Anticipation-induced delta phase reset improves human olfactory perception.

Anticipating an odor improves detection and perception, yet the underlying neural mechanisms of olfactory anticipation are not well understood. In this study, we used human intracranial electroencephalography (iEEG) to show that anticipation resets the phase of delta oscillations in piriform cortex prior to odor arrival. Anticipatory phase reset correlates with ensuing odor-evoked theta power and improvements in perceptual accuracy. These effects were consistently present in each individual subject and were not driven by potential confounds of pre-inhale motor preparation or power changes. Together, these findings suggest that states of anticipation enhance olfactory perception through phase resetting of delta oscillations in piriform cortex.

Common functional connectivity alterations in focal epilepsies identified by machine learning.

OBJECTIVE: This study was undertaken to identify shared functional network characteristics among focal epilepsies of different etiologies, to distinguish epilepsy patients from controls, and to lateralize seizure focus using functional connectivity (FC) measures derived from resting state functional magnetic resonance imaging (MRI). METHODS: Data were taken from 103 adult and 65 pediatric focal epilepsy patients (with or without lesion on MRI) and 109 controls across four epilepsy centers. We used three whole-brain FC measures: parcelwise connectivity matrix, mean FC, and degree of FC. We trained support vector machine models with fivefold cross-validation (1) to distinguish patients from controls and (2) to lateralize the hemisphere of seizure onset in patients. We reported the regions and connections with the highest importance from each model as the common FC differences between the compared groups. RESULTS: FC measures related to the default mode and limbic networks had higher importance relative to other networks for distinguishing epilepsy patients from controls. In lateralization models, regions related to somatosensory, visual, default mode, and basal ganglia showed higher importance. The epilepsy versus control classification model trained using a 400-parcel connectivity matrix achieved a median testing accuracy of 75.6% (median area under the curve [AUC] = .83) in repeated independent testing. Lateralization accuracy using the 400-parcel connectivity matrix reached a median accuracy of 64.0% (median AUC = .69). SIGNIFICANCE: Machine learning models revealed common FC alterations in a heterogeneous group of patients with focal epilepsies. The distribution of the most altered regions supports the hypothesis that shared functional alteration exists beyond the seizure onset zone and its epileptic network. We showed that FC measures can distinguish patients from controls, and further lateralize focal epilepsies. Future studies are needed to confirm these findings by using larger numbers of epilepsy patients.

Low-frequency stimulation of a fiber tract in bilateral temporal lobe epilepsy.

OBJECTIVE: Pharmacoresistant bilateral mesial temporal lobe epilepsy often implies poor resective surgical candidacy. Low-frequency stimulation of a fiber tract connected to bilateral hippocampi, the fornicodorsocommissural tract, has been shown to be safe and efficacious in reducing seizures in a previous short-term study. Here, we report a single-blinded, within-subject control, long-term deep-brain stimulation trial of low-frequency stimulation of the fornicodorsocommissural tract in bilateral mesial temporal lobe epilepsy. Outcomes of interest included safety with respect to verbal memory scores and reduction of seizure frequency. METHODS: Our enrollment goal was 16 adult subjects to be randomized to 2-Hz or 5-Hz low-frequency stimulation of the fornicodorsocommissural tract starting at 2 mA. The study design consisted of four two-month blocks of stimulation with a 50%-duty cycle, alternating with two-month blocks of no stimulation. RESULTS: We terminated the study after enrollment of five subjects due to slow accrual. Fornicodorsocommissural tract stimulation elicited bilateral hippocampal evoked responses in all subjects. Three subjects underwent implantation of pulse generators and long-term low-frequency stimulation with mean monthly seizures of 3.14 ±â€¯2.67 (median 3.0 [IQR 1-4.0]) during stimulation-off blocks, compared with 0.96 ±â€¯1.23 (median 1.0 [IQR 0-1.0]) during stimulation-on blocks (p = 0.0005) during the blinded phase. Generalized Estimating Equations showed that low-frequency stimulation reduced monthly seizure-frequency by 0.71 per mA (p < 0.001). Verbal memory scores were stable with no psychiatric complications or other adverse events. SIGNIFICANCE: The results demonstrate feasibility of stimulating both hippocampi using a single deep-brain stimulation electrode in the fornicodorsocommissural tract, efficacy of low-frequency stimulation in reducing seizures, and safety as regards verbal memory.

