Limbic and paralimbic respiratory modulation: From inhibition to enhancement.

OBJECTIVE: Increased understanding of the role of cortical structures in respiratory control may help the understanding of seizure-induced respiratory dysfunction that leads to sudden unexpected death in epilepsy (SUDEP). The aim of this study was to characterize respiratory responses to electrical stimulation (ES), including inhibition and enhancement of respiration. METHODS: We prospectively recruited 19 consecutive patients with intractable epilepsy undergoing stereotactic electroencephalography (EEG) evaluation from June 2015 to June 2018. Inclusion criteria were patients ≥18 years in whom ES was indicated for clinical mapping of ictal onset or eloquent cortex as part of the presurgical evaluation. ES was carried out at 50 Hz, 0.2 msec, and 1-10 mA current intensity. Common brain regions sampled across all patients were amygdala (AMY), hippocampus (HG), anterior cingulate gyrus (CING), orbitofrontal cortex (OrbF), temporal neocortex (TNC), temporal pole (TP), and entorhinal cortex (ERC). Seven hundred fifty-five stimulations were conducted. Quantitative analysis of breathing signal, that is, changes in breathing rate (BR), depth (TV), and minute ventilation (MV), was carried out during ES using the BreathMetrics breathing waveform analysis toolbox. Electrocardiography, arterial oxygen saturation, end-tidal and transcutaneous carbon dioxide, nasal airflow, and abdominal and thoracic plethysmography were monitored continuously during stimulations. RESULTS: Electrical stimulation of TP and CING (at lower current strengths <3 mA) increased TV and MV. At >7-10 mA, CING decreased TV and MV. On the other hand, decreased TV and MV occurred with stimulation of mesial temporal structures such as AMY and HG. Breathing changes were dependent on stimulation intensity. Lateral temporal, entorhinal, and orbitofrontal cortices did not affect breathing either way. SIGNIFICANCE: These findings suggest that breathing responses other than apnea can be induced by ES. Identification of two regions-the temporal pole and anterior cingulate gyrus-for enhancement of breathing may be important in paving the way to future development of strategies for prevention of SUDEP.

Robot-assisted stereoelectroencephalography exploration of the limbic thalamus in human focal epilepsy: implantation technique and complications in the first 24 patients.

OBJECTIVE: Despite numerous imaging studies highlighting the importance of the thalamus in a patient's surgical prognosis, human electrophysiological studies involving the limbic thalamic nuclei are limited. The objective of this study was to evaluate the safety and accuracy of robot-assisted stereotactic electrode placement in the limbic thalamic nuclei of patients with suspected temporal lobe epilepsy (TLE). METHODS: After providing informed consent, 24 adults with drug-resistant, suspected TLE undergoing evaluation with stereoelectroencephalography (SEEG) were enrolled in the prospective study. The trajectory of one electrode planned for clinical sampling of the operculoinsular cortex was modified to extend it to the thalamus, thereby preventing the need for additional electrode placement for research. The anterior nucleus of the thalamus (ANT) (n = 13) and the medial group of thalamic nuclei (MED) (n = 11), including the mediodorsal and centromedian nuclei, were targeted. The postimplantation CT scan was coregistered to the preoperative MR image, and Morel's thalamic atlas was used to confirm the accuracy of implantation. RESULTS: Ten (77%) of 13 patients in the ANT group and 10 (91%) of 11 patients in the MED group had electrodes accurately placed in the thalamic nuclei. None of the patients had a thalamic hemorrhage. However, trace asymptomatic hemorrhages at the cortical-level entry site were noted in 20.8% of patients, who did not require additional surgical intervention. SEEG data from all the patients were interpretable and analyzable. The trajectories for the ANT implant differed slightly from those of the MED group at the entry point-i.e., the precentral gyrus in the former and the postcentral gyrus in the latter. CONCLUSIONS: Using judiciously planned robot-assisted SEEG, the authors demonstrate the safety of electrophysiological sampling from various thalamic nuclei for research recordings, presenting a technique that avoids implanting additional depth electrodes or compromising clinical care. With these results, we propose that if patients are fully informed of the risks involved, there are potential benefits of gaining mechanistic insights to seizure genesis, which may help to develop neuromodulation therapies.

