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

Yasunori Nagahama Departments of Neurosurgery and

Search for other papers by Yasunori Nagahama in
Current site
Google Scholar
PubMed
Close
 MD
,
Sandra Dewar Neurology, David Geffen School of Medicine, University of California, Los Angeles, California

Search for other papers by Sandra Dewar in
Current site
Google Scholar
PubMed
Close
 PhD, RN
,
Eric Behnke Departments of Neurosurgery and
Neurology, David Geffen School of Medicine, University of California, Los Angeles, California

Search for other papers by Eric Behnke in
Current site
Google Scholar
PubMed
Close
 BS
,
Dawn Eliashiv Neurology, David Geffen School of Medicine, University of California, Los Angeles, California

Search for other papers by Dawn Eliashiv in
Current site
Google Scholar
PubMed
Close
 MD
,
John M. Stern Neurology, David Geffen School of Medicine, University of California, Los Angeles, California

Search for other papers by John M. Stern in
Current site
Google Scholar
PubMed
Close
 MD
,
Guldamla Kalender Departments of Neurosurgery and

Search for other papers by Guldamla Kalender in
Current site
Google Scholar
PubMed
Close
 BA
,
Tony A. Fields Neurology, David Geffen School of Medicine, University of California, Los Angeles, California

Search for other papers by Tony A. Fields in
Current site
Google Scholar
PubMed
Close
 BS
,
Charles Wilson Neurology, David Geffen School of Medicine, University of California, Los Angeles, California

Search for other papers by Charles Wilson in
Current site
Google Scholar
PubMed
Close
 PhD
,
Richard Staba Neurology, David Geffen School of Medicine, University of California, Los Angeles, California

Search for other papers by Richard Staba in
Current site
Google Scholar
PubMed
Close
 PhD
,
Jerome Engel Jr. Neurology, David Geffen School of Medicine, University of California, Los Angeles, California

Search for other papers by Jerome Engel Jr. in
Current site
Google Scholar
PubMed
Close
 MD, PhD
, and
Itzhak Fried Departments of Neurosurgery and

Search for other papers by Itzhak Fried in
Current site
Google Scholar
PubMed
Close
 MD, PhD
Free access

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.

ABBREVIATIONS

AMTL = anteromedial temporal lobectomy; DRE = drug-refractory epilepsy; EEG = electroencephalography; iEEG = intracranial EEG; MST = multiple subpial transection; RNS = responsive neurostimulation; SEEG = stereo-EEG; SUDEP = sudden unexpected death in epilepsy; UCLA = University of California, Los Angeles.

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.

In Brief

Researchers examined their institutional series of "hybrid" stereo-electroencephalography (SEEG) combined with microelectrodes in 218 consecutive patients over 26 years to evaluate its clinical and scientific utility and safety. Hybrid SEEG was safe and effective in guiding epilepsy surgery and provided unique information at the single-neuron level to advance our understanding of epilepsy and neurocognitive processes unique to humans. This approach may become a useful tool to interrogate personalized brain networks in other brain disorders.

Invasive intracranial electroencephalography (iEEG) provides information critical to identifying epileptogenic zones with spatial and temporal resolution necessary to guide specific surgical procedures in patients with drug-refractory epilepsy (DRE). Stereo-electroencephalography (SEEG) uses stereotactically placed depth electrodes to sample deep and superficial areas of the brain and is increasingly employed at epilepsy centers worldwide.1,2 The term "depth electrodes" is often used to describe these probes, emphasizing targeting of deep structures as opposed to the sampling of cortical surfaces by subdural electrode arrays.

Since epilepsy and cognitive networks are inextricably intertwined, iEEG also affords rare scientific opportunities for the investigation of epileptogenic mechanisms and the neurocognitive processes unique to humans at temporal and spatial resolutions not possible with other noninvasive studies.3,4 Hybrid depth electrodes consist of specialized outer cylindrical electrodes and internal microwire bundles. In addition to standard iEEG, direct recordings at the level of the single neuron (i.e., single-unit recording) can be achieved through the tips of individual microwires.5 The few clinical studies reporting on the use of hybrid electrodes included small numbers of patients and focused mainly on the accuracy and safety of these electrodes.6,7

SEEG presents a unique area of brain medicine, affording examination of brain networks in monitored settings in awake patients over a period of 1–2 weeks in precise spatial and temporal detail. One of the challenges of clinical research involving this methodology is the long-term follow-up needed after subsequent surgical interventions guided by SEEG to evaluate seizure outcome, which is the primary outcome measure of this method. This challenge is especially timely, as surgical options available after monitoring with SEEG have become more diverse due to the advent of new neuromodulation techniques, such as closed-loop responsive neurostimulation (RNS, NeuroPace) and deep brain stimulation.810 Furthermore, SEEG, traditionally limited to DRE, is increasingly regarded as an approach to interrogate pathological networks in other disorders such as refractory major depression and obsessive-compulsive disorder.1113 We describe a large SEEG clinical series in which we placed hybrid electrodes (hybrid SEEG) over a period of 26 years at a single institution. The purpose of this study was to assess the utility and safety of SEEG in DRE, long-term seizure outcomes, and unique scientific contributions of single-unit recordings to the investigation of brain networks.

Methods

Patient Population

Consecutive patients (n = 218) with DRE underwent SEEG placement and video-EEG monitoring between January 1993 and December 2018 at the University of California, Los Angeles (UCLA) Medical Center. Patients underwent initial, standard presurgical evaluations, followed by a multidisciplinary consensus decision regarding the next treatment steps. When the clinical information was insufficient to support focal epilepsy surgery, SEEG was recommended provided that a clear hypothesis for electrode placement had been determined. Several changes during the study period affected patient selection for SEEG and consideration of additional patients for this procedure. Introduction of magnetic source imaging, SPECT, functional MRI–EEG, and EEG source analysis all enabled better identification of potential targets for hypothesis-based SEEG placement. With the approval of RNS, patients with more than one focus and patients with seizure networks involving functional areas could now be considered for SEEG investigation to guide placement of RNS leads.

Written informed consent for the placement of electrodes was obtained. Patients were also invited to participate in research involving single-unit recordings, for which a separate informed consent was signed. All related research was approved by the UCLA institutional review board. All patients were given the option of SEEG placement with conventional clinical SEEG electrodes, and much care was taken during the informed consent process to clarify the option of not participating in the research without any influence on clinical care.14 All electrode implantation surgeries were performed by the senior author (I.F.).

Surgical Technique

Electrode placement in individual cases was planned based on a hypothesis about epilepsy networks, developed from the presurgical workup, strategically sampling with each electrode the superficial and deep structures suspected to be involved in seizure onset and propagation. Multiple contacts along each electrode were maximally utilized to record from several areas of interest while minimizing the number of electrodes used in each patient. Electrodes were routinely placed bilaterally (Fig. 1A), covering not only the primarily suspected side of epilepsy networks but also the contralateral side to better understand seizure propagation, as the information is often helpful in determining the origin of the seizures. For instance, the distinction between neocortical seizures and mesial temporal lobe seizures can be made on the basis of the quicker contralateral spread of the former compared with the latter.15

FIG. 1.
FIG. 1.