The effects of ammonia stimulation on kainate-induced status epilepticus and anterior piriform cortex electrophysiology.

OBJECTIVE: Strong olfactory stimulation (OS) with such substances as toluene or ammonia has been reported to suppress seizures. We aimed to investigate the role of ammonia stimulation on acute kainic acid (KA)-induced seizures. We also investigated any possible effects of ammonia stimulation on the electrophysiology of the anterior piriform cortex (APC). METHODS: Adult male Sprague-Dawley rats were implanted with bilateral hippocampal electrodes and an electrode in the left APC. Animals were exposed to either distilled water (control) or ammonia stimulation for 20 s every 5 min during KA induction of status epilepticus (SE). The electroencephalogram (EEG) was analyzed for seizure frequency, duration, severity, and total KA doses given prior to reaching SE. Seizure-free EEG epochs that coincided with OS were chosen and analyzed via wavelet analysis for any spectral changes. RESULTS: We found no significant differences in seizure frequency, duration, severity, or administered KA doses before SE between the groups. In the experimental group, a wavelet analysis of variance (WANOVA) revealed a significant stimulation-induced increase of power in the delta and alpha bands prior to the first KA injection and higher power in the delta and theta bands after KA injection. CONCLUSIONS: Whereas the spectral analysis of the APC revealed specific OS-induced changes, our findings suggest that OS with ammonia does not result in altering the threshold of attaining KA-induced SE. This does not rule out a potential role for OS in reducing recurrent seizures in the KA or other epilepsy models.

Acute and spontaneous seizure onset zones in the intraperitoneal kainic acid model.

OBJECTIVE: Hippocampal monitoring is often used in the intraperitoneal kainic acid (KA) seizure model for detection and quantification of early ictal activity. Here, we investigated extra-hippocampal seizure onset zones (SOZs) in this model. METHODS: Eight male Sprague Dawley rats implanted with depth electrodes were continuously recorded during intraperitoneal KA injections until status epilepticus (SE) was induced. Another group of four rats was monitored chronically up to two weeks after emergence of spontaneous recurrent seizures. All rats had hippocampal electrodes. Other sampled brain regions included, among others, the claustrum, piriform cortex, and orbital cortex. Seizures recorded with video-EEG were visually analyzed. RESULTS: In the 58 seizures recorded during KA injections, the SOZ was extrahippocampal in 7 (12%), diffuse in 29 (50%), and hippocampal in 22 (38%). Of the 14 spontaneous seizures recorded, none were solely extrahippocampal, 10 (71%) were diffuse, and 4 (29%) were of hippocampal onset. All extra-hippocampal seizures propagated to the hippocampus within 4 to 50s (mean=14, n=7). No distinctive semiological manifestations correlated with the SOZs. SIGNIFICANCE: We conclude that seizures can have multifocal SOZs in the KA model. This finding is important to consider when using this model, among other purposes, to screen for new therapies, study pharmacoresistance, or investigate comorbidities of epilepsy.

Yawning induced by focal electrical stimulation in the human brain.

The primary function of yawning is not fully understood. We report a case in which electrical stimulation of the putamen in the human brain consistently elicited yawning. A 46-year-old woman with intractable epilepsy had invasive depth electrode monitoring and cortical stimulation mapping as part of her presurgical epilepsy evaluation. The first two contacts of a depth electrode that was intended to sample the left insula were in contact with the putamen. Stimulation of these contacts at 6mA and 8mA consistently elicited yawning on two separate days. Engagement in arithmetic and motor tasks during stimulation did not result in yawning. When considering the role of the putamen in motor control and its extensive connectivity to cortical and brainstem regions, our findings suggest that it plays a key role in the execution of motor movements necessitated by yawning. Furthermore, given the role of the anterior insula in attention and focused tasks, activation of this area while engaged in arithmetic and motor tasks could inhibit the putaminal processing necessary for yawning. Many have hypothesized the function of yawning; however, it remains debatable whether yawning serves a primarily physiological or communicative function or perhaps both.