Dynamics of seizure-induced behavioral and autonomic arousal.

PURPOSE: Arousal is the most primitive, powerful instinct with survival benefit present in all vertebrates. Even though the arousal systems are classically viewed as "ascending" brainstem phenomena, there is a "descending" cortical feedback system that maintains consciousness. In this study, we provide electrophysiological confirmation that seizures localized to the anterior cingulum can behaviorally manifest as paroxysms of arousal from sleep. METHODS: Temporal dynamics of arousal induced by anterior cingulate seizures were analyzed by using multiple modalities including stereoelectroencephalography (phase lag index and phase amplitude coupling), lead-1 ECG (point-process heart rate variability analysis) and diffusion tractography (DTI). RESULTS: The ictal arousal was associated with an increase in synchronization in the alpha band and an increase in local theta or alpha-gamma phase-amplitude coupling. In comparison to seizures that lacked clinical manifestations, ictal arousal was associated with an increase in heart rate but not heart rate variability. Finally, DTI demonstrated degeneration in white fiber tracts passing between the anterior cingulum and anterior thalamus ipsilateral to the epileptogenic cortex. The patient underwent resection of the anterior cingulum, and histopathology confirmed focal cortical dysplasia type II. CONCLUSION: Anterior cingulate seizures inducing behavioral arousal have identifiable autonomic and EEG signatures.

Corticocortical evoked potentials reveal projectors and integrators in human brain networks.

The cerebral cortex is composed of subregions whose functional specialization is largely determined by their incoming and outgoing connections with each other. In the present study, we asked which cortical regions can exert the greatest influence over other regions and the cortical network as a whole. Previous research on this question has relied on coarse anatomy (mapping large fiber pathways) or functional connectivity (mapping inter-regional statistical dependencies in ongoing activity). Here we combined direct electrical stimulation with recordings from the cortical surface to provide a novel insight into directed, inter-regional influence within the cerebral cortex of awake humans. These networks of directed interaction were reproducible across strength thresholds and across subjects. Directed network properties included (1) a decrease in the reciprocity of connections with distance; (2) major projector nodes (sources of influence) were found in peri-Rolandic cortex and posterior, basal and polar regions of the temporal lobe; and (3) major receiver nodes (receivers of influence) were found in anterolateral frontal, superior parietal, and superior temporal regions. Connectivity maps derived from electrical stimulation and from resting electrocorticography (ECoG) correlations showed similar spatial distributions for the same source node. However, higher-level network topology analysis revealed differences between electrical stimulation and ECoG that were partially related to the reciprocity of connections. Together, these findings inform our understanding of large-scale corticocortical influence as well as the interpretation of functional connectivity networks.

Evoked effective connectivity of the human neocortex.

The role of cortical connectivity in brain function and pathology is increasingly being recognized. While in vivo magnetic resonance imaging studies have provided important insights into anatomical and functional connectivity, these methodologies are limited in their ability to detect electrophysiological activity and the causal relationships that underlie effective connectivity. Here, we describe results of cortico-cortical evoked potential (CCEP) mapping using single pulse electrical stimulation in 25 patients undergoing seizure monitoring with subdural electrode arrays. Mapping was performed by stimulating adjacent electrode pairs and recording CCEPs from the remainder of the electrode array. CCEPs reliably revealed functional networks and showed an inverse relationship to distance between sites. Coregistration to Brodmann areas (BA) permitted group analysis. Connections were frequently directional with 43% of early responses and 50% of late responses of connections reflecting relative dominance of incoming or outgoing connections. The most consistent connections were seen as outgoing from motor cortex, BA6-BA9, somatosensory (SS) cortex, anterior cingulate cortex, and Broca's area. Network topology revealed motor, SS, and premotor cortices along with BA9 and BA10 and language areas to serve as hubs for cortical connections. BA20 and BA39 demonstrated the most consistent dominance of outdegree connections, while BA5, BA7, auditory cortex, and anterior cingulum demonstrated relatively greater indegree. This multicenter, large-scale, directional study of local and long-range cortical connectivity using direct recordings from awake, humans will aid the interpretation of noninvasive functional connectome studies.