SEEG with the use of hybrid Behnke-Fried electrodes. A: Postoperative anteroposterior radiograph demonstrating bilateral electrode coverage with orthogonally placed depth electrodes. B: The proximal portion of an outer cylindrical electrode with macrocontacts without (upper) and with (lower) an inner microwire bundle. Note that individual microwires are spread apart and extend approximately 5 mm beyond the tip of the outer electrode in the lower panel. C: Hippocampal subfields of a left temporal lobe showing localizations of microwires as well as macrocontacts. Figure is available in color online only.

Electrode trajectories were planned on contrast-enhanced T1-weighted MRI fused with vascular imaging. With improvement in imaging-based stereotactic planning and imaging fusion technology, transition was made from MRI with the stereotactic frame on the day of surgery to CT and CT angiography with the frame on the day of surgery and fusion of CT imaging to preoperatively obtained MR images. Digital subtraction angiography was used earlier in this series, but MR angiography and MR venography along with CT angiography have been used since 2014.

Depth electrodes were stereotactically placed under general anesthesia using a Leksell stereotactic system (Elekta AB) with a custom-designed modification to the side rings to enable efficient placement of electrodes along trajectories orthogonal to the sagittal plane (Fig. 1A). The majority of the electrodes were placed orthogonally with adjustment of y- and z-coordinates and of distances to the targets in an otherwise standard fashion. A Leksell arc was used in a few cases for oblique electrode placement, mostly for insular targets. In a limited number of cases, a small craniotomy was fashioned for placement of additional subdural cortical electrodes after completion of stereotactic placement of depth electrodes.

Hybrid Behnke-Fried Electrodes

For the patients who participated in research involving single-unit recording, hybrid electrodes (Behnke-Fried electrodes) were used exclusively, without concurrent use of standard clinical SEEG electrodes, to record from any clinically indicated areas (Fig. 1B). Microelectrodes were originally introduced at UCLA and placed through rigid stainless steel tubes of macroelectrodes used to record iEEG, demonstrating the ability of microwires to record single neurons in the human brain.16,17 The Behnke-Fried electrodes have been used since 1993 and consist of MRI-compatible, flexible, polyurethane probes with a lumen allowing insertion of 40-mm platinum/iridium microwires.5 Each microwire is very soft and flexible, with a minimal risk of tissue injury. Each hybrid electrode consists of two components: an outer cylindrical electrode with multiple macrocontacts along its length and an inner microwire bundle. The former enables recording of iEEG and local field potentials while the latter enables recording of individual neurons at the tips of individual microwires. For placement of a hybrid electrode, an outer macroelectrode was first inserted with its stylet, followed by removal of the stylet and placement of a microwire bundle through the lumen of the outer macroelectrode, with the tips of the microwires extending out 3–5 mm from the distal end of the electrode.

In our efforts to improve unit recording and unit yield, the length of the microwire extension beyond the tips of macroelectrodes was carefully adjusted for each microwire bundle based on preoperative imaging and the planned location of macroelectrode placement for optimum placement of microwire tips within the gray matter of the brain. Following surgery, successful recordings of single units in a clinical setting is a major challenge. Postoperative imaging served to identify the location of the microwires and establish expectation of unit yield based on gray and white matter localizations. The clinical environment on the wards is often noisy with electrical and other sources of noise, which often requires considerable time and experience to obtain optimal recording. A description of the recording systems used involve multiple factors, including cables and shielding, buffering stages, amplification, and analog-to-digital conversion, and is beyond the scope of this report. In addition, data analysis techniques for microelectrode recordings, including spike detection and sorting, are also critical in determining the final unit yield.

Over the years, multiple types of microwire bundles have been developed to probe different research questions, each containing a variable number of microwires, most commonly 9 but ranging up to 16. Some have included a microdialysis catheter to enable collection of interstitial fluid, along with microwires (typically 4 microwires).5 Other bundles had one microwire that can be used for microstimulation.18

Postoperative Care and Complications

Postoperative high-resolution CT was fused with preoperative MRI to localize macrocontacts and microwire tips (Fig. 1C). Following placement, patients were monitored in the epilepsy monitoring unit. Antiseizure medicines were tapered as necessary, and prophylactic intravenous antibiotics were prescribed for the duration of the study. Electrodes were removed in the operating room once a sufficient number of seizures was recorded. Perioperative complications, defined as clinically significant adverse events from electrode placement requiring neurosurgical interventions and/or resulting in permanent neurological deficits (e.g., hemorrhage and infection) were recorded.

Seizure Outcomes and Follow-Up

The outcome information for patients who underwent subsequent epilepsy surgery was obtained from retrospective chart reviews conducted in April and May 2020, with the seizure outcome determined at the time of the last clinical follow-up for individual patients. Outcomes after resective surgery were classified according to the Engel classification.19 Given the advent of RNS as a method to focally modulate epilepsy networks to decrease seizure burden, the outcomes of these cases with or without resection ("focal neuromodulation" cases) were classified according to the percentage reduction of disabling seizures (i.e., 100%, 90% or greater, 50% or greater, less than 50%, or no reduction of disabling seizures). Disease complexity coupled with long follow-up and the evolution of surgical techniques meant that some patients required more than one surgical intervention after SEEG. For patients who had an RNS device placed after initial resective surgery, outcomes were classified based on the latter criteria, with assumption that their epilepsy networks were only partially resected. Follow-up durations for patients who underwent subsequent surgical intervention(s) were recorded relative to the dates of the initial surgical interventions after SEEG.

Statistical Analysis

Descriptive statistics were used to describe basic demographic and clinical characteristics, complications, outcomes of subsequent epilepsy surgery, and to record the hybrid electrodes used.

Results

Sample Characteristics

The study population (n = 218) comprised 117 men and 101 women with a mean age of 34.2 years (range 12–69 years) (Table 1). Twenty-five (11.5%) patients had a history of prior surgical interventions for epilepsy. The mean number of depth electrodes placed per patient was 10.2 (range 6–16), covering the bilateral hemispheres in all cases, and most commonly the frontotemporal areas. Monitoring lasted a mean of 12.0 days (range 4–39), and an epilepsy network was identified in 191 (87.6%) cases. Perioperative complications were noted in 2 (1.0%) cases (one hemorrhage and one infection; details are provided below). No long-term neurological deficits or mortality related to SEEG procedures was noted.

TABLE 1.