Effects of low-frequency electrical stimulation of the anterior piriform cortex on kainate-induced seizures in rats.

OBJECTIVE: Recent evidence in animals and humans suggests that low-frequency stimulation (LFS) has significant antiepileptic properties. The anterior piriform cortex (APC) is a highly susceptible seizure-trigger zone and may be critical for the initiation and propagation of seizures originating from cortical and limbic foci. We used the kainic acid (KA) seizure model in rats to assess the therapeutic effect of LFS of the APC on seizures. METHODS: Adult male Sprague-Dawley rats were implanted with electrodes in the left APC and recording electrodes bilaterally in the hippocampal CA3 regions. Rats were monitored continuously with video-EEG after the emergence of spontaneous recurrent seizures that followed induction of status epilepticus by intraperitoneal KA. After two weeks of baseline recordings to determine seizure frequency, LFS of the APC was applied 60-min On 15-min Off, for two weeks with 1Hz biphasic square waves, 0.2ms pulse width, at 200µA. Another 2-week period of video-EEG monitoring was done after the cessation of LFS to study the carry-over effect. Changes in seizure frequency, severity, and duration between baseline, during LFS, and post-LFS were analyzed using the Poisson regression model. RESULTS: Overall seizure frequency decreased during the post-LFS period to 5% of that at baseline (p=0.003). Severe seizures (stages 4 and 5 on the Racine scale) decreased to 0% of the baseline during the post-LFS period. CONCLUSIONS: Two weeks of LFS of the APC reduced spontaneous seizure frequency and severity in the KA model with the effect outlasting the stimulation. Our findings suggest that the APC can be an important therapeutic target for stimulation in epilepsy.

Prevalence and Risk Factors for Early Seizure in Patients with Traumatic Brain Injury: Analysis from National Trauma Data Bank.

BACKGROUND: Traumatic brain injury (TBI) is a well-known risk factor for seizures. We aimed to identify the frequency and risk factors for seizure occurrence during hospitalization for TBI. METHODS: We used ICD-9-CM codes to identify patients 18 years of age or older from the National Trauma Data Bank who were admitted with TBI. We also used ICD-9-CM codes to identify the subset who had seizures during hospitalization. Patient demographics, comorbidities, Glasgow Coma Scale (GCS) score, Injury Severity Score Abbreviated Injury Scale (ISSAIS), in-hospital complications, and discharge disposition were compared in the seizure group (SG) and no-seizure group (NSG). RESULTS: A total of 1559 patients had in-hospital seizures, comprising 0.4% of all patients admitted with TBI. The mean age of SG was 3 years older than NSG [51 vs. 48; p < 0.0001]. African-American ethnicity (20 vs. 12%, p < 0.0001) and moderate TBI (8 vs. 4%, p < 0.0001) were more common in SG. History of alcohol dependence was more common in the SG (25 vs. 11%, p < 0.0001). Fall was the most common mechanism of injury in SG (56 vs. 36% in NSG; p < 0.0001). Subdural hematoma was more common in SG (31 vs. 21%, p < 0.0001). SG had higher rates of pneumonia, ARDS, acute kidney injury, and increased ICP. The average length of hospital stay was significantly higher in SG (10 vs. 6 days, p < 0.0001), and these patients had higher rate of discharge to nursing facility (32 vs. 25%, p < 0.0001). CONCLUSION: In-hospital seizures occur in 0.4% of all TBI patients. Although infrequent, seizure occurrence is associated with higher rates of hospital complications such as pneumonia and ARDS and is an independent predictor of longer hospital stay and worse hospital outcome.

Multiple hippocampal transections for intractable hippocampal epilepsy: Seizure outcome.