Intracortical mechanisms of single pulse electrical stimulation (SPES) evoked excitations and inhibitions in humans.

Cortico-cortical evoked potentials (CCEPs) elicited by single-pulse electric stimulation (SPES) are widely used to assess effective connectivity between cortical areas and are also implemented in the presurgical evaluation of epileptic patients. Nevertheless, the cortical generators underlying the various components of CCEPs in humans have not yet been elucidated. Our aim was to describe the laminar pattern arising under SPES evoked CCEP components (P1, N1, P2, N2, P3) and to evaluate the similarities between N2 and the downstate of sleep slow waves. We used intra-cortical laminar microelectrodes (LMEs) to record CCEPs evoked by 10 mA bipolar 0.5 Hz electric pulses in seven patients with medically intractable epilepsy implanted with subdural grids. Based on the laminar profile of CCEPs, the latency of components is not layer-dependent, however their rate of appearance varies across cortical depth and stimulation distance, while the seizure onset zone does not seem to affect the emergence of components. Early neural excitation primarily engages middle and deep layers, propagating to the superficial layers, followed by mainly superficial inhibition, concluding in a sleep slow wave-like inhibition and excitation sequence.

The role of superficial and deep layers in the generation of high frequency oscillations and interictal epileptiform discharges in the human cortex.

Describing intracortical laminar organization of interictal epileptiform discharges (IED) and high frequency oscillations (HFOs), also known as ripples. Defining the frequency limits of slow and fast ripples. We recorded potential gradients with laminar multielectrode arrays (LME) for current source density (CSD) and multi-unit activity (MUA) analysis of interictal epileptiform discharges IEDs and HFOs in the neocortex and mesial temporal lobe of focal epilepsy patients. IEDs were observed in 20/29, while ripples only in 9/29 patients. Ripples were all detected within the seizure onset zone (SOZ). Compared to hippocampal HFOs, neocortical ripples proved to be longer, lower in frequency and amplitude, and presented non-uniform cycles. A subset of ripples (≈ 50%) co-occurred with IEDs, while IEDs were shown to contain variable high-frequency activity, even below HFO detection threshold. The limit between slow and fast ripples was defined at 150 Hz, while IEDs' high frequency components form clusters separated at 185 Hz. CSD analysis of IEDs and ripples revealed an alternating sink-source pair in the supragranular cortical layers, although fast ripple CSD appeared lower and engaged a wider cortical domain than slow ripples MUA analysis suggested a possible role of infragranularly located neural populations in ripple and IED generation. Laminar distribution of peak frequencies derived from HFOs and IEDs, respectively, showed that supragranular layers were dominated by slower (< 150 Hz) components. Our findings suggest that cortical slow ripples are generated primarily in upper layers while fast ripples and associated MUA in deeper layers. The dissociation of macro- and microdomains suggests that microelectrode recordings may be more selective for SOZ-linked ripples. We found a complex interplay between neural activity in the neocortical laminae during ripple and IED formation. We observed a potential leading role of cortical neurons in deeper layers, suggesting a refined utilization of LMEs in SOZ localization.

Ictal high-frequency activity in limbic thalamic nuclei varies with electrographic seizure-onset patterns in temporal lobe epilepsy.

OBJECTIVE: To characterize ictal high-frequency activity (HFA, 80-500 Hz) within the limbic thalami and correlate HFA with seizure onset patterns in patients with temporal lobe epilepsy (TLE). METHODS: Patients with TLE undergoing stereoelectroencephalography (SEEG) for presurgical workup were prospectively recruited for electrode implantation in one of the anterior (AN), centromedian (CeM), or mediodorsal (MD) thalamic nuclei. HFA was computed by three complementary methods: (1.) power-spectral density (PSD), (2.) power-law based (i.e., 1/f) regression, and (3.) envelope-based (ENV) power analysis. Electrographic onset patterns in the seizure onset zone were classified in three distinct patterns, including low amplitude fast activity (LAFA). RESULTS: From 11 patients, 44 seizures were analyzed. Ictal HFA was observed in all three thalamic nuclei. HFA was greatest during ictal onset in the AN and MD and greatest during termination in the CeM (P < 0.001). LAFA-onset seizures were associated with earlier peak HFA compared to those with other onset patterns (P = 0.006). CONCLUSIONS: Dynamics of ictal HFA seem to vary by thalamic subnuclei. AN and MD may facilitate seizure propagation while CeM may play a role in termination. LAFA-onset seizures rapidly propagate to the thalamus. SIGNIFICANCE: Characterizing nucleus-specific ictal dynamics of neural activities facilitates precise therapy for epilepsy treatment with closed-loop deep brain stimulation.