Demographics and clinical characteristics (n = 218)

VariableValue
Mean age (range), yrs34.2 (12–69)
Male sex, n (%)117 (53.7)
Prior epilepsy surgeries, n (%)
 AMTL or selAH3 (1.4)
 Subdural iEEG w/ or w/o resection3 (1.4)
 VNS17 (7.8)
 RNS & VNS1 (0.5)
 AMTL & VNS1 (0.5)
Total no. of depth electrodes2218
Mean no. of depth electrodes/pt (range)10.2 (6–16)
Depth electrode coverage by hemisphere, n (%)
 Lt < rt72 (33.0)
 Lt > rt65 (29.8)
 Lt = rt81 (37.2)
Depth electrode coverage by lobe, n (%)
 Frontal179 (82.1)
 Temporal216 (99.1)
 Parietal41 (18.8)
 Occipital24 (11.0)
 Insula8 (3.7)
Concurrent use of subdural electrodes, n (%)5 (2.3)
Mean monitoring duration (range), days12.0 (4–39)
Results of intracranial recordings, n (%)
 Localized191 (87.6)
 Not localized16 (7.3)
 Information not available11 (5.0)
Complications from intracranial recordings, n (%)
 Hemorrhage1 (0.5)
 Infection1 (0.5)

seIAH = selective amygdalohippocampectomy.

Seizure Outcomes After SEEG-Guided Focal Epilepsy Surgery

Focal surgical procedures were performed in 139 (63.8%) patients after SEEG (Table 2). Resections were performed in 108 (77.7%) patients and laser ablation in 1 (0.7%; included in the resective group), with the remaining 30 (21.6%) patients receiving RNS. In 14 cases, additional iEEG using subdural cortical electrodes was required to better localize seizures and map functional areas. Follow-up of 1 year or longer was available for 130 patients, with a mean follow-up of 7.2 years (range 1.0–26.3 years). Of these patients, 102 (78.5%) received resections and 28 (21.5%) received RNS. Within the resective group, 65 (63.7%) patients achieved Engel class I outcome. In the neuromodulation group, 21 (75.0%) patients had 50% or greater improvement in seizure frequency, and 9 (32.1%) patients achieved 90% or greater seizure reduction.

TABLE 2.

Seizure outcomes with at least 1 year of follow-up after focal surgical interventions (n = 130)

Resective ProceduresTotal, nFollow-Up ≥1 yr, nModified Engel Outcome, n (%)
Class IClass IIClass IIIClass IV
AMTL*696645 (68.2)7 (10.6)11 (16.7)3 (4.5)
Temporal resections, sparing mesial structures974 (57.1)0 (0)2 (28.6)1 (14.3)
AMTL plus551 (20.0)0 (0)4 (80.0)0 (0)
Extratemporal resections222014 (70.0)0 (0)3 (15.0)3 (15.0)
Multilobar resections§441 (25.0)2 (50.0)1 (25.0)0 (0)
Total10910265 (63.7)9 (8.8)21 (20.6)7 (6.9)
Neuromodulation ProceduresTotal, nFollow-Up ≥1 yr, n% Reduction of Disabling Seizures, n (%)
100%≥90%≥50%<50%0%
RNS24221 (4.5)5 (22.7)9 (40.9)1 (4.5)6 (27.3)
RNS w/ resection**661 (16.7)2 (33.3)3 (50.0)0 (0)0 (0)
Total30282 (7.1)7 (25.0)12 (42.9)1 (3.6)6 (21.4)

The mean follow-up for the 102 patients in the resective procedure group with a minimum 1-year follow-up was 8.0 years (range 1.0–26.3 years). The mean follow-up for the 28 patients in the neuromodulation procedure group with a minimum 1-year follow-up was 4.3 years (range 1.4–21.1 years). The overall mean follow-up for the 130 patients with a minimum 1-year follow-up was 7.2 years (range 1.0–26.3 years).

One patient had VNS device placement after AMTL with Engel class III outcome, and another patient had laser interstitial thermal therapy of the mesial temporal lobe with Engel class III outcome.

This group represents cases of temporal plus epilepsy, where the epileptogenic zones extend beyond the typical extent of AMTL to include additional neighboring areas, such as the orbitofrontal area, suprasylvian operculum, insula, and temporo-parieto-occipital junction. This group included 2 patients who underwent resective surgery involving the presumed entire epileptogenic zone in one procedure, 1 patient with a prior history of AMTL who underwent extension of the prior resection following SEEG, and 2 patients who underwent a sequence of AMTL followed by extension of the resection in two separate procedures following SEEG.

This group included 1 patient who had two frontal resections followed by VNS with Engel class IV outcome, 1 patient who had MST in the frontal lobe with Engel class III outcome, and 1 patient who had frontal resection along with MST with Engel class I outcome.

This group included 1 patient who had multilobar resection with MST followed by VNS with Engel class II outcome.

This group included 2 patients who initially underwent VNS device placement after SEEG, followed by RNS device placement.

This group included 3 patients who underwent concurrent resection and RNS placement in one procedure after SEEG, 1 patient who underwent a sequence of mesial-sparing anterolateral temporal resection followed by RNS placement after SEEG, 1 patient who underwent a sequence of AMTL with extended posterior temporal resection followed by extension of the resection along with RNS placement after SEEG, and 1 patient who underwent a sequence of MST followed by RNS placement after SEEG.

Of note, 3 of the 6 patients in the RNS with resection group underwent concurrent resection and RNS placement, whereas the other 3 patients had their initial resective procedure followed later by RNS placement without repeat SEEG (1 patient had additional resection concurrently with RNS placement). Their outcomes all improved after the second intervention (i.e., following RNS placement, 1 patient with an Engel III outcome improved by 50% or greater seizure reduction, another with Engel III outcome improved by 90% or greater reduction, and a patient with Engel IV outcome improved by 50% or greater reduction). When these patients were included in the resection group, the outcome for the resection group only minimally changed to 65 (61.9%) patients with Engel class I outcome, 9 (8.6%) patients with Engel class II outcome, 23 (21.9%) patients with Engle class III outcome, and with 8 (7.6%) patients with Engel class IV outcome.

In this series, the first RNS device was placed in 2014. From 1993 through 2013, 159 patients underwent SEEG procedures, of whom 88 (55.3%) patients had focal resective surgery and 4 (2.5%) patients had focal neuromodulation interventions (after 2014). From 2014 through 2018, 59 patients underwent SEEG procedures, of whom 21 (35.6%) and 26 (44.1%) patients had resective and neuromodulation interventions, respectively. Therefore, because of the availability of RNS in 2014, the proportion of SEEG patients undergoing focal epilepsy surgery grew from 57.9% to 79.7% between these time periods. Of note, 3 additional patients in this series underwent deep brain stimulation surgery targeting the anterior nucleus of the thalamus after SEEG (these outcomes are not included in Table 2).

During the follow-up period, 5 patients died of sudden unexpected death in epilepsy (SUDEP), none related to SEEG procedures, despite having undergone subsequent epilepsy surgery (details are provided below). Three additional patients died of unrelated causes.

