Processing of auditory feedback in perisylvian and insular cortex.

When we speak, we not only make movements with our mouth, lips, and tongue, but we also hear the sound of our own voice. Thus, speech production in the brain involves not only controlling the movements we make, but also auditory and sensory feedback. Auditory responses are typically suppressed during speech production compared to perception, but how this manifests across space and time is unclear. Here we recorded intracranial EEG in seventeen pediatric, adolescent, and adult patients with medication-resistant epilepsy who performed a reading/listening task to investigate how other auditory responses are modulated during speech production. We identified onset and sustained responses to speech in bilateral auditory cortex, with a selective suppression of onset responses during speech production. Onset responses provide a temporal landmark during speech perception that is redundant with forward prediction during speech production. Phonological feature tuning in these "onset suppression" electrodes remained stable between perception and production. Notably, the posterior insula responded at sentence onset for both perception and production, suggesting a role in multisensory integration during feedback control.

Phase coding of spatial representations in the human entorhinal cortex.

The grid-like activity pattern of cells in the mammalian entorhinal cortex provides an internal reference frame for allocentric self-localization. The same neurons maintain robust phase couplings with local field oscillations. We found that neurons of the human entorhinal cortex display consistent spatial and temporal phase locking between spikes and slow gamma band local field potentials (LFPs) during virtual navigation. The phase locking maintained an environment-specific map over time. The phase tuning of spikes to the slow gamma band LFP revealed spatially periodic phase grids with environment-dependent scaling and consistent alignment with the environment. Using a Bayesian decoding model, we could predict the avatar's position with near perfect accuracy and, to a lesser extent, that of heading direction as well. These results imply that the phase of spikes relative to spatially modulated gamma oscillations encode allocentric spatial positions. We posit that a joint spatiotemporal phase code can implement the combined neural representation of space and time in the human entorhinal cortex.

Context-dependent spatially periodic activity in the human entorhinal cortex.

The spatially periodic activity of grid cells in the entorhinal cortex (EC) of the rodent, primate, and human provides a coordinate system that, together with the hippocampus, informs an individual of its location relative to the environment and encodes the memory of that location. Among the most defining features of grid-cell activity are the 60° rotational symmetry of grids and preservation of grid scale across environments. Grid cells, however, do display a limited degree of adaptation to environments. It remains unclear if this level of environment invariance generalizes to human grid-cell analogs, where the relative contribution of visual input to the multimodal sensory input of the EC is significantly larger than in rodents. Patients diagnosed with nontractable epilepsy who were implanted with entorhinal cortical electrodes performing virtual navigation tasks to memorized locations enabled us to investigate associations between grid-like patterns and environment. Here, we report that the activity of human entorhinal cortical neurons exhibits adaptive scaling in grid period, grid orientation, and rotational symmetry in close association with changes in environment size, shape, and visual cues, suggesting scale invariance of the frequency, rather than the wavelength, of spatially periodic activity. Our results demonstrate that neurons in the human EC represent space with an enhanced flexibility relative to neurons in rodents because they are endowed with adaptive scalability and context dependency.

Predictors of Postoperative Seizure Recurrence: A Longitudinal Study of Temporal and Extratemporal Resections.

Objective. We investigated the longitudinal outcome of resective epilepsy surgery to identify the predictors of seizure recurrence. Materials and Methods. We retrospectively analyzed patients who underwent resections for intractable epilepsy over a period of 7 years. Multiple variables were investigated as potential predictors of seizure recurrence. The time to first postoperative seizure was evaluated using survival analysis and univariate analysis at annual intervals. Results. Among 70 patients, 54 (77%) had temporal and 16 (23%) had extratemporal resections. At last follow-up (mean 48 months; range 24-87 months), the outcome was Engel class I in 84% (n = 59) of patients. Seizure recurrence followed two patterns: recurrence was "early" (within 2 years) in 82% of patients, of whom 83% continued to have seizures despite optimum medical therapy; recurrence was "late" (after 2 years) in 18%, of whom 25% continued to have seizures subsequently. Among the variables of interest, only resection site and ictal EEG remained as independent predictors of seizure recurrence over the long term (p < 0.05). Extratemporal resection and discordance between ictal EEG and resection area were associated with 4.2-fold and 5.6-fold higher risk of seizure recurrence, respectively. Conclusions. Extratemporal epilepsy and uncertainty in ictal EEG localization are independent predictors of unfavorable outcome. Seizure recurrence within two years of surgery indicates poor long-term outcome.