Direct Cortical Stimulation to Probe the Ictogenicity of the Epileptogenic Nodes in Temporal Lobe Epilepsy.

Accurate mapping of the seizure onset zone (SOZ) is critical to the success of epilepsy surgery outcomes. Epileptogenicity index (EI) is a statistical method that delineates hyperexcitable brain regions involved in the generation and early propagation of seizures. However, EI can overestimate the SOZ for particular electrographic seizure onset patterns. Therefore, using direct cortical stimulation (DCS) as a probing tool to identify seizure generators, we systematically evaluated the causality of the high EI nodes (>0.3) in replicating the patient's habitual seizures. Specifically, we assessed the diagnostic yield of high EI nodes, i.e., the proportion of high EI nodes that evoked habitual seizures. A retrospective single-center study that included post-stereo encephalography (SEEG) confirmed TLE patients (n = 37) that had all high EI nodes stimulated, intending to induce a seizure. We evaluated the nodal responses (true and false responder rate) to stimulation and correlated with electrographic seizure onset patterns (hypersynchronous-HYP and low amplitude fast activity patterns-LAFA) and clinically defined SOZ. The ictogenicity (i.e., the propensity to induce the patient's habitual seizure) of a high EI node was only 44.5%. The LAFA onset pattern had a significantly higher response rate to DCS (i.e., higher evoked seizures). The concordance of an evoked habitual seizure with a clinically defined SOZ with good outcomes was over 50% (p = 0.0025). These results support targeted mapping of SOZ in LAFA onset patterns by performing DCS in high EI nodes to distinguish seizure generators (true responders) from hyperexcitable nodes that may be involved in early propagation.

Laminar distribution of electrically evoked hippocampal short latency ripple activity highlights the importance of the subiculum in vivo in human epilepsy, an intraoperative study.

OBJECTIVE: The goal of this study was to define the pathology and anesthesia dependency of single pulse electrical stimulation (SPES) dependent high-frequency oscillations (HFOs, ripples, fast ripples) in the hippocampal formation. METHODS: Laminar profile of electrically evoked short latency (<100 ms) high-frequency oscillations (80-500 Hz) was examined in the hippocampus of therapy-resistant epileptic patients (6 female, 2 male) in vivo, under general anesthesia. RESULTS: Parahippocampal SPES evoked HFOs in all recorded hippocampal subregions (Cornu Ammonis 2-3, dentate gyrus, and subiculum) were not uniform, rather the combination of ripples, fast ripples, sharp transients, and multiple unit activities. Mild and severe hippocampal sclerosis (HS) differed in the probability to evoke fast ripples: it decreased with the severity of sclerosis in CA2-3 but increased in the subiculum. Modulation in the ripple spectrum was observed only in the subiculum with increased fast HFO rate and frequency in severe HS. Inhalational anesthetics (isoflurane) suppressed the chance to evoke HFOs compared to propofol. CONCLUSION: The presence of early HFOs in the dentate gyrus and early fast HFOs (>250 Hz) in the other subregions indicate the pathological nature of these evoked oscillations. Subiculum was found to be active producing HFOs in parallel with the cell loss in the hippocampus proper, which emphasize the role of this region in the generation of epileptic activity.

Machine learning approach to detect focal-onset seizures in the human anterior nucleus of the thalamus.

