The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the transition to seizure is complex, potentially leading to imprecise delineation of ...epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing and others suggesting reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principle applies in limbic structures. We analysed simultaneous electrocorticography (ECoG) and neuronal recordings of 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, which at times co-existed within seizures. Overall, 156 single units were isolated, subclassified by cell-type and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (P < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition, with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (P = 0.014). This study provides evidence for entrained high-gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, reduced neuronal firing suggested preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or indicates a 'seizure-responsive' state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help to refine the surgical treatment of mesial temporal lobe epilepsy.
For patients with drug-resistant epilepsy, surgical intervention may be an effective treatment option if the epileptogenic zone (EZ) can be well localized. Subdural strip and grid electrode (SDE) ...implantations have long been used as the mainstay of intracranial seizure localization in the United States. Stereoelectroencephalography (SEEG) is an alternative approach in which depth electrodes are placed through percutaneous drill holes to stereotactically defined coordinates in the brain. Long used in certain centers in Europe, SEEG is gaining wider popularity in North America, bolstered by the advent of stereotactic robotic assistance and mounting evidence of safety, without the need for catheter-based angiography. Rates of clinically significant hemorrhage, infection, and other complications appear lower with SEEG than with SDE implants. SEEG also avoids unnecessary craniotomies when seizures are localized to unresectable eloquent cortex, found to be multifocal or nonfocal, or ultimately treated with stereotactic procedures such as laser interstitial thermal therapy (LITT), radiofrequency thermocoagulation (RF-TC), responsive neurostimulation (RNS), or deep brain stimulation (DBS). While SDE allows for excellent localization and functional mapping on the cortical surface, SEEG offers a less invasive option for sampling disparate brain areas, bilateral investigations, and deep or medial targets. SEEG has shown efficacy for seizure localization in the temporal lobe, the insula, lesional and nonlesional extra-temporal epilepsy, hypothalamic hamartomas, periventricular nodular heterotopias, and patients who have had prior craniotomies for resections or grids. SEEG offers a valuable opportunity for cognitive neurophysiology research and may have an important role in the study of dysfunctional networks in psychiatric disease and understanding the effects of neuromodulation.
Humans can easily focus on one speaker in a multi-talker acoustic environment, but how different areas of the human auditory cortex (AC) represent the acoustic components of mixed speech is unknown. ...We obtained invasive recordings from the primary and nonprimary AC in neurosurgical patients as they listened to multi-talker speech. We found that neural sites in the primary AC responded to individual speakers in the mixture and were relatively unchanged by attention. In contrast, neural sites in the nonprimary AC were less discerning of individual speakers but selectively represented the attended speaker. Moreover, the encoding of the attended speaker in the nonprimary AC was invariant to the degree of acoustic overlap with the unattended speaker. Finally, this emergent representation of attended speech in the nonprimary AC was linearly predictable from the primary AC responses. Our results reveal the neural computations underlying the hierarchical formation of auditory objects in human AC during multi-talker speech perception.
•Mixed speech is encoded differently in primary and nonprimary auditory cortex (AC)•Primary AC selectively represented individual speakers unchanged with attention•Nonprimary AC represented the attended speaker invariant to acoustic overlap•These results show the neural underpinnings of auditory object formation in AC
How different areas of the human auditory cortex (AC) represent mixed speech is unclear. O’Sullivan et al. obtained invasive recordings from subjects listening to multi-talker speech. They found that the primary AC represented the individual speakers and was unchanged by attention. In contrast, the nonprimary AC selectively represented the attended speaker, was invariant to the acoustic overlap with unattended speaker, and was linearly predictable from the primary AC. These results reveal the neural underpinnings of the hierarchical formation of auditory objects in human AC.
Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations ...of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.
The correlation of clinical semiology with neuronal firing in human seizures has not been well described. Similarly, the neuronal firing patterns underlying high-frequency oscillations during ...seizures remain controversial. Using implanted subdural electrodes and a microelectrode array in a patient with focal status epilepticus, in which 40 habitual focal motor seizures and 101 subclinical seizures were captured, the authors analyzed the association of EEG, high-frequency oscillations, and multiunit activity to facial motor semiology. The development of ictal high-frequency oscillations in subdural electrodes overlying face motor cortex was temporally associated with clonic facial movements. In representative seizures selected for multiunit analysis, synchronization of neuronal firing in the adjacent microelectrode array aligned with clinical onset and was greater in clinical seizures compared with subclinical seizures. This report demonstrates the electrophysiologic signatures of focal seizures at the level of neuronal firing, high-frequency oscillations, and EEG as they organize from microscale to macroscale, with clinical correlation.
Abstract
BACKGROUND
Accurate tissue sampling in nonenhancing (NE) gliomas is a unique surgical challenge due to their intratumoral histological heterogeneity and absence of contrast enhancement as a ...guide for intraoperative stereotactic guidance. Instead, T2/fluid-attenuated inversion-recovery (FLAIR) hyperintensity on MRI is commonly used as an imaging surrogate for pathological tissue, but sampling from this region can yield nondiagnostic or underdiagnostic brain tissue. Sodium fluorescein is an intraoperative fluorescent dye that has a high predictive value for tumor identification in areas of contrast enhancement and NE in glioblastomas. However, the underlying histopathological alterations in fluorescent regions of NE gliomas remain undefined.
OBJECTIVE
To evaluate whether fluorescein can identify diagnostic tissue and differentiate regions with higher malignant potential during surgery for NE gliomas, thus improving sampling accuracy.
METHODS
Thirteen patients who presented with NE, T2/FLAIR hyperintense lesions suspicious for glioma received fluorescein (10%, 3 mg/kg intravenously) during surgical resection.