Temporal lobe volume predicts Wada memory test performance in patients with mesial temporal sclerosis.

The Wada test is widely used in the presurgical evaluation of potential temporal lobectomy patients to predict postoperative memory function. Expected asymmetry (EA), defined as Wada memory lateralized to the nonsurgical hemisphere, or a higher score after injection of the surgical hemisphere would be considered favorable in terms of postoperative memory outcome. However, in some cases, nonlateralized memory (NM) results, with no appreciable asymmetry, may occur because of impaired scores after both injections, often leading to denial of surgery. The reason for such nonlateralized Wada memory in patients with intractable temporal lobe epilepsy (TLE) remains unclear. Given that quantitative morphometric magnetic resonance imaging studies in TLE patients have shown bilateral regional atrophy in temporal and extratemporal structures, we hypothesized that the volume loss in contralateral temporal structures could contribute to nonlateralized Wada memory performance. To investigate this, we examined the relationship between the volume changes of temporal structures and Wada memory scores in patients with intractable TLE with mesial temporal sclerosis (MTS) using an age- and gender-matched control group. Memory was considered nonlateralized if the absolute difference in the total correct recall scores between ipsilateral and contralateral injections was <11%. Among 21 patients, Wada memory was lateralized in 15 and nonlateralized in 6 patients, with all the nonlateralized scores being observed in left TLE. The recall scores after ipsilateral injection were significantly lower in patients with an NM profile than an EA profile (23 ± 14% vs. 59 ± 18% correct recall, p ≤ 0.001). However, the recall scores after contralateral injection were low but similar between the two groups (25 ± 17% vs. 25 ± 15% correct recall, p=0.97). Compared to controls, all the patients showed greater volume loss in the temporal regions. However, patients with a NM profile showed significantly more volume loss than those with a lateralized memory profile in both contralateral and ipsilateral temporal regions (p<0.05). Left hemispheric Wada memory performance correlated positively with the size of the left mesial and neocortical temporal structures (r=0.49-0.63, p=0.005-0.04). Our study suggests that volume loss in the nonsurgical temporal structures is associated with nonlateralized Wada memory results in patients with intractable TLE.

Effectiveness of multimodality treatment for autoimmune limbic epilepsy.

We evaluated the outcome of multimodality treatment in autoimmune limbic epilepsy in 3 consecutive patients (2 male and 1 female; age 33-55 years) presenting with a combination of focal non-convulsive status epilepticus, memory impairment, and psychosis. MRI showed right or bitemporal T2 or FLAIR hyperintensity. Video-EEG showed seizures of right temporo-occipital or bitemporal independent onset. Extensive workup failed to reveal infectious aetiology or an underlying tumour. However, the autoantibody panel was positive for one or more of these antibodies: anti-VGKC, anti-GABAB, anti-VGCC (P/Q, N types), and anti-GAD65. All patients received: (1) conventional antiepileptic drugs including levetiracetam, lacosamide, phenobarbital, lamotrigine, and valproate; (2) immunomodulatory therapy including methylprednisolone, plasmapheresis, and intravenous immunoglobulin; and (3) rituximab. After a 4-6-week in-hospital course, the seizures resolved in all patients but 2 had persistent memory impairment. None had treatment-related complications. At the time of last follow-up, 2-3 months later, 2 patients remained seizure-free while 2 had residual memory impairment. Our findings suggest that multimodality treatment with a combination of conventional AEDs, immunomodulatory therapy, and rituximab is effective and safe in autoimmune limbic epilepsy.

High frequency oscillations and infraslow activity in epilepsy.