PURPOSE: The purpose of this study was to evaluate the seizure outcomes after transverse multiple hippocampal transections (MHTs) in 13 patients with intractable TLE. METHODS: Thirteen patients with normal memory scores, including 8 with nonlesional hippocampi on MRI, had temporal lobe epilepsy (TLE) necessitating depth electrode implantation. After confirming hippocampal seizure onset, they underwent MHT. Intraoperative monitoring was done with 5-6 hippocampal electrodes spaced at approximately 1-cm intervals and spike counting for 5-8min before each cut. The number of transections ranged between 4 and 7. Neuropsychological assessment was completed preoperatively and postoperatively for all patients and will be reported separately. RESULTS: Duration of epilepsy ranged between 5 and 55years. There were no complications. Intraoperatively, MHT resulted in marked spike reduction (p=0.003, paired t-test). Ten patients (77%) are seizure-free (average follow-up was 33months, range 20-65months) without medication changes. One of the 3 patients with persistent seizures had an MRI revealing incomplete transections, another had an additional neocortical seizure focus (as suggested by pure aphasic seizures), and the third had only 2 seizures in 4years, one of which occurred during antiseizure medication withdrawal. Verbal and visual memory outcomes will be reported separately. Right and left hippocampal volumes were not different preoperatively (n=12, p=0.64, Wilcoxon signed-rank test), but the transected hippocampal volume decreased postoperatively (p=0.0173). CONCLUSIONS: Multiple hippocampal transections provide an effective intervention and a safe alternative to temporal lobectomy in patients with hippocampal epilepsy.

Low-frequency electrical stimulation of a fiber tract in temporal lobe epilepsy.

OBJECTIVE: Surgical resection of the temporal lobe is an effective treatment for medically intractable temporal lobe epilepsy, but can cause memory impairment. Deep brain stimulation in epilepsy has targeted gray matter structures using high frequencies, but achieved limited success. We tested the hypothesis that low-frequency stimulation of the fornix reduces interictal epileptiform discharges and seizures in patients with intractable mesial temporal lobe epilepsy, without affecting memory. METHODS: We implanted depth electrodes in 11 patients for surgical evaluation of intractable epilepsy. Low-frequency stimulation of the fornix occurred in 4-hour sessions in the video-electroencephalography unit. Mental status assessment was performed at baseline and during stimulation. We studied the effect of stimulation on hippocampal spikes and seizures. RESULTS: There were no complications, and the patients were unaware of the stimulation. Fornix stimulation elicited evoked responses in the hippocampus and the posterior cingulate gyrus. Hourly Mini-Mental Status Examination (MMSE) scores showed an increase during stimulation when compared to prestimulation MMSE, largely due to improvement in recall, possibly representing a practice effect. Hippocampal spikes were significantly reduced during and outlasting each stimulation session. Seizure odds (n = 7) were reduced by 92% in the 2 days that followed stimulation. INTERPRETATION: Low-frequency stimulation of the fornix activates the hippocampus and other areas of the declarative memory circuit. The results of this preliminary study suggest that low-frequency stimulation is tolerable and reduces epileptiform discharges and seizures in patients with intractable mesial temporal lobe epilepsy. A controlled clinical trial may be warranted.

Role of ictal baseline shifts and ictal high-frequency oscillations in stereo-electroencephalography analysis of mesial temporal lobe seizures.

OBJECTIVE: To assess the role of ictal baseline shifts (IBS) and ictal high-frequency oscillations (iHFOs) in intracranial electroencephalography (EEG) presurgical evaluation by analysis of the spatial and temporal relationship of IBS, iHFOs with ictal conventional stereo-electroencephalography (icEEG) in mesial temporal lobe seizures (MTLS). METHODS: We studied 15 adult patients with medically refractory MTLS who underwent monitoring with depth electrodes. Seventy-five ictal EEG recordings at 1,000 Hz sampling rate were studied. Visual comparison of icEEG, IBS, and iHFOs were performed using Nihon-Kohden Neurofax systems (acquisition range 0.016-300 Hz). Each recorded ictal EEG was analyzed with settings appropriate for displaying icEEG, IBS, and iHFOs. RESULTS: IBS and iHFOs were observed in all patients and in 91% and 81% of intracranial seizures, respectively. IBS occurred before (22%), at (57%), or after (21%) icEEG onset. In contrast, iHFOs occurred at (30%) or after (70%) icEEG onset. The onset of iHFOs was 11.5 s later than IBS onset (p < 0.0001). All of the earliest onset of IBS and 70% of the onset of iHFOs overlapped with the ictal onset zone (IOZ). Compared with iHFOs, interictal HFOs (itHFOs) were less correlated with IOZ. In contrast to icEEG, IBS and iHFOs had smaller spatial distributions in 70% and 100% of the seizures, respectively. An IBS dipole was observed in 66% of the seizures. Eighty-seven percent of the dipoles had a negative pole at the anterior/medial part of amygdala/hippocampus complex (A-H complex) and a positive pole at the posterior/lateral part of the A-H complex. SIGNIFICANCE: The results suggest that evaluation of IBS and iHFOs, in addition to routine icEEG, helps in more accurately defining the IOZ. This study also shows that the onset and the spatial distribution of icEEG, IBS, and iHFOs do not overlap, suggesting that they reflect different cellular or network dynamics.

