Outcome of stereo-electroencephalography with single-unit recording in drug-refractory epilepsy.

OBJECTIVE: The aim of this study was to evaluate the utility and safety of "hybrid" stereo-electroencephalography (SEEG) in guiding epilepsy surgery and in providing information at single-neuron levels (i.e., single-unit recording) to further the understanding of the mechanisms of epilepsy and the neurocognitive processes unique to humans. METHODS: The authors evaluated 218 consecutive patients undergoing SEEG procedures from 1993 through 2018 at a single academic medical center to assess the utility and safety of this technique in both guiding epilepsy surgery and providing single-unit recordings. The hybrid electrodes used in this study contained macrocontacts and microwires to simultaneously record intracranial EEG and single-unit activity (hybrid SEEG). The outcomes of SEEG-guided surgical interventions were examined, as well as the yield and scientific utility of single-unit recordings in 213 patients who participated in the research involving single-unit recordings. RESULTS: All patients underwent SEEG implantation by a single surgeon and subsequent video-EEG monitoring (mean of 10.2 electrodes per patient and 12.0 monitored days). Epilepsy networks were localized in 191 (87.6%) patients. Two clinically significant procedural complications (one hemorrhage and one infection) were noted. Of 130 patients who underwent subsequent focal epilepsy surgery with a minimum 12-month follow-up, 102 (78.5%) underwent resective surgery and 28 (21.5%) underwent closed-loop responsive neurostimulation (RNS) with or without resection. Seizure freedom was achieved in 65 (63.7%) patients in the resective group. In the RNS group, 21 (75.0%) patients achieved 50% or greater seizure reduction. When the initial period of 1993 through 2013 before responsive neurostimulator implantation in 2014 was compared with the subsequent period of 2014 through 2018, the proportion of SEEG patients undergoing focal epilepsy surgery grew from 57.9% to 79.7% due to the advent of RNS, despite a decline in focal resective surgery from 55.3% to 35.6%. A total of 18,680 microwires were implanted in 213 patients, resulting in numerous significant scientific findings. Recent recordings from 35 patients showed a yield of 1813 neurons, with a mean yield of 51.8 neurons per patient. CONCLUSIONS: Hybrid SEEG enables safe and effective localization of epileptogenic zones to guide epilepsy surgery and provides unique scientific opportunities to investigate neurons from various brain regions in conscious patients. This technique will be increasingly utilized due to the advent of RNS and may prove a useful approach to probe neuronal networks in other brain disorders.

Wireless Programmable Recording and Stimulation of Deep Brain Activity in Freely Moving Humans.

Uncovering the neural mechanisms underlying human natural ambulatory behavior is a major challenge for neuroscience. Current commercially available implantable devices that allow for recording and stimulation of deep brain activity in humans can provide invaluable intrinsic brain signals but are not inherently designed for research and thus lack flexible control and integration with wearable sensors. We developed a mobile deep brain recording and stimulation (Mo-DBRS) platform that enables wireless and programmable intracranial electroencephalographic recording and electrical stimulation integrated and synchronized with virtual reality/augmented reality (VR/AR) and wearables capable of external measurements (e.g., motion capture, heart rate, skin conductance, respiration, eye tracking, and scalp EEG). When used in freely moving humans with implanted neural devices, this platform is adaptable to ecologically valid environments conducive to elucidating the neural mechanisms underlying naturalistic behaviors and to the development of viable therapies for neurologic and psychiatric disorders.

Theta Oscillations in the Human Medial Temporal Lobe during Real-World Ambulatory Movement.