Clinical Details of Significant Complications

Case 1 (infection)

A 36-year male underwent implantation of 9 depth electrodes and an 8-day course of intracranial monitoring, without any perioperative complications. This patient did not participate in the research protocol. The patient required an operative intervention involving draining of suspected left-sided intracerebral abscess through two temporal burr holes (although no clear pus was noted intraoperatively) and washout/debridement of a right temporal wound about 2 weeks after the electrode removal. Wound culture was positive for Propionibacterium acnes. The patient was subsequently treated with long-term intravenous vancomycin and ceftazidime. The patient did not undergo further epilepsy surgery due to the lack of clear localization of an epileptogenic zone. He did not have permanent neurological sequelae.

Case 2 (hemorrhage)

A 28-year-old male underwent implantation of 11 depth electrodes with microwires. The postoperative CT scan revealed a left-sided acute subdural hematoma with a 3-mm midline shift and subarachnoid hemorrhage in the bilateral sylvian fissure, but the patient was initially conservatively managed with close neurological monitoring. Repeat CT scanning on postoperative day 3 showed a new left temporal intraparenchymal hemorrhage. All electrodes were removed on postoperative day 4. The patient was closely monitored, without requiring hematoma evacuation. Hematology workup was conducted but the findings were inconclusive. The patient recovered well without significant neurological sequelae. As no seizures had been recorded in this patient prior to explanting the electrodes, no definitive resective surgery could be offered and the patient elected to undergo palliative vagus nerve stimulation (VNS) device placement 1 year later.

Clinical Details of SUDEP During Follow-Up After SEEG-Guided Epilepsy Surgery

A 27-year-old patient underwent left frontal multiple subpial transection (MST) and biopsy and achieved an Engel class III outcome at 20 months but died of SUDEP 36 months after the epilepsy surgery. A 21-year-old female underwent right anteromedial temporal lobectomy (AMTL) and achieved an Engel class II outcome at 5.5 years but subsequently died of SUDEP (exact time of death unknown). A 41-year-old female underwent left mesial-sparing temporal resection and achieved an Engel class II outcome but died of SUDEP 3.5 months after the epilepsy surgery (self-reduction of antiepileptic drugs was noted). A 41-year-old female underwent right AMTL and achieved Engel class II at 10 months but died of SUDEP 15 months after the epilepsy surgery (noncompliance with antiepileptic drugs was noted). A 49-year-old female underwent right AMTL and achieved an Engel class I outcome at 6 weeks but died subsequently of SUDEP. Only the first 2 SUDEP patients (i.e., the aforementioned 27- and 21-year-old patients) were included in our outcome analysis for those patients with 1 year or longer follow-up, using their most recent available outcomes before SUDEP, to clarify the relative seizure control obtained after the surgical intervention and describe the long-term risk for SUDEP when full seizure control is not obtained.

Microwires and Single-Unit Recording

Of the 218 patients, 213 participated in the research involving placement of microwires for single-unit recording (Table 3). A total of 2168 hybrid electrodes were implanted (range 6–16 electrodes per patient). These hybrid electrodes enabled placement of 1813 standard microwire bundles, 192 microdialysis microwire bundles, and 158 microwire bundles that included a microstimulation microwire. Therefore, 18,680 microwires were implanted in these 213 patients (mean 87.7 per patient, range 44–135). These microwires were most commonly placed to record from the mesial temporal lobe (211 patients) and mesial frontal area (174 patients). The total unit yield for the recent 35 patients, in whom prospectively obtained yield information was available, was 1813 units, with a mean yield per patient and per microwire of 51.8 and 0.55, respectively (Fig. 2).

TABLE 3.

Single-unit recording with microwires in 213 patients who participated in research

VariableValue
Behnke-Fried electrodes, total n2168
Behnke-Fried electrodes/pt, n (range)10.2 (6–16)
Standard microwire bundles, total n (range/pt)1813 (3–14)
Microdialysis microwire bundles, total n (range/pt)192 (0–4)
Microstimulation microwire bundles, total n (range/pt)158 (0–5)
Sites w/ electrodes w/ microwires, n
 Hippocampus459
 Entorhinal cortex297
 Amygdala344
 Parahippocampal gyrus179
 Other temporal areas118
 Orbitofrontal/anterior cingulate cortex455
 SMA/pre-SMA123
 Other frontal areas62
 Parietal81
 Occipital45
No. of microwires
 Total no.18,680
 Mean no./pt87.7 (44–135)
Sites w/ electrodes w/ microstimulation, n
 Hippocampus37
 Entorhinal cortex89
 Amygdala17
 Parahippocampal gyrus12
 Orbitofrontal1
 Fusiform gyrus2
Unit yield for the most recent 35 pts w/ information available
 Total unit yield1813
 Mean unit yield/pt (range)51.8 (2–139)
 Median unit yield50
 Mean unit yield/microwire0.55*
Estimated unit yield for the entire group of 213 pts10,199

SMA = supplementary motor area.

A total of 3321 microwires were placed through 372 Behnke-Fried electrodes in these 35 patients, enabling recording from a total of 1813 units (unit yield of 0.546 units/microwire).

Estimated unit yield with the assumption of 0.546 units per microwire.

FIG. 2.
FIG. 2.

Normalized firing rate simultaneously recorded from 90 units over 20 minutes in multiple brain sites while a patient was watching a movie. Each row represents the color-coded raster of firing rate from a unit (neuron) isolated from a microwire in the hybrid SEEG electrode from the particular site depicted on the left. Note the episodic changes in discharge over the length of the movie and high firing rate of cell in left hippocampus (LMH). LA = left amygdala; LEC = left entorhinal cortex; LOF = left orbitofrontal cortex; LPSMA = left presupplementary motor area; RA = right amygdala; RAC = right anterior cingulate cortex; RMH = right hippocampus; ROF = right orbitofrontal cortex; RPSMA = right presupplementary motor area; REC = right entorhinal cortex. Figure is available in color online only.

The recording from these individual neurons has led to significant findings related to the mechanism of epilepsy and neurocognitive processes unique to humans. The discovery of interictal high-frequency oscillations (80–500 Hz) in the human hippocampus and entorhinal cortex has advanced our understanding of the mechanisms generating seizures.20 Human ripples (80–200 Hz) correspond with interneuron firing and preferred phases of pyramidal firing21 and occur predominantly during non-REM sleep.22,23 Fast ripples (200–500 Hz) are generated from local clusters of discharging pyramidal cells and are strongly associated with hippocampal areas capable of generating seizures.24,25 In the epileptic mesial temporal lobe, fast ripples are pathological high-frequency oscillations as are some ripples, particularly in the dentate gyrus.26 Focal limbic seizures begin when small clusters of bursting neurons increase in size and coalesce, and reach a critical mass to generate a seizure.