RESULTS
Patchy fluorescence was identified within the T2/FLAIR hyperintense area in 10 of 13 (77%) patients. Samples taken from fluorescent regions were more likely to demonstrate diagnostic glioma tissue and cytologic atypia (P < .05). Fluorescein demonstrated a 95% positive predictive value for the presence of diagnostic tissue. Samples from areas of fluorescence also demonstrated greater total cell density and higher Ki-67 labeling than nonfluorescent biopsies (P < .05).
CONCLUSION
Fluorescence in NE gliomas is highly predictive of diagnostic tumor tissue and regions of higher cell density and proliferative activity.
To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.
Adults treated with brain-responsive ...neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.
Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (
< 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (
< 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (
< 0.05, 1-tailed χ
).
Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.
NCT00572195.
This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.
Abstract
BACKGROUND
Cytoreductive surgery is considered controversial for primary central nervous system lymphoma (PCNSL).
OBJECTIVE
To investigate survival following craniotomy or biopsy for PCNSL
...METHODS
The National Cancer Database-Participant User File (NCDB, n = 8936), Surveillance, Epidemiology, and End Results Program (SEER, n = 4636), and an institutional series (IS, n = 132) were used. We retrospectively investigated the relationship between craniotomy, prognostic factors, and survival for PCNSL using case–control design.
RESULTS
In NCDB, craniotomy was associated with increased median survival over biopsy (19.5 vs 11.0 mo), independent of subsequent radiation and chemotherapy (hazard ratio HR 0.80, P < .001). We found a similar trend with survival for craniotomy vs biopsy in the IS (HR 0.68, P = .15). In SEER, gross total resection was associated with increased median survival over biopsy (29 vs 10 mo, HR 0.68, P < .001). The survival benefit associated with craniotomy was greater within recursive partitioning analysis (RPA) class 1 group in NCDB (95.1 vs 29.1 mo, HR 0.66, P < .001), but was smaller for RPA 2-3 (14.9 vs 10.0 mo, HR 0.86, P < .001). A surgical risk category (RC) considering lesion location and number, age, and frailty was developed. Craniotomy was associated with increased survival vs biopsy for patients with low RC (133.4 vs 41.0 mo, HR 0.33, P = .01), but not high RC in the IS.
CONCLUSION
Craniotomy is associated with increased survival over biopsy for PCNSL in 3 retrospective datasets. Prospective studies are necessary to adequately evaluate this relationship. Such studies should evaluate patients most likely to benefit from cytoreductive surgery, ie, those with favorable RPA and RC.
Spike-sorting algorithms have been used to identify the firing patterns of isolated neurons ('single units') from implanted electrode recordings in patients undergoing assessment for epilepsy ...surgery, but we do not know their potential for providing helpful clinical information. It is important therefore to characterize both the stability of these recordings and also their context. A critical consideration is where the units are located with respect to the focus of the pathology. Recent analyses of neuronal spiking activity, recorded over extended spatial areas using microelectrode arrays, have demonstrated the importance of considering seizure activity in terms of two distinct spatial territories: the ictal core and penumbral territories. The pathological information in these two areas, however, is likely to be very different. We investigated, therefore, whether units could be followed reliably over prolonged periods of times in these two areas, including during seizure epochs. We isolated unit recordings from several hundred neurons from four patients undergoing video-telemetry monitoring for surgical evaluation of focal neocortical epilepsies. Unit stability could last in excess of 40 h, and across multiple seizures. A key finding was that in the penumbra, spike stereotypy was maintained even during the seizure. There was a net tendency towards increased penumbral firing during the seizure, although only a minority of units (10-20%) showed significant changes over the baseline period, and notably, these also included neurons showing significant reductions in firing. In contrast, within the ictal core territories, regions characterized by intense hypersynchronous multi-unit firing, our spike sorting algorithms failed as the units were incorporated into the seizure activity. No spike sorting was possible from that moment until the end of the seizure, but recovery of the spike shape was rapid following seizure termination: some units reappeared within tens of seconds of the end of the seizure, and over 80% reappeared within 3 min (τrecov = 104 ± 22 s). The recovery of the mean firing rate was close to pre-ictal levels also within this time frame, suggesting that the more protracted post-ictal state cannot be explained by persistent cellular neurophysiological dysfunction in either the penumbral or the core territories. These studies lay the foundation for future investigations of how these recordings may inform clinical practice.See Kimchi and Cash (doi:10.1093/awv264) for a scientific commentary on this article.
Objective
To describe the development of the Stereotactic Laser Ablation for Temporal Lobe Epilepsy study protocol in the context of current practice. An ideal treatment for drug‐resistant epilepsy ...remains an ongoing area of research. Although there are several options available, each has challenges that not only make deciding on the appropriate treatment not clear‐cut but also create difficulties in designing clinical studies to provide evidence in support of the treatment.
Methods
A prospective, single‐arm, multicenter study designed to evaluate safety and efficacy of the VisualaseTM MRI‐Guided Laser Ablation System for the treatment of temporal lobe epilepsy will include up to 150 patients with a primary efficacy endpoint of seizure freedom (defined as Engel Class I) for the first 12 months following the procedure and a primary safety endpoint of incidence of qualifying device‐, procedure‐, or anesthesia‐related adverse events through 12 months following the procedure.
Results
Primary endpoints will be assessed against historical values of safety and efficacy of anterior temporal lobectomy.
Significance
The scientific and payor communities typically demand randomized controlled trials (RCTs) as definitive evidence for safety and efficacy claims. However, in circumstances where the medical device has already been cleared by regulatory authorities and is readily available in the market, an RCT may not be feasible to execute. It is therefore crucial to gain acceptance by both the scientific community and regulators to design a study that will satisfy all concerned.
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