Objective.There is an unmet need to develop seizure detection algorithms from brain regions outside the epileptogenic cortex. The study aimed to demonstrate the feasibility of classifying seizures and interictal states from local field potentials (LFPs) recorded from the human thalamus-a subcortical region remote to the epileptogenic cortex. We tested the hypothesis that spectral and entropy-based features extracted from LFPs recorded from the anterior nucleus of the thalamus (ANT) can distinguish its state of ictal recruitment from other interictal states (including awake, sleep).Approach. Two supervised machine learning tools (random forest and the random kitchen sink) were used to evaluate the performance of spectral (discrete wavelet transform-DWT), and time-domain (multiscale entropy-MSE) features in classifying seizures from interictal states in patients undergoing stereo-electroencephalography (EEG) evaluation for epilepsy surgery. Under the supervision of IRB, field potentials were recorded from the ANT in consenting adults with drug-resistant temporal lobe epilepsy. Seizures were confirmed in the ANT using line-length and visual inspection. Wilcoxon rank-sum method was used to test the differences in spectral patterns between seizure and interictal (awake and sleep) states.Main results.79 seizures (10 patients) and 158 segments (approx. 4 h) of interictal stereo-EEG data were analyzed. The mean seizure detection latencies with line length in the ANT varied between seizure types (range 5-34 s). However, the DWT and MSE in the ANT showed significant changes for all seizure types within the first 20 s after seizure onset. The random forest (accuracy 93.9% and false-positive 4.6%) and the random kitchen sink (accuracy 97.3% and false-positive 1.8%) classified seizures and interictal states.Significance.These results suggest that features extracted from the thalamic LFPs can be trained to detect seizures that can be used for monitoring seizure counts and for closed-loop seizure abortive interventions.

Precision mapping of the epileptogenic network with low- and high-frequency stimulation of anterior nucleus of thalamus.

OBJECTIVE: The goal of thalamic deep brain stimulation in epilepsy is to engage and modulate the epileptogenic network. We demonstrate how the anterior nucleus of thalamus (ANT) stimulation engages the epileptogenic network using electrophysiological measures (gamma response and post-stimulation excitability). METHODS: Five patients with suspected temporal lobe epilepsy syndrome, undergoing stereo-electroencephalography (SEEG), were enrolled in the IRB approved study to undergo recording and stimulation of the ANT. We analyzed the extent of gamma-band response (activation or suppression) and post-stimulation change in excitability in various cortical regions during low (10 Hz) and high (50 Hz) frequency stimulations. RESULTS: 10 Hz stimulation increased cortical gamma, whereas 50 Hz stimulation suppressed the gamma responses. The maximum response to stimuli was in the hippocampus. High epileptogenicity regions were more susceptible to stimulation. Both 10-and 50 Hz stimulations decreased post-stimulation cortical excitability. The greater the gamma-band activation with 10 Hz stimulation, the greater was the decrease in post-stimulation excitability. CONCLUSIONS: We define an EEG marker that delineates stimulation-specific nodal engagement. We proved that nodes that were engaged with the thalamus during stimulation were more likely to show a short term decrease in post-stimulation excitability. SIGNIFICANCE: Patient-specific engagement patterns during stimulation can be mapped with SEEG that can be used to optimize stimulation parameters.

Acute modulation of the limbic network with low and high-frequency stimulation of the human fornix.

Targeted stimulation of white matter has opened newer perspectives in the field of neuromodulation, towards an attempt to improve memory or as a therapy for epilepsy. Stimulation of the fornix, being a part of the Papez circuit, is likely to modulate the limbic network excitability. However, the stimulation-frequency dependent variability in network excitability is unknown. In the case study, which involved stereo electroencephalographic (SEEG) recording of field potentials in a 48-year old left-handed woman with suspected temporal lobe epilepsy, we demonstrated the network effects of acute low (1 and 10 Hz) and high (50 Hz) frequency electrical stimulation of fornix. Mapping the short-latency evoked responses to forniceal stimulation confirmed the SEEG target localization within the Papez circuit. Low and high-frequency stimulation of the fornix produced opposite effects in the post-stimuli excitability, with the latter causing increased excitability in the limbic network that culminated in a clinical seizure. A distinct spectral peak around 8 Hz confirmed that sensing field potentials from the forniceal white matter is feasible. This is the first case study that provided an insight into how the temporal patterning of forniceal stimulation altered the downstream limbic network excitability.

Reorganization of Large-Scale Functional Networks During Low-Frequency Electrical Stimulation of the Cortical Surface.