In pre-surgical evaluation of epilepsy, there has been an increased interest in the study of electroencephalogram (EEG) activity outside the 1-70 Hz band of conventional frequency activity (CFA). Research over the last couple of decades has shown that EEG activity in the 70-600 Hz range, termed high frequency oscillations (HFOs), can be recorded intracranially from all brain regions both interictally and at seizure onset. In patients with epilepsy, HFOs are now considered as pathologic regardless of their frequency band although it may be difficult to distinguish them from the physiologic HFOs, which occur in a similar frequency range. Interictal HFOs are likely to be confined mostly to the seizure onset zone, thus providing a new measure for localizing it. More importantly, several studies have linked HFOs to underlying epileptogenicity, suggesting that HFOs can serve as potential biomarkers for the illness. Along with HFOs, analysis of ictal baseline shifts (IBS; or direct current shifts) and infraslow activity (ISA) (ISA: <0.1 Hz) has also attracted attention. Studies have shown that: IBSs can be recorded using the routine AC amplifiers with long time constants; IBSs occur at the time of conventional EEG onset, but in a restricted spatial distribution compared with conventional frequencies; and inclusion of IBS contacts in the resection can be associated with favorable seizure outcome. Only a handful of studies have evaluated all the EEG frequencies together in the same patient group. The latter studies suggest that the seizure onset is best localized by the ictal HFOs, the IBSs tend to provide a broader localization and the conventional frequencies could be non-localizing. However, small number of patients included in these studies precludes definitive conclusions regarding post-operative seizure outcome based on selective or combined resection of HFO, IBS and CFA contacts. Large, preferably prospective, studies are needed to further evaluate the implications of different EEG frequencies in epilepsy.

Seizure localization using broadband EEG: comparison of conventional frequency activity, high-frequency oscillations, and infraslow activity.

In neocortical epilepsy, we showed that the seizure onset defined by ictal high-frequency oscillations (HFO: ≥ 70 Hz) with subsequent evolution into slower frequency activity (i.e., HFOs+) was smaller in spatial distribution than that defined by conventional frequency activity (1-70 Hz), and that resection of HFO+ areas resulted in favorable seizure outcome. This study further investigates ictal broadband EEG in the same cohort of patients by examining the infraslow activity, including ictal baseline ("direct current") shifts (IBS) and peri-ictal infraslow activity (0.02 to 0.2 Hz). The seizure onset zone had been defined and resected based on HFO+ by a prospectively defined protocol. We reviewed 11 representative seizures from 6 patients by visual and spectral analyses using appropriate filters and timescales. The HFO seizure onset, in the high gamma or ripple frequency, preceded or followed the IBS closely (<300 ms). The IBS were negative or positive, ∼1 mV in amplitude and 2 to 3 seconds long. Although the HFO+ were always ipsilateral to the surgical hemisphere, the IBS could be ipsilateral or contralateral. Compared with conventional frequency activity, the HFO+ and IBS were significantly smaller in spatial distribution and likely to be concordant. The peri-ictal infraslow activity consisted of distinct periodic or rhythmic (0.12 to 0.16 Hz) patterns, poorly concordant with IBS or HFO+. Although not statistically significant, better seizure outcome tended to correlate with smaller seizure onset zones and more complete resection of the HFO+ and IBS contacts. We conclude that IBS, like HFO+, define a smaller seizure onset zone and probably a more accurate epileptogenic zone in neocortical epilepsy.

Ictal high-frequency oscillations in neocortical epilepsy: implications for seizure localization and surgical resection.