The findings from the single-unit recording related to the human cognition include discovery of place cells in the human hippocampus,27 grid-like cells in the entorhinal cortex,28 concept cells in the medial temporal lobe,29 mirror neurons,30 phase precession,31 and mechanisms of conscious perception.32,33 These recordings also showed the role of the mesial temporal lobe in encoding information for memory as well as in imagery.34,35 Reactivation of memory traces were demonstrated at the single-neuron level during free recall,36 and preactivation prior to conscious intent was found in the supplementary motor area and vicinity.37 Mechanisms of human sleep and sleep deprivation revealed local slow wave sleep at the single-neuron level, as well as neuronal activity in the auditory cortex and beyond.22,38 The opportunities to electrically stimulate distinct brain structures with both macrostimulation and microstimulation through microwires led to discovery of memory encoding enhancement with entorhinal stimulation.18,39,40

Discussion

The human brain in health and disease represents one of the most complex challenges to modern science and medicine. Noninvasive modalities, such as scalp EEG and functional MRI, are useful for the diagnosis of neurological diseases and research of brain function but are all limited by poor temporal and/or spatial resolution. Few clinical situations in medicine offer opportunities to interrogate brain networks involved in disease by recording of neuronal activity directly inside the human brain. Such opportunities present themselves in select cases of DRE; in movement disorders such as Parkinson’s disease, essential tremor, and dystonia; and in a few instances of brain-machine interface for patients with quadriplegia.3,4,41 In recent years, this invasive interrogation of pathological networks has been extended in preliminary studies aimed at the treatment of neuropsychiatric disorders such as major depression.1113,42 At the same time, these unique clinical settings have been used with increasing vigor and extent to study native cognitive networks of the human brain.4,40,43 We describe our institutional experience spanning 26 years of using hybrid depth electrodes to effectively and safely localize epilepsy networks and guide epilepsy surgery and to simultaneously investigate the epileptogenic mechanisms and the neurocognitive processes unique to humans with unparalleled temporal and spatial resolution.

The effectiveness of our approach with electrode coverage of areas of suspected seizure onset and propagation, including bilateral brain regions, was supported by the excellent outcome of subsequent epilepsy surgery. Engel class I and II outcomes of 63.7% and 8.8%, respectively, at a mean follow-up of 8.0 years are comparable to the reported Engel class I and II outcomes of 66.2% and 16.2% at a much shorter mean follow-up of 18 months in one study from the US1 and comparable to an International League Against Epilepsy class 1 or 2 outcome of 59.4% at least 2 years after resection surgery in another large study from Europe.2 The proportion of patients who achieved 50% or greater seizure reduction (i.e., responders) in this series was 75.0% at a mean follow-up of 4.3 years, improved compared with the reported responder rate of 55% at 2 years in the original pivotal trial,8 and comparable to the more recent study with a reported responder rate of 77% at 2 years and 84% at 3 or more years despite the differences in the definition of follow-up durations.44 The effectiveness of our approach was accompanied by the high safety profile (i.e., one hemorrhagic and one infectious complication, no procedural mortality, and no long-term neurological deficits). The low risks of the complications (i.e., 0.5% for hemorrhage and 0.5% for infection) in this series are comparable to the safety profile of SEEG reported in one systematic review and meta-analysis (i.e., pooled prevalence of 1% and 0.8%, respectively).45 A total of 5 SUDEP cases, none related to the SEEG procedures, were observed during follow-up, highlighting the gravity of SUDEP and complexity in the management of patients with DRE, as previously described.46

The successful clinical use of SEEG was safely combined with the use of research microwires to obtain single-unit recording. A total of 18,680 microwires were implanted over the 26 years to effectively record from the estimated 10,199 units (i.e., > 50 units per patient), although the recording equipment used during the early years limited the number of channels recorded simultaneously. To the best of our knowledge, this represents the largest experience of successful single-unit recording from the human brain reported in the literature. Furthermore, accurate localization of the tips of microwires as well as macrocontacts enabled detailed analysis of single-unit recording according to spatial (e.g., subfields of hippocampus) information (Fig. 1C).47 The single-unit recording over the 26 years of this study has led to significant discoveries, providing unique insights to the mechanisms of epilepsy as well as to the cognitive processes unique to humans.

There has been a recent increase in the use of SEEG within the epilepsy community in North America due to its effectiveness and safety.1 Stereotactic placement of depth electrodes can also be combined with placement of cortical subdural electrodes.48 In addition to guiding resective surgery, SEEG has become useful in confirming candidacy for RNS and in guiding RNS lead placement specifically in patients who were previously considered poor candidates for traditional resective epilepsy surgery. In this series, there has been an increase over the recent years in the percentage of patients undergoing focal epilepsy surgery following SEEG due to an increase in the percentage of patients receiving RNS. These trends likely reflect both the complexity of referred cases and the preference for nonresective treatment for some patients. Therefore, given the evolving nature of surgical management of patients with DRE, opportunities to investigate the human brain at single-neuron levels might be expected to rise.

Our paper highlights the unique opportunities of hybrid SEEG to examine the human brain at the single-neuron level and thus play a potentially crucial role in advancing the field of neuroscience research and the understanding of mechanisms of epilepsy. These findings raise the possibility that microelectrode recordings may be used as part of the clinical evaluation of the epilepsy patient.49 For instance, high-frequency oscillations as a marker of epileptogenic tissue may be more successfully recorded from microwires than from macrocontacts of intracranial or extracranial leads. Furthermore, the use of SEEG to probe disease and cognitive networks in epilepsy can be used to investigate patient-specific brain networks involved in other diseases, such as major depression, posttraumatic stress disorder, obsessive-compulsive disorder, and addiction. The feasibility of recording brain signals with spatial and temporal resolution down to the level of single neurons, as demonstrated in our hybrid SEEG series, suggests potential uses of this technology in other brain disorders. Acquiring such brain signals in awake patients who can declare their percepts, memories, intentions, and emotions, as demonstrated in multiple cognitive studies in our series, may be especially important in tailoring personalized therapy in other disorders, as recently reported in a few cases of major depression.1113 Furthermore, unique insights on the neural basis of human faculties obtained through detailed SEEG studies can be used in the construction of neuroprosthetic devices to restore cognitive function such as speech and memory.39,50

Conclusions

This study represents a unique series of SEEG cases that records over 26 years of experience at a single center. The hypothesis-based SEEG approach helped localize epileptogenic zones and effectively guided focal epilepsy surgery in many cases, whether by resection or neuromodulation devices. The advent of RNS led to an increase in SEEG patients undergoing focal epilepsy surgery despite a decline in focal resective surgery over time in this series. The clinical use of SEEG was safely combined with investigation of the human brain at the single-neuron level to advance our understanding of the mechanisms of human epilepsy and neurocognitive processes unique to humans. Such hybrid SEEG may become a useful tool to interrogate personalized brain networks in other brain disorders.

Acknowledgments

This work was supported by the National Institute of Neurosurgical Disorders and Stroke (grant nos. R01NS084017 and UO1NS108930 to I.F.) and the National Science Foundation (grant no. 1756473 to I.F.).

Disclosures

Dr. Dewar reported being coeditor of the epilepsy surgery section of Epilepsy.com. Dr. Eliashiv reported grants from NeuroPace and Medtronic postapproval trial and being a speaker for UCB SK Life Science outside the submitted work.