Electrical stimulation of a small brain area reversibly disrupts consciousness.

The neural mechanisms that underlie consciousness are not fully understood. We describe a region in the human brain where electrical stimulation reproducibly disrupted consciousness. A 54-year-old woman with intractable epilepsy underwent depth electrode implantation and electrical stimulation mapping. The electrode whose stimulation disrupted consciousness was between the left claustrum and anterior-dorsal insula. Stimulation of electrodes within 5mm did not affect consciousness. We studied the interdependencies among depth recording signals as a function of time by nonlinear regression analysis (h(2) coefficient) during stimulations that altered consciousness and stimulations of the same electrode at lower current intensities that were asymptomatic. Stimulation of the claustral electrode reproducibly resulted in a complete arrest of volitional behavior, unresponsiveness, and amnesia without negative motor symptoms or mere aphasia. The disruption of consciousness did not outlast the stimulation and occurred without any epileptiform discharges. We found a significant increase in correlation for interactions affecting medial parietal and posterior frontal channels during stimulations that disrupted consciousness compared with those that did not. Our findings suggest that the left claustrum/anterior insula is an important part of a network that subserves consciousness and that disruption of consciousness is related to increased EEG signal synchrony within frontal-parietal networks.

Lacosamide-induced rash.

Cutaneous eruptions and hypersensitivity represent frequently reported side effects of anti-seizure medications. However, these side-effects have rarely been previously reported for lacosamide, a newer-generation anti-seizure medication with a novel mechanism of action. Here, we report a case of diffuse skin eruption in a patient with history of epilepsy soon after initiation of lacosamide. The rash resolved after discontinuation of lacosamide and use of antihistamines and steroids. We also review the information on drug hypersensitivity syndrome.

Connectivity between perisylvian and bilateral basal temporal cortices.

Language processing requires the orchestrated action of different neuronal populations, and some studies suggest that the role of the basal temporal (BT) cortex in language processing is bilaterally distributed. Our aim was to demonstrate connectivity between perisylvian cortex and both BT areas. We recorded corticocortical evoked potentials (CCEPs) in 8 patients with subdural electrodes implanted for surgical evaluation of intractable epilepsy. Four patients had subdural grids over dominant perisylvian and BT areas, and 4 had electrode strips over both BT areas and left posterior superior temporal gyrus (LPSTG). After electrocortical mapping, patients with grids had 1-Hz stimulation of language areas. Patients with strips did not undergo mapping but had 1-Hz stimulation of the LPSTG. Posterior language area stimulation elicited CCEPs in ipsilateral BT cortex in 3/4 patients with left hemispheric grids. CCEPs were recorded in bilateral BT cortices in 3/4 patients with strips upon stimulation of the LPSTG, and in the LPSTG in the fourth patient upon stimulation of either BT area. This is the first in vivo demonstration of connectivity between LPSTG and both BT cortices. The role of BT cortex in language processing may be bilaterally distributed and related to linking visual information with phonological representations stored in the LPSTG.

Accuracy of frame-based stereotactic depth electrode implantation during craniotomy for subdural grid placement.