The theta rhythm-a slow (6-12 Hz) oscillatory component of the local field potential-plays a critical role in spatial navigation and memory by coordinating the activity of neuronal ensembles within the medial temporal lobe (MTL). Although theta has been extensively studied in freely moving rodents, its presence in humans has been elusive and primarily investigated in stationary subjects. Here we used a unique clinical opportunity to examine theta within the human MTL during untethered, real-world ambulatory movement. We recorded intracranial electroencephalographic activity from participants chronically implanted with the wireless NeuroPace responsive neurostimulator (RNS) and tracked their motion with sub-millimeter precision. Our data revealed that movement-related theta oscillations indeed exist in humans, such that theta power is significantly higher during movement than immobility. Unlike in rodents, however, theta occurs in short bouts, with average durations of ∼400 ms, which are more prevalent during fast versus slow movements. In a rare opportunity to study a congenitally blind participant, we found that both the prevalence and duration of theta bouts were increased relative to the sighted participants. These results provide critical support for conserved neurobiological characteristics of theta oscillations during ambulatory spatial navigation, while highlighting some fundamental differences across species in these oscillations between humans and rodents.

Three-dimensional surface maps link local atrophy and fast ripples in human epileptic hippocampus.

OBJECTIVES: There is compelling evidence that pathological high-frequency oscillations (HFOs), called fast ripples (FR, 150-500Hz), reflect abnormal synchronous neuronal discharges in areas responsible for seizure genesis in patients with mesial temporal lobe epilepsy (MTLE). It is hypothesized that morphological changes associated with hippocampal atrophy (HA) contribute to the generation of FR, yet there is limited evidence that hippocampal FR-generating sites correspond with local areas of atrophy. METHODS: Interictal HFOs were recorded from hippocampal microelectrodes in 10 patients with MTLE. Rates of FR and ripple discharge from each microelectrode were evaluated in relation to local measures of HA obtained using 3-dimensional magnetic resonance imaging (MRI) hippocampal modeling. RESULTS: Rates of FR discharge were 3 times higher in areas of significant local HA compared with rates in nonatrophic areas. Furthermore, FR occurrence correlated directly with the severity of damage in these local atrophic regions. In contrast, we found no difference in rates of ripple discharge between local atrophic and nonatrophic areas. INTERPRETATION: The proximity between local HA and microelectrode-recorded FR suggests that morphological changes such as neuron loss and synaptic reorganization may contribute to the generation of FR. Pathological HFOs, such as FR, may provide a reliable surrogate marker of abnormal neuronal excitability in hippocampal areas responsible for the generation of spontaneous seizures in patients with MTLE. Based on these data, it is possible that MRI-based measures of local HA could identify FR-generating regions, and thus provide a noninvasive means to localize epileptogenic regions in hippocampus.

Three-dimensional hippocampal atrophy maps distinguish two common temporal lobe seizure-onset patterns.

PURPOSE: Current evidence suggests that the mechanisms underlying depth electrode-recorded seizures beginning with hypersynchronous (HYP) onset patterns are functionally distinct from those giving rise to low-voltage fast (LVF) onset seizures. However, both groups have been associated with hippocampal atrophy (HA), indicating a need to clarify the anatomic correlates of each ictal onset type. We used three-dimensional (3D) hippocampal mapping to quantify HA and determine whether each onset group exhibited a unique distribution of atrophy consistent with the functional differences that distinguish the two onset morphologies. METHODS: Sixteen nonconsecutive patients with medically refractory epilepsy were assigned to HYP or LVF groups according to ictal onset patterns recorded with intracranial depth electrodes. Using preimplant magnetic resonance imaging (MRI), levels of volumetrically defined HA were determined by comparison with matched controls, and the distribution of local atrophy was mapped onto 3D hippocampal surface models. RESULTS: HYP and LVF groups exhibited significant and equivalent levels of HA ipsilateral to seizure onset. Patients with LVF onset seizures also showed significant contralateral volume reductions. On ipsilateral contour maps HYP patients exhibited an atrophy pattern consistent with classical hippocampal sclerosis (HS), whereas LVF atrophy was distributed more laterally and diffusely. Contralateral LVF maps also showed regions of subicular atrophy. DISCUSSION: The HS-like distribution of atrophy and the restriction of HA to the ipsilateral hippocampus in HYP patients are consistent with focal hippocampal onsets, and suggest a mechanism utilizing intrahippocampal circuitry. In contrast, the bilateral distribution of nonspecific atrophy in the LVF group may reflect mechanisms involving both hippocampal and extrahippocampal networks.