Author Contributions

Conception and design: Fried, Dewar, Nagahama. Acquisition of data: Nagahama, Dewar, Fried, Behnke, Eliashiv, Stern, Kalender, Wilson. Analysis and interpretation of data: Fried, Nagahama, Dewar, Eliashiv, Stern, Wilson, Engel. Drafting the article: Nagahama, Fried, Dewar. Critically revising the article: Fried, Nagahama, Dewar, Eliashiv, Staba, Engel. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Fried. Statistical analysis: Nagahama, Dewar. Administrative/technical/material support: Fried, Behnke, Fields, Wilson, Staba. Study supervision: Fried.

Supplemental Information

Current Affiliations

Yasunori Nagahama: Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.

Sandra Dewar: Department of Neurology, Virginia Commonwealth University, Richmond, Virginia.

References

  • 1

    González-Martínez J, Bulacio J, Thompson S, et al. Technique, results, and complications related to robot-assisted stereoelectroencephalography. Neurosurgery. 2016;78(2):169180.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Cardinale F, Rizzi M, Vignati E, et al. Stereoelectroencephalography: retrospective analysis of 742 procedures in a single centre. Brain. 2019;142(9):26882704.

  • 3

    Engel AK, Moll CK, Fried I, Ojemann GA. Invasive recordings from the human brain: clinical insights and beyond. Nat Rev Neurosci. 2005;6(1):3547.

  • 4

    Parvizi J, Kastner S. Promises and limitations of human intracranial electroencephalography. Nat Neurosci. 2018;21(4):474483.

  • 5

    Fried I, Wilson CL, Maidment NT, et al. Cerebral microdialysis combined with single-neuron and electroencephalographic recording in neurosurgical patients. Technical note. J Neurosurg. 1999;91(4):697705.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Hefft S, Brandt A, Zwick S, et al. Safety of hybrid electrodes for single-neuron recordings in humans. Neurosurgery. 2013;73(1):7885.

  • 7

    Carlson AA, Rutishauser U, Mamelak AN. Safety and utility of hybrid depth electrodes for seizure localization and single-unit neuronal recording. Stereotact Funct Neurosurg. 2018;96(5):311319.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Heck CN, King-Stephens D, Massey AD, et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia. 2014;55(3):432441.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Nagahama Y, Zervos TM, Murata KK, et al. Real-world preliminary experience with responsive neurostimulation in pediatric epilepsy: a multicenter retrospective observational study. Neurosurgery. 2021;89(6):9971004.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010;51(5):899908.

  • 11

    Scangos KW, Makhoul GS, Sugrue LP, Chang EF, Krystal AD. State-dependent responses to intracranial brain stimulation in a patient with depression. Nat Med. 2021;27(2):229231.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Scangos KW, Khambhati AN, Daly PM, et al. Closed-loop neuromodulation in an individual with treatment-resistant depression. Nat Med. 2021;27(10):16961700.

  • 13

    Sheth SA, Bijanki KR, Metzger B, et al. Deep brain stimulation for depression informed by intracranial recordings. Biol Psychiatry. 2022;92(3):246251.

  • 14

    Feinsinger A, Pouratian N, Ebadi H, et al. Ethical commitments, principles, and practices guiding intracranial neuroscientific research in humans. Neuron. 2022;110(2):188194.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Brekelmans GJF, van Emde Boas W, Velis DN, van Huffelen AC, Debets RMC, van Veelen CWM. Mesial temporal versus neocortical temporal lobe seizures: demonstration of different electroencephalographic spreading patterns by combined use of subdural and intracerebral electrodes. J Epilepsy. 1995;8(4):309320.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Babb TL, Carr E, Crandall PH. Analysis of extracellular firing patterns of deep temporal lobe structures in man. Electroencephalogr Clin Neurophysiol. 1973;34(3):247257.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Wilson CL, Babb TL, Halgren E, Crandall PH. Visual receptive fields and response properties of neurons in human temporal lobe and visual pathways. Brain. 1983;106(Pt 2):473-502.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Titiz AS, Hill MRH, Mankin EA, et al. Theta-burst microstimulation in the human entorhinal area improves memory specificity. Elife. 2017;6:e

  • 19

    Engel J Jr, Van Ness PC, Rasmussen TB, Ojemann LM. Outcome with respect to epileptic seizures. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies. 2nd ed. Raven Press; 1993:609-621.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Bragin A, Engel J Jr, Wilson CL, Fried I, Buzsáki G. High-frequency oscillations in human brain. Hippocampus. 1999;9(2):137142.

  • 21

    Le Van Quyen M, Bragin A, Staba R, Crépon B, Wilson CL, Engel J Jr. Cell type-specific firing during ripple oscillations in the hippocampal formation of humans. J Neurosci. 2008;28(24):61046110.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Nir Y, Staba RJ, Andrillon T, et al. Regional slow waves and spindles in human sleep. Neuron. 2011;70(1):153169.

  • 23

    Andrillon T, Nir Y, Staba RJ, et al. Sleep spindles in humans: insights from intracranial EEG and unit recordings. J Neurosci. 2011;31(49):1782117834.

  • 24

    Staba RJ, Wilson CL, Bragin A, Fried I, Engel J Jr. Quantitative analysis of high-frequency oscillations (80-500 Hz) recorded in human epileptic hippocampus and entorhinal cortex. J Neurophysiol. 2002;88(4):17431752.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Bragin A, Wilson CL, Staba RJ, Reddick M, Fried I, Engel J Jr. Interictal high-frequency oscillations (80-500 Hz) in the human epileptic brain: entorhinal cortex. Ann Neurol. 2002;52(4):407415.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Engel J Jr, Bragin A, Staba R, Mody I. High-frequency oscillations: what is normal and what is not? Epilepsia. 2009;50(4):598604.

  • 27

    Ekstrom AD, Kahana MJ, Caplan JB, et al. Cellular networks underlying human spatial navigation. Nature. 2003;425(6954):184188.

  • 28

    Jacobs J, Weidemann CT, Miller JF, et al. Direct recordings of grid-like neuronal activity in human spatial navigation. Nat Neurosci. 2013;16(9):11881190.

  • 29

    Quiroga RQ, Reddy L, Kreiman G, Koch C, Fried I. Invariant visual representation by single neurons in the human brain. Nature. 2005;435(7045):11021107.

  • 30

    Mukamel R, Ekstrom AD, Kaplan J, Iacoboni M, Fried I. Single-neuron responses in humans during execution and observation of actions. Curr Biol. 2010;20(8):750756.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Qasim SE, Fried I, Jacobs J. Phase precession in the human hippocampus and entorhinal cortex. Cell. 2021;184(12):32423255.e10.

  • 32

    Kreiman G, Fried I, Koch C. Single-neuron correlates of subjective vision in the human medial temporal lobe. Proc Natl Acad Sci U S A. 2002;99(12):83788383.