PURPOSE: To investigate the characteristics of intracranial ictal high-frequency oscillations (HFOs). METHODS: Among neocortical epilepsy patients who underwent intracranial monitoring and surgery, we studied patients with well-defined, unifocal seizure onsets characterized by discrete HFOs (≥70 Hz). Patients with multifocal or bilateral independent seizure onsets, electroencephalography (EEG) acquired at <1,000 Hz sampling rate, and nonresective surgery were excluded. Based on a prospectively defined protocol, we defined the seizure-onset zone (SOZ) presurgically to include only those channels with HFOs that showed subsequent sustained evolution (HFOs+ channels) but not the channels that lacked evolution (HFOs- channels). We then resected the SOZ as defined above, 1 cm of the surrounding cortex, and immediate spread area, modified by the presence of eloquent cortex in the vicinity. For purposes of this study, we also defined the SOZ based on the conventional frequency activity (CFA, <70 Hz) at seizure onset, although that information was not considered for preoperative determination of the surgical boundary. We investigated the temporal and spatial characteristics of the ictal HFOs post hoc by visual and spectral methods, and also compared them to the seizure onset defined by the CFA. KEY FINDINGS: Of 14 consecutive neocortical epilepsy patients, six patients met the inclusion criteria. Magnetic resonance imaging (MRI) was normal or showed heterotopia. All had subdural electrodes, with additional intracerebral depth electrodes in some. Electrode coverage was extensive (median 94 channels), including limited contralateral coverage. Seizure onsets were lobar or multilobar. Resections were performed per protocol, except in two patients where complete resection of the SOZ could not be done due to overlap with speech area. Histology was abnormal in all patients. Postoperative outcome was class I/II (n = 5, 83%) or class III over a mean follow-up of 27 months. Post hoc analysis of 15 representative seizures showed that the ictal HFOs were widespread at seizure onset but evolved subsequently with different characteristics. In contrast to HFOs-, the HFOs+ were significantly higher in peak frequency (97.1 vs. 89.1 Hz, p = 0.001), more robust (nearly twofold higher peak power, p < 0.0001), and spatially restricted [mean 12.2 vs. 22.4 channels; odds ratio (OR) 0.51, 95% confidence interval (CI) 0.42-0.62; p < 0.0001]. The seizure onset defined by HFOs+ was earlier (by an average of 0.41 s), and occurred in a significantly different and smaller distribution (OR 0.27, 95% CI 0.21-0.34, p < 0.0001), than the seizure onset defined by the CFA. As intended, the HFOs+ channels were 10 times more likely to have been resected than the HFOs- channels (OR 9.7, 95% CI 5-17, p < 0.0001). SIGNIFICANCE: Our study demonstrates the widespread occurrence of ictal HFOs at seizure onset, outlines a practical method to localize the SOZ based on their restricted pattern of evolution, and highlights the differences between the SOZs defined by HFOs and CFA. We show that smaller resections, restricted mainly to the HFOs channels with evolution, can lead to favorable seizure outcome. Our findings support the notion of widespread epileptic networks underlying neocortical epilepsy.

Sequential intrarectal diazepam and intravenous levetiracetam in treating acute repetitive and prolonged seizures.

In this retrospective study of institutionalized patients with mental retardation, we present the efficacy and safety of sequential treatment with intrarectal diazepam (IRD) gel (Diastat) and intravenous levetiracetam (IVL) in comparison with either treatment alone for acute repetitive or prolonged seizures (ARPS). We defined ARPS as >or=3 seizures of any type within 1 h or a single seizure of any type lasting >or=3 min. Eighty-eight ARPS episodes were treated in 25 patients (14 female, age 21-72 years), with mainly symptomatic generalized epilepsy. There were no adverse events directly attributable to the administration of IRD or IVL. Seizure recurrence within 4 h of treatment, the primary outcome measure, was significantly lower after combined sequential IRD + IVL treatment (3 of 36) compared to IRD alone (6 of 24, p = 0.048) or IVL alone (10 of 28, p = 0.039). There was no statistically significant difference between the individual IRD and IVL treatments (p = 0.604). The estimated odds ratio (OR) indicated that the risk of seizure recurrence was higher after IRD or IVL monotherapy compared to combined IRD + IVL treatment. Subsequent emergency room (ER) transfers following seizure recurrence were least likely after IVL treatment (10%) compared to combined IRD + IVL (67%) or IRD (83%) treatment. These findings suggest that although IRD or IVL monotherapy is efficacious, the combination is superior in controlling ARPS in this special group of institutionalized patients. In addition, we speculate that a more reliable onset of action after IVL treatment results in rapid seizure control and fewer ER transfers, despite seizure recurrence.