We investigated the functional network reorganization caused by low-frequency electrical stimulation (LFES) of human brain cortical surface. Intracranial EEG data from subdural grid positions were analyzed in 16 pre-surgery epileptic patients. LFES was performed by injecting current pulses (10mA, 0.2ms pulse width, 0.5Hz, 25 trials) into all adjacent electrode contacts. Dynamic functional connectivity analysis was carried out on two frequency bands (low: 1-4Hz; high: 10-40Hz) to investigate the early, high frequency and late, low frequency responses elicited by the stimulation. The centralization increased in early compared to late responses, suggesting a more prominent role of direct neural links between primarily activated areas and distant brain regions. Injecting the current into the seizure onset zone (SOZ) evoked a more integrated functional topology during the early (N1) period of the response, whereas during the late (N2) period - regardless of the stimulation site - the connectedness of the SOZ was elevated compared to the non-SOZ tissue. The abnormal behavior of the epileptic sub-network during both part of the responses supports the idea of the pathogenic role of impaired inhibition and excitation mechanisms in epilepsy.

Practice trends and the outcome of neuromodulation therapies in epilepsy: A single-center study.

Neuromodulation therapies (VNS, RNS, and DBS) can improve seizure control in persons with epilepsy. However, there is a significant service gap in integrating these therapies in clinical care. Our epilepsy center has established an epilepsy neuromodulation clinic to improve access to patients, communication with referring physicians, track outcome and train future providers in programming neuromodulation devices. We report the (a) treatment outcome of the available neuromodulation therapies (ie, reduction in seizure frequency over 6-12 months follow-up); and (b) demonstrate the benefit of the specialized clinic (rapid titration, continuity of care, superior access for patient and vendors). In this single-center, retrospective study, forty-three adults (VNS = 27; RNS = 16) with drug-resistant epilepsy were followed in the clinic during the 19 months study period. About 44-69% of patients reported > 60% decrease in seizure. All patients were scheduled in the clinic within 2-4 weeks, and stimulations were optimized rapidly. About 40% of patients participated in research while 28% were referred for additional diagnostic studies. Nineteen students and fellows were trained in programming neurostimulator. Epilepsy neuromodulation clinic can serve as an optimal solution for patients as well as providers due to rapid access, better continuity of care, higher recruitment for research studies, and training health professionals.

Spectral organization of focal seizures within the thalamotemporal network.

OBJECTIVE: To investigate dynamic changes in neural activity between the anterior nucleus of the thalamus (ANT) and the seizure onset zone (SOZ) in patients with drug-resistant temporal lobe epilepsy (TLE) based on anatomic location, seizure subtype, and state of vigilance (SOV). METHODS: Eleven patients undergoing stereoelectroencephalography for seizure localization were recruited prospectively for local field potential (LFP) recording directly from the ANT. The SOZ was identified using line length and epileptogenicity index. Changes in power spectral density (PSD) were compared between the two anatomic sites as seizures (N = 53) transitioned from interictal baseline to the posttermination stage. RESULTS: At baseline, the thalamic LFPs were significantly lower and distinct from the SOZ with the presence of higher power in the fast ripple band (P < 0.001). Temporal changes in ictal power of neural activity within ANT mimic those of the SOZ, are increased significantly at seizure onset (P < 0.05), and are distinct for seizures that impaired awareness or that secondarily generalized (P < 0.05). The onset of seizure was preceded by a decrease in the mean power spectral density (PSD) in ANT and SOZ (P < 0.05). Neural activity correlated with different states of vigilance at seizure onset within the ANT but not in the SOZ (P = 0.005). INTERPRETATION: The ANT can be recruited at the onset of mesial temporal lobe seizures, and the recruitment pattern differs with seizure subtypes. Furthermore, changes in neural dynamics precede seizure onset and are widespread to involve temporo-thalamic regions, thereby providing an opportunity to intervene early with closed-loop DBS.

Early ictal recruitment of midline thalamus in mesial temporal lobe epilepsy.