Low frequency electrical stimulation through subdural electrodes in a case of refractory status epilepticus.

OBJECTIVE: We delivered low frequency stimulation through subdural electrodes to suppress seizures in a case of refractory status epilepticus (RSE). METHODS: A 26-year-old female developed RSE after several days of febrile illness. Seizure control required continuous infusion of two anesthetics plus high doses of 2-4 enteral antiepileptic drugs. After 3 months of RSE, subdural strips were placed to determine surgical candidacy. Five independent ictal onset zones were identified. Because she was a poor candidate for epilepsy surgery and had a poor prognosis, the implanted subdural electrodes were used to administer 0.5 Hz stimulations to the ictal onset zones in 30 min trains daily for 7 consecutive days in an attempt to suppress seizures. RESULTS: After 1 day of stimulation, one anesthetic agent was successfully discontinued. Seizures only returned by the 4th day when the second anesthetic had been reduced by 60%. Upon returning, seizures arose from only one of the 5 original ictal onset zones. Unfortunately, RSE persisted, and she eventually died. CONCLUSIONS: In this case of RSE, low frequency stimulation through subdural electrodes transiently suppressed seizures from all but one ictal onset zone and allowed significant reduction in seizure medication. SIGNIFICANCE: Low frequency cortical stimulation may be useful in suppressing seizures.

A lack of effect from transcranial magnetic stimulation (TMS) on the vagus nerve stimulator (VNS).

OBJECTIVE: The effects of transcranial magnetic stimulation (TMS) on vagus nerve stimulation (VNS) are unknown. Understanding these effects is important before exposing individuals with an implanted VNS to TMS, as could occur in epilepsy or depression TMS research. To explore this issue, the TMS-induced current in VNS leads and whether TMS has an effect on the VNS pulse generator was assessed. METHODS: Ex vivo measurement of current in VNS leads during single-pulse TMS and pulse generator function before, during, and after single-pulse TMS was assessed. RESULTS: At the highest intensity and with the TMS coil held approximately 5 mm from the VNS wires, a 200 nA, 1.0 ms current was induced by TMS. This translates to an induced charge density of 3.3 nC/cm2/phase. The function of the pulse generator was unaffected by single-pulse TMS, even when its case was directly stimulated by the coil. CONCLUSIONS: TMS-induced current in VNS electrodes was not only well outside of the range known to be injurious to peripheral nerve, but also below the activation threshold of nerve fibers. SIGNIFICANCE: Using single-pulse TMS in individuals with VNS should not result in nerve stimulation or damage. Furthermore, single-pulse TMS does not affect the VNS pulse generator's function.

Cellular networks underlying human spatial navigation.

Place cells of the rodent hippocampus constitute one of the most striking examples of a correlation between neuronal activity and complex behaviour in mammals. These cells increase their firing rates when the animal traverses specific regions of its surroundings, providing a context-dependent map of the environment. Neuroimaging studies implicate the hippocampus and the parahippocampal region in human navigation. However, these regions also respond selectively to visual stimuli. It thus remains unclear whether rodent place coding has a homologue in humans or whether human navigation is driven by a different, visually based neural mechanism. We directly recorded from 317 neurons in the human medial temporal and frontal lobes while subjects explored and navigated a virtual town. Here we present evidence for a neural code of human spatial navigation based on cells that respond at specific spatial locations and cells that respond to views of landmarks. The former are present primarily in the hippocampus, and the latter in the parahippocampal region. Cells throughout the frontal and temporal lobes responded to the subjects' navigational goals and to conjunctions of place, goal and view.