Adjunctive pregabalin therapy in mentally retarded, developmentally delayed patients with epilepsy.

This retrospective study evaluated the efficacy and tolerability of adjunctive pregabalin (PGB) therapy in mentally retarded, developmentally delayed patients. The primary efficacy measure was the change in the median frequency of seizure days per week between the baseline (8 weeks prior to initiating PGB) and treatment (12 weeks of titration and maintenance) periods. Inclusion criteria were: documented epilepsy treated with antiepileptic drug, at least one seizure during the baseline period, and lack of prior exposure to PGB. Seven patients (four female, three male, mean age=43) with multiple seizure types (generalized tonic-clonic, tonic, partial, and atypical absence) met the inclusion criteria. The mean dose of PGB was 293 mg/day (range=150-350 mg/day). PGB was efficacious, resulting in a significant reduction in the median frequency of seizure days/week between baseline and treatment (1.38 vs 0.50, P=0.018). The 50% responder rate was 71%. The adverse effects at last follow-up (mean 13 months) included weight gain, myoclonus, and sedation.

Diagnostic yield of sequential routine EEG and extended outpatient video-EEG monitoring.

OBJECTIVE: To investigate the diagnostic yield of outpatient video-EEG monitoring (OVEM) in patients with suspected but unconfirmed epilepsy. METHODS: OVEM data, comprised of 20-min video-EEG (REEG) followed by 4h of video-EEG monitoring (EXM), from 179 consecutive patients were retrospectively analyzed. Three diagnostic categories were defined: localization-related epilepsy (LRE), generalized epilepsy (GE), and nonepileptic seizures (NES). Outcome measures were: frequency of events; diagnostic yield of entire OVEM; relative yields of REEG alone and EXM after nondiagnostic REEG; EXM diagnostic rate (yield of EXM after nondiagnostic REEG/yield of entire OVEM). RESULTS: Habitual events occurred in 14 (8%) and 25 (15%) patients during REEG and EXM, respectively. Overall, OVEM was diagnostic in 90/179 patients (50%): LRE 21%; GE 15%; NES 15%. REEG alone was diagnostic in 49/179 patients (27%): LRE 7%; GE 13%; NES 7%. After nondiagnostic REEG, the subsequent EXM was diagnostic in 41/130 patients (32%): LRE (n=24); GE (n=2); NES (n=15). The EXM diagnostic rate (95% confidence interval) was 0.65 (0.47-0.80) for LRE, 0.08 (0.01-0.25) for GE, and 0.56 (0.35-0.75) for NES. CONCLUSIONS: OVEM is useful in establishing and classifying epilepsy. Compared to REEG, EXM is relatively more beneficial in the diagnosis of LRE and NES rather than GE. SIGNIFICANCE: This study outlines the benefits of extended outpatient video-EEG monitoring after nondiagnostic routine EEG.

Intracarotid amobarbital procedure in post-temporal lobectomy patients.

We describe two patients who underwent intracarotid amobarbital procedure (IAP) postoperatively following temporal lobectomy (one right temporal and one left temporal lobectomy), prompted by consideration of reoperation for persistent, intractable seizures. IAP memory score, consisting of the percentage of correctly recognized dually encoded stimuli, was calculated for each hemisphere. Both patients performed well on the IAP baseline memory assessment prior to injections, and both were left hemisphere dominant for language. The IAP memory results were consistent with the postoperative neuropsychological memory evaluation in that the patient who had undergone nonlanguage-dominant temporal resection performed within normal limits, while the patient who had undergone language-dominant temporal resection performed poorly, although not completely amnestic, on memory testing. Injection of the nonsurgical, presumably healthy, hemisphere resulted in complete failure of memory in both patients, implying that baseline memory was dependent on the functional integrity of the nonsurgical hemisphere, inactivation of which led to complete memory disruption. Secondly, the hippocampus in the nonlanguage-dominant hemisphere was able to support memory to some extent, if not completely, when it functioned in isolation without the influence of the language-dominant hemisphere during the IAP. These findings are discussed in the context of functional reserve and adequacy models.