  • 33

    Quian Quiroga R, Kraskov A, Mormann F, Fried I, Koch C. Single-cell responses to face adaptation in the human medial temporal lobe. Neuron. 2014;84(2):363369.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Fried I, MacDonald KA, Wilson CL. Single neuron activity in human hippocampus and amygdala during recognition of faces and objects. Neuron. 1997;18(5):753765.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Cameron KA, Yashar S, Wilson CL, Fried I. Human hippocampal neurons predict how well word pairs will be remembered. Neuron. 2001;30(1):289298.

  • 36

    Gelbard-Sagiv H, Mukamel R, Harel M, Malach R, Fried I. Internally generated reactivation of single neurons in human hippocampus during free recall. Science. 2008;322(5898):96101.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Fried I, Mukamel R, Kreiman G. Internally generated preactivation of single neurons in human medial frontal cortex predicts volition. Neuron. 2011;69(3):548562.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Nir Y, Andrillon T, Marmelshtein A, et al. Selective neuronal lapses precede human cognitive lapses following sleep deprivation. Nat Med. 2017;23(12):14741480.

  • 39

    Suthana N, Haneef Z, Stern J, et al. Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med. 2012;366(6):502510.

  • 40

    Mankin EA, Fried I. Modulation of human memory by deep brain stimulation of the entorhinal-hippocampal circuitry. Neuron. 2020;106(2):218235.

  • 41

    Cash SS, Hochberg LR. The emergence of single neurons in clinical neurology. Neuron. 2015;86(1):7991.

  • 42

    Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651660.

  • 43

    Mukamel R, Fried I. Human intracranial recordings and cognitive neuroscience. Annu Rev Psychol. 2012;63:511537.

  • 44

    Razavi B, Rao VR, Lin C, et al. Real-world experience with direct brain-responsive neurostimulation for focal onset seizures. Epilepsia. 2020;61(8):17491757.

  • 45

    Mullin JP, Shriver M, Alomar S, et al. Is SEEG safe? A systematic review and meta-analysis of stereo-electroencephalography-related complications. Epilepsia. 2016;57(3):386401.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Sperling MR, Barshow S, Nei M, Asadi-Pooya AA. A reappraisal of mortality after epilepsy surgery. Neurology. 2016;86(21):19381944.

  • 47

    Ekstrom A, Suthana N, Behnke E, Salamon N, Bookheimer S, Fried I. High-resolution depth electrode localization and imaging in patients with pharmacologically intractable epilepsy. J Neurosurg. 2008;108(4):812815.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Nagahama Y, Schmitt AJ, Nakagawa D, et al. Intracranial EEG for seizure focus localization: evolving techniques, outcomes, complications, and utility of combining surface and depth electrodes. J Neurosurg. 2019;130(4):11801192.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Chari A, Thornton RC, Tisdall MM, Scott RC. Microelectrode recordings in human epilepsy: a case for clinical translation. Brain Commun. 2020;2(2):fcaa082.

  • 50

    Moses DA, Metzger SL, Liu JR, et al. Neuroprosthesis for decoding speech in a paralyzed person with anarthria. N Engl J Med. 2021;385(3):217227.

  • Collapse
  • Expand
Illustration from Phillips et al. (pp 1604–1612). © Michael McDowell, published with permission.
  • FIG. 1.

    SEEG with the use of hybrid Behnke-Fried electrodes. A: Postoperative anteroposterior radiograph demonstrating bilateral electrode coverage with orthogonally placed depth electrodes. B: The proximal portion of an outer cylindrical electrode with macrocontacts without (upper) and with (lower) an inner microwire bundle. Note that individual microwires are spread apart and extend approximately 5 mm beyond the tip of the outer electrode in the lower panel. C: Hippocampal subfields of a left temporal lobe showing localizations of microwires as well as macrocontacts. Figure is available in color online only.

  • FIG. 2.

    Normalized firing rate simultaneously recorded from 90 units over 20 minutes in multiple brain sites while a patient was watching a movie. Each row represents the color-coded raster of firing rate from a unit (neuron) isolated from a microwire in the hybrid SEEG electrode from the particular site depicted on the left. Note the episodic changes in discharge over the length of the movie and high firing rate of cell in left hippocampus (LMH). LA = left amygdala; LEC = left entorhinal cortex; LOF = left orbitofrontal cortex; LPSMA = left presupplementary motor area; RA = right amygdala; RAC = right anterior cingulate cortex; RMH = right hippocampus; ROF = right orbitofrontal cortex; RPSMA = right presupplementary motor area; REC = right entorhinal cortex. Figure is available in color online only.

  • 1

    González-Martínez J, Bulacio J, Thompson S, et al. Technique, results, and complications related to robot-assisted stereoelectroencephalography. Neurosurgery. 2016;78(2):169180.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Cardinale F, Rizzi M, Vignati E, et al. Stereoelectroencephalography: retrospective analysis of 742 procedures in a single centre. Brain. 2019;142(9):26882704.

  • 3

    Engel AK, Moll CK, Fried I, Ojemann GA. Invasive recordings from the human brain: clinical insights and beyond. Nat Rev Neurosci. 2005;6(1):3547.

  • 4

    Parvizi J, Kastner S. Promises and limitations of human intracranial electroencephalography. Nat Neurosci. 2018;21(4):474483.

  • 5

    Fried I, Wilson CL, Maidment NT, et al. Cerebral microdialysis combined with single-neuron and electroencephalographic recording in neurosurgical patients. Technical note. J Neurosurg. 1999;91(4):697705.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Hefft S, Brandt A, Zwick S, et al. Safety of hybrid electrodes for single-neuron recordings in humans. Neurosurgery. 2013;73(1):7885.

  • 7

    Carlson AA, Rutishauser U, Mamelak AN. Safety and utility of hybrid depth electrodes for seizure localization and single-unit neuronal recording. Stereotact Funct Neurosurg. 2018;96(5):311319.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Heck CN, King-Stephens D, Massey AD, et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia. 2014;55(3):432441.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Nagahama Y, Zervos TM, Murata KK, et al. Real-world preliminary experience with responsive neurostimulation in pediatric epilepsy: a multicenter retrospective observational study. Neurosurgery. 2021;89(6):9971004.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010;51(5):899908.

  • 11

    Scangos KW, Makhoul GS, Sugrue LP, Chang EF, Krystal AD. State-dependent responses to intracranial brain stimulation in a patient with depression. Nat Med. 2021;27(2):229231.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Scangos KW, Khambhati AN, Daly PM, et al. Closed-loop neuromodulation in an individual with treatment-resistant depression. Nat Med. 2021;27(10):16961700.

  • 13

    Sheth SA, Bijanki KR, Metzger B, et al. Deep brain stimulation for depression informed by intracranial recordings. Biol Psychiatry. 2022;92(3):246251.