BACKGROUND: Frame-based stereotaxy and open craniotomy may seem mutually exclusive, but invasive electrophysiological monitoring can require broad sampling of the cortex and precise targeting of deeper structures. OBJECTIVES: The purpose of this study is to describe simultaneous frame-based insertion of depth electrodes and craniotomy for placement of subdural grids through a single surgical field and to determine the accuracy of depth electrodes placed using this technique. METHODS: A total of 6 patients with intractable epilepsy underwent placement of a stereotactic frame with the center of the planned cranial flap equidistant from the fixation posts. After volumetric imaging, craniotomy for placement of subdural grids was performed. Depth electrodes were placed using frame-based stereotaxy. Postoperative CT determined the accuracy of electrode placement. RESULTS: A total of 31 depth electrodes were placed. Mean distance of distal electrode contact from the target was 1.0 ± 0.15 mm. Error was correlated to distance to target, with an additional 0.35 mm error for each centimeter (r = 0.635, p < 0.001); when corrected, there was no difference in accuracy based on target structure or method of placement (prior to craniotomy vs. through grid, p = 0.23). CONCLUSION: The described technique for craniotomy through a stereotactic frame allows placement of subdural grids and depth electrodes without sacrificing the accuracy of a frame or requiring staged procedures.

Deep Brain Stimulation of the Centromedian Nucleus of the Thalamus for Lennox-Gastaut Syndrome: A Systematic Review and Individual Patient Data Analysis.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a severe childhood-onset pharmacoresistant epilepsy. Deep brain stimulation (DBS) of the centromedian nucleus of the thalamus (CMN) has been utilized. OBJECTIVE: To conduct a systematic review and individual patient data (IPD) analysis to characterize outcomes of DBS of CMN in LGS. METHODS: PubMed, Embase, and Scopus were searched per Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Articles were screened by title/abstract then full text. Included articles were reviewed for bibliographic, demographic, and outcome data. IPD were extracted from studies providing IPD for all patients. RESULTS: Of 72 resultant articles, 10 studies (114 patients) were included. Six of 7 studies reporting the outcome of ≥50% seizure reduction indicated that ≥50% of patients achieved this, with improved functional ability. Seizure freedom rate was generally <10%. Six studies with 47 patients provided IPD. The mean ages at epilepsy onset and CMN DBS were 3.9 ± 4.5 years and 17.4 ± 8.8 years, respectively. Nineteen of 41 (46.3%) patients had positive MRI findings. Seizure types included atypical absence in 39 (83.0%) patients, generalized tonic-clonic in 32 (68.1%), tonic in 22 (46.8%), and atonic in 20 (42.6%). Thirty-eight (80.9%) patients experienced ≥50% reduction in seizure frequency, and only 3 (6.4%) experienced seizure freedom. The mean seizure reduction was 62.9% ± 31.2% overall. Quality of life improved in 30/34 (88.2%) and was unchanged in the remainder (11.8%). The complication rate was 2/41 (4.9%). The mean length of follow-up was 19.8 ± 26.1 months (IQR: 4-18 months). CONCLUSION: Limited data indicate that DBS of the CMN may be effective and safe for people with LGS.

Functional anomaly mapping lateralizes temporal lobe epilepsy with high accuracy in individual patients.

Mesial temporal lobe epilepsy (mTLE) is associated with variable dysfunction beyond the temporal lobe. We used functional anomaly mapping (FAM), a multivariate machine learning approach to resting state fMRI analysis to measure subcortical and cortical functional aberrations in patients with mTLE. We also examined the value of individual FAM in lateralizing the hemisphere of seizure onset in mTLE patients. Methods: Patients and controls were selected from an existing imaging and clinical database. After standard preprocessing of resting state fMRI, time-series were extracted from 400 cortical and 32 subcortical regions of interest (ROIs) defined by atlases derived from functional brain organization. Group-level aberrations were measured by contrasting right (RTLE) and left (LTLE) patient groups to controls in a support vector regression models, and tested for statistical reliability using permutation analysis. Individualized functional anomaly maps (FAMs) were generated by contrasting individual patients to the control group. Half of patients were used for training a classification model, and the other half for estimating the accuracy to lateralize mTLE based on individual FAMs. Results: Thirty-two right and 14 left mTLE patients (33 with evidence of hippocampal sclerosis on MRI) and 94 controls were included. At group levels, cortical regions affiliated with limbic and somatomotor networks were prominent in distinguishing RTLE and LTLE from controls. At individual levels, most TLE patients had high anomaly in bilateral mesial temporal and medial parietooccipital default mode regions. A linear support vector machine trained on 50% of patients could accurately lateralize mTLE in remaining patients (median AUC =1.0 [range 0.97-1.0], median accuracy = 96.87% [85.71-100Significance: Functional anomaly mapping confirms widespread aberrations in function, and accurately lateralizes mTLE from resting state fMRI. Future studies will evaluate FAM as a non-invasive localization method in larger datasets, and explore possible correlations with clinical characteristics and disease course.