The causal role of midline thalamus in the initiation and early organization of mesial temporal lobe seizures is studied. Three patients undergoing stereoelectroencephalography were enrolled for the placement of an additional depth electrode targeting the midline thalamus. The midline thalamus was recruited in all three patients at varying points of seizure initiation (0-13 sec) and propagation (9-60 sec). Stimulation of either thalamus or hippocampus induced similar habitual seizures. Seizure-induced in the hippocampus rapidly recruited the thalamus. Evoked potentials demonstrated stronger connectivity from the hippocampus to the thalamus than in the opposite direction. The midline thalamus can be within the seizure initiation and symptomatogenic circuits.

Modulation of neural oscillations by vagus nerve stimulation in posttraumatic multifocal epilepsy: case report.

The putative mechanism of vagus nerve stimulation (VNS) for medically refractory epilepsy is desynchronization of hippocampal and thalamocortical circuitry; however, the nature of the dose-response relationship and temporal dynamics is poorly understood. For greater elucidation, a study in a nonepileptic rat model was previously conducted and showed that rapid-cycle (RC) VNS achieved superior desynchrony compared to standard-cycle (SC) VNS. Here, the authors report on the first in-human analysis of the neuromodulatory dose-response effects of VNS in a patient with posttraumatic, independent, bilateral mesial temporal lobe epilepsy refractory to medications and SC-VNS who was referred as a potential candidate for a responsive neurostimulation device. During stereotactic electroencephalography (SEEG) recordings, the VNS device was initially turned off, then changed to SC-VNS and then RC-VNS settings. Spectral analysis revealed a global reduction of power in the theta (4-8 Hz) and alpha (8-15 Hz) bands with both SC- and RC-VNS compared to the stimulation off setting (p < 0.001). Furthermore, in the alpha band, both SC- and RC-VNS were associated with greater global desynchrony compared to the off setting (p < 0.001); and, specifically, in the bilateral epileptogenic hippocampi, RC-VNS further reduced spectral power compared to SC-VNS (p < 0.001). The dose-response and temporal effects suggest that VNS modulates regional and global dynamics differently.

Auras localized to the temporal lobe disrupt verbal memory and learning - Causal evidence from direct electrical stimulation of the hippocampus.

Auras (focal aware seizure; FAS) are subjective ictal events with retained consciousness. Epileptiform activities can disrupt cognitive tasks, but studies are limited to seizures with impaired awareness. As a proof of concept, we examined the cognitive effects of direct electrical stimulation to the left hippocampus which induced a habitual FAS in a patient with left mesial temporal lobe epilepsy. During the induced habitual FAS, verbal memory performance declined significantly as compared to pre-stimulation testing. Tasks measuring auditory working memory and psychomotor processing speed were not affected by the stimulation. The study confirms that FAS can impair episodic verbal memory and learning.

Automated detection of mesial temporal and temporoperisylvian seizures in the anterior thalamic nucleus.

BACKGROUND AND PURPOSE: Focal seizures can arise from coordinated activity across large-scale epileptic networks and propagate to regions that are not functionally altered but are recruited by epileptiform discharges. In preclinical models of focal epilepsy, the thalamus is recruited by cortical onset seizures, but it remains to be demonstrated in clinical studies. In this pilot study, the authors investigate whether seizures with onset within and outside the mesial temporal structures are detected in the anterior thalamus (ATN). METHODS: After written consent, three subjects with suspected temporal lobe epilepsy undergoing stereotactic electrode implantation were recruited prospectively for thalamocortical depth EEG recordings. Three seizure detection metrics (line length-LL, Laplace operator-Lap; Teager energy-TE) were studied within the seizure onset zone and ATN. RESULTS: The LL, Lap, and TE metrics detected 40 (95%) seizures each in the ATN before the behavioral manifestation. Rates of detection in the seizure onset zone were 40 (95%), 42 (100%), and 41 (98%), respectively. The mean detection latency in ATN from SOZ ranged from 0.25 to 5.17 s. Seizures were localized to amygdala-hippocampus, temporal pole, anterior insula and superior temporal gyrus. CONCLUSIONS: The pilot study demonstrates that seizures in mesial temporal and temporal-plus epilepsies (i.e., temporoperisylvian) can be detected reliably in the ATN. Further studies are needed to validate these findings.