  • 14

    Feinsinger A, Pouratian N, Ebadi H, et al. Ethical commitments, principles, and practices guiding intracranial neuroscientific research in humans. Neuron. 2022;110(2):188194.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Brekelmans GJF, van Emde Boas W, Velis DN, van Huffelen AC, Debets RMC, van Veelen CWM. Mesial temporal versus neocortical temporal lobe seizures: demonstration of different electroencephalographic spreading patterns by combined use of subdural and intracerebral electrodes. J Epilepsy. 1995;8(4):309320.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Babb TL, Carr E, Crandall PH. Analysis of extracellular firing patterns of deep temporal lobe structures in man. Electroencephalogr Clin Neurophysiol. 1973;34(3):247257.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Wilson CL, Babb TL, Halgren E, Crandall PH. Visual receptive fields and response properties of neurons in human temporal lobe and visual pathways. Brain. 1983;106(Pt 2):473-502.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Titiz AS, Hill MRH, Mankin EA, et al. Theta-burst microstimulation in the human entorhinal area improves memory specificity. Elife. 2017;6:e

  • 19

    Engel J Jr, Van Ness PC, Rasmussen TB, Ojemann LM. Outcome with respect to epileptic seizures. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies. 2nd ed. Raven Press; 1993:609-621.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Bragin A, Engel J Jr, Wilson CL, Fried I, Buzsáki G. High-frequency oscillations in human brain. Hippocampus. 1999;9(2):137142.

  • 21

    Le Van Quyen M, Bragin A, Staba R, Crépon B, Wilson CL, Engel J Jr. Cell type-specific firing during ripple oscillations in the hippocampal formation of humans. J Neurosci. 2008;28(24):61046110.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Nir Y, Staba RJ, Andrillon T, et al. Regional slow waves and spindles in human sleep. Neuron. 2011;70(1):153169.

  • 23

    Andrillon T, Nir Y, Staba RJ, et al. Sleep spindles in humans: insights from intracranial EEG and unit recordings. J Neurosci. 2011;31(49):1782117834.

  • 24

    Staba RJ, Wilson CL, Bragin A, Fried I, Engel J Jr. Quantitative analysis of high-frequency oscillations (80-500 Hz) recorded in human epileptic hippocampus and entorhinal cortex. J Neurophysiol. 2002;88(4):17431752.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Bragin A, Wilson CL, Staba RJ, Reddick M, Fried I, Engel J Jr. Interictal high-frequency oscillations (80-500 Hz) in the human epileptic brain: entorhinal cortex. Ann Neurol. 2002;52(4):407415.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Engel J Jr, Bragin A, Staba R, Mody I. High-frequency oscillations: what is normal and what is not? Epilepsia. 2009;50(4):598604.

  • 27

    Ekstrom AD, Kahana MJ, Caplan JB, et al. Cellular networks underlying human spatial navigation. Nature. 2003;425(6954):184188.

  • 28

    Jacobs J, Weidemann CT, Miller JF, et al. Direct recordings of grid-like neuronal activity in human spatial navigation. Nat Neurosci. 2013;16(9):11881190.

  • 29

    Quiroga RQ, Reddy L, Kreiman G, Koch C, Fried I. Invariant visual representation by single neurons in the human brain. Nature. 2005;435(7045):11021107.

  • 30

    Mukamel R, Ekstrom AD, Kaplan J, Iacoboni M, Fried I. Single-neuron responses in humans during execution and observation of actions. Curr Biol. 2010;20(8):750756.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Qasim SE, Fried I, Jacobs J. Phase precession in the human hippocampus and entorhinal cortex. Cell. 2021;184(12):32423255.e10.

  • 32

    Kreiman G, Fried I, Koch C. Single-neuron correlates of subjective vision in the human medial temporal lobe. Proc Natl Acad Sci U S A. 2002;99(12):83788383.

  • 33

    Quian Quiroga R, Kraskov A, Mormann F, Fried I, Koch C. Single-cell responses to face adaptation in the human medial temporal lobe. Neuron. 2014;84(2):363369.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Fried I, MacDonald KA, Wilson CL. Single neuron activity in human hippocampus and amygdala during recognition of faces and objects. Neuron. 1997;18(5):753765.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Cameron KA, Yashar S, Wilson CL, Fried I. Human hippocampal neurons predict how well word pairs will be remembered. Neuron. 2001;30(1):289298.

  • 36

    Gelbard-Sagiv H, Mukamel R, Harel M, Malach R, Fried I. Internally generated reactivation of single neurons in human hippocampus during free recall. Science. 2008;322(5898):96101.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Fried I, Mukamel R, Kreiman G. Internally generated preactivation of single neurons in human medial frontal cortex predicts volition. Neuron. 2011;69(3):548562.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Nir Y, Andrillon T, Marmelshtein A, et al. Selective neuronal lapses precede human cognitive lapses following sleep deprivation. Nat Med. 2017;23(12):14741480.

  • 39

    Suthana N, Haneef Z, Stern J, et al. Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med. 2012;366(6):502510.

  • 40

    Mankin EA, Fried I. Modulation of human memory by deep brain stimulation of the entorhinal-hippocampal circuitry. Neuron. 2020;106(2):218235.

  • 41

    Cash SS, Hochberg LR. The emergence of single neurons in clinical neurology. Neuron. 2015;86(1):7991.

  • 42

    Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651660.

  • 43

    Mukamel R, Fried I. Human intracranial recordings and cognitive neuroscience. Annu Rev Psychol. 2012;63:511537.

  • 44

    Razavi B, Rao VR, Lin C, et al. Real-world experience with direct brain-responsive neurostimulation for focal onset seizures. Epilepsia. 2020;61(8):17491757.

  • 45

    Mullin JP, Shriver M, Alomar S, et al. Is SEEG safe? A systematic review and meta-analysis of stereo-electroencephalography-related complications. Epilepsia. 2016;57(3):386401.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Sperling MR, Barshow S, Nei M, Asadi-Pooya AA. A reappraisal of mortality after epilepsy surgery. Neurology. 2016;86(21):19381944.

  • 47

    Ekstrom A, Suthana N, Behnke E, Salamon N, Bookheimer S, Fried I. High-resolution depth electrode localization and imaging in patients with pharmacologically intractable epilepsy. J Neurosurg. 2008;108(4):812815.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Nagahama Y, Schmitt AJ, Nakagawa D, et al. Intracranial EEG for seizure focus localization: evolving techniques, outcomes, complications, and utility of combining surface and depth electrodes. J Neurosurg. 2019;130(4):11801192.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Chari A, Thornton RC, Tisdall MM, Scott RC. Microelectrode recordings in human epilepsy: a case for clinical translation. Brain Commun. 2020;2(2):fcaa082.

  • 50

    Moses DA, Metzger SL, Liu JR, et al. Neuroprosthesis for decoding speech in a paralyzed person with anarthria. N Engl J Med. 2021;385(3):217227.

Metrics

All Time Past Year Past 30 Days
Abstract Views 1847 1017 0
Full Text Views 581 397 70
PDF Downloads 609 391 66
EPUB Downloads 0 0 0