Towards optimizing single pulse electrical stimulation: High current intensity, short pulse width stimulation most effectively elicits evoked potentials.

BACKGROUND: While single pulse electrical stimulation (SPES) is increasingly used to study effective connectivity, the effects of varying stimulation parameters on the resulting cortico-cortical evoked potentials (CCEPs) have not been systematically explored. OBJECTIVE: We sought to understand the interacting effects of stimulation pulse width, current intensity, and charge on CCEPs through an extensive testing of this parameter space and analysis of several response metrics. METHODS: We conducted SPES in 11 patients undergoing intracranial EEG monitoring using five combinations of current intensity (1.5, 2.0, 3.0, 5.0, and 7.5 mA) and pulse width at each of three charges (0.750, 1.125, and 1.500 µC/phase) to study how CCEP amplitude, distribution, latency, morphology, and stimulus artifact amplitude vary with each parameter. RESULTS: Stimulations with a greater charge or a greater current intensity and shorter pulse width at a given charge generally resulted in greater CCEP amplitudes and spatial distributions, shorter latencies, and increased waveform correlation. These effects interacted such that stimulations with the lowest charge and highest current intensities resulted in greater response amplitudes and spatial distributions than stimulations with the highest charge and lowest current intensities. Stimulus artifact amplitude increased with charge, but this could be mitigated by using shorter pulse widths. CONCLUSIONS: Our results indicate that individual combinations of current intensity and pulse width, in addition to charge, are important determinants of CCEP magnitude, morphology, and spatial extent. Together, these findings suggest that high current intensity, short pulse width stimulations are optimal SPES settings for eliciting strong and consistent responses while minimizing charge.

Can semiology predict psychogenic nonepileptic seizures? A prospective study.

OBJECTIVE: Reducing health and economic burdens from diagnostic delay of psychogenic nonepileptic seizures (PNES) requires prompt referral for video electroencephalography (VEEG) monitoring, the diagnostic gold standard. Practitioners make VEEG referrals when semiology suggests PNES, although few semiological signs are supported by well-designed studies, and most VEEG studies neglect to concurrently measure how accurately seizure witnesses can ascertain semiology. In this study, we estimate the value of eyewitness-reported and video-documented semiology for predicting PNES, and we measure accuracy of eyewitness reports. METHODS: We prospectively interviewed eyewitnesses of seizures in patients referred for VEEG monitoring, to inquire about 48 putative PNES and ES signs. Multiple, EEG-blinded, epileptologists independently evaluated seizure videos and documented the presence/absence of signs. We used generalized estimating equations to identify reliable video-documented PNES and ES signs, and we compared eyewitness reports with video findings to assess how accurately signs are reported. We used logistic regression to determine whether eyewitness reports could predict VEEG-ascertained seizure type. RESULTS: We analyzed 120 seizures (36 PNES, 84 ES) from 35 consecutive subjects. Of 45 video-documented signs, only 3 PNES signs ("preserved awareness," "eye flutter," and "bystanders can intensify or alleviate") and 3 ES signs ("abrupt onset," "eye-opening/widening," and postictal "confusion/sleep") were significant and reliable indicators of seizure type. Eyewitness reports of these 6 signs were inaccurate and not statistically different from guessing. Consequentially, eyewitness reports of signs did not predict VEEG-ascertained diagnosis. We validated our findings in a second, prospective cohort of 36 consecutive subjects. INTERPRETATION: We identified 6 semiological signs that reliably distinguish PNES and ES, and found that eyewitness reports of these signs are unreliable. We offer suggestions to improve the accuracy of eyewitness reports.