with epilepsy. The following study describes the novel use of the fast gray matter acquisition T1 inversion recovery (FGATIR) MRI sequence to delineate the mammillothalamic tract for direct targeting of the ANT through visualizing the termination of the mammillothalamic tract in the ANT. The day prior to surgery in a 19-year-old, right-handed woman with a 5-year history of epilepsy, MRI was performed on a 3-T Siemens Prisma scanner (Siemens AG, Healthcare Sector) using a 64-channel head and neck coil. As part of the imaging protocol, noncontrast magnetization-prepared rapid gradient echo (MP-RAGE) and diffusion tensor imaging (DTI) sequences were obtained for targeting purposes. The ANT was directly targeted using the FGATIR sequence, and bilateral Medtronic 3389 leads were placed. At the last follow-up (2 months), the patient reported an approximate 75% decrease in seizure frequency, as well as a decrease in seizure severity.