Recurrent Hippocampo-neocortical sleep-state divergence in humans.

Sleep is assumed to be a unitary, global state in humans and most other animals that is coordinated by executive centers in the brain stem, hypothalamus, and basal forebrain. However, the common observation of unihemispheric sleep in birds and marine mammals, as well as the recently discovered nonpathological regional sleep in rodents, calls into question whether the whole human brain might also typically exhibit different states between brain areas at the same time. We analyzed sleep states independently from simultaneously recorded hippocampal depth electrodes and cortical scalp electrodes in eight human subjects who were implanted with depth electrodes for pharmacologically intractable epilepsy evaluation. We found that the neocortex and hippocampus could be in nonsimultaneous states, on average, one-third of the night and that the hippocampus often led in asynchronous state transitions. Nonsimultaneous bout lengths varied from 30 s to over 30 min. These results call into question the conclusions of studies, across phylogeny, that measure only surface cortical state but seek to assess the functions and drivers of sleep states throughout the brain.

Changes in interhemispheric coherence after total corpus callosotomy: a scalp EEG study in children with non-lesional generalized epilepsy.

PURPOSE: Coherence analysis in electroencephalography (EEG) allows measurement of the degree of consistency of amplitude between pairs of electrodes. Theoretically, disconnective epilepsy surgery should decrease coherence between corresponding areas. The study aimed to evaluate postoperative changes in interhemispheric coherence values after corpus callosotomy (CC). METHODS: Non-lesional, drug-resistant, generalized epilepsy patients who underwent total CC were retrospectively collected. To evaluate coherence, we divided the scalp interictal EEG into "baseline" and "discharge" states after excluding periods with artifacts. Interhemispheric coherence values were obtained between eight pairs of symmetrically opposite scalp electrodes in six different frequency bands. We analyzed both pre- and postoperative EEG sessions and calculated the percentage of difference (POD) in coherence values. RESULTS: We collected 13 patients and analyzed 2496 interhemispheric coherence values. Preoperative coherence values differed significantly between baseline and discharge states (p = 0.0003), but postoperative values did not (p = 0.11). For baseline state, coherence values were decreased after CC and median POD was - 22.3% (p < 0.0001). Delta frequency showed the most decreased POD (-44.3%, p = 0.0009). Median POD was lowest in the Fp1-Fp2 pair of electrodes. For discharge state, coherence values were decreased after CC and median POD was - 24.7% (p < 0.0001). Delta frequency again showed the most decreased POD (-55.9%, p = 0.0016). Median POD was lowest in the F7-F8 pair. CONCLUSION: After total CC, interhemispheric coherence decreased significantly in both baseline and discharge states. The most decreased frequency band was the delta band, which may be used as a representative frequency band in future studies.

Interictal and seizure-onset EEG patterns in malformations of cortical development: A systematic review.

OBJECTIVES: Malformations of cortical development (MCDs) are common causes of drug-resistant epilepsy. The mechanisms underlying the associated epileptogenesis and ictogenesis remain poorly elucidated. EEG can help in understanding these mechanisms. We systematically reviewed studies reporting scalp or intracranial EEG features of MCDs to characterise interictal and seizure-onset EEG patterns across different MCD types. METHODS: We conducted a systematic review in accordance with PRISMA guidelines. MEDLINE, PubMed, and Cochrane databases were searched for studies describing interictal and seizure-onset EEG patterns in MCD patients. A classification framework was implemented to group EEG features into 20 predefined patterns, comprising nine interictal (five, scalp EEG; four, intracranial EEG) and 11 seizure-onset (five, scalp EEG; six, intracranial EEG) patterns. Logistic regression was used to estimate the odds ratios (OR) of each seizure-onset pattern being associated with specific MCD types. RESULTS: Our search yielded 1682 studies, of which 27 comprising 936 MCD patients were included. Of the nine interictal EEG patterns, five (three, scalp EEG; two, intracranial EEG) were detected in ≥2 MCD types, while four (rhythmic epileptiform discharges type 1 and type 2 on scalp EEG; repetitive bursting spikes and sporadic spikes on intracranial EEG) were seen only in focal cortical dysplasia (FCD). Of the 11 seizure-onset patterns, eight (three, scalp EEG; five, intracranial EEG) were found in ≥2 MCD types, whereas three were observed only in FCD (suppression on scalp EEG; delta brush on intracranial EEG) or tuberous sclerosis complex (TSC; focal fast wave on scalp EEG). Among scalp EEG seizure-onset patterns, paroxysmal fast activity (OR = 0.13; 95% CI: 0.03-0.53; p = 0.024) and repetitive epileptiform discharges (OR = 0.18; 95% CI: 0.05-0.61; p = 0.036) were less likely to occur in TSC than FCD. Among intracranial EEG seizure-onset patterns, low-voltage fast activity was more likely to be detected in heterotopia (OR = 19.3; 95% CI: 6.22-60.1; p < 0.001), polymicrogyria (OR = 6.70; 95% CI: 2.25-20.0; p = 0.004) and TSC (OR = 4.27; 95% CI: 1.88-9.70; p = 0.005) than FCD. SIGNIFICANCE: Different MCD types can share similar interictal or seizure-onset EEG patterns, reflecting common underlying biological mechanisms. However, selected EEG patterns appear to point to distinct MCD types, suggesting certain differences in their neuronal networks.

Quantitative analysis of visually reviewed normal scalp EEG predicts seizure freedom following anterior temporal lobectomy.

OBJECTIVE: Anterior temporal lobectomy (ATL) is a widely performed and successful intervention for drug-resistant temporal lobe epilepsy (TLE). However, up to one third of patients experience seizure recurrence within 1 year after ATL. Despite the extensive literature on presurgical electroencephalography (EEG) and magnetic resonance imaging (MRI) abnormalities to prognosticate seizure freedom following ATL, the value of quantitative analysis of visually reviewed normal interictal EEG in such prognostication remains unclear. In this retrospective multicenter study, we investigate whether machine learning analysis of normal interictal scalp EEG studies can inform the prediction of postoperative seizure freedom outcomes in patients who have undergone ATL. METHODS: We analyzed normal presurgical scalp EEG recordings from 41 Mayo Clinic (MC) and 23 Cleveland Clinic (CC) patients. We used an unbiased automated algorithm to extract eyes closed awake epochs from scalp EEG studies that were free of any epileptiform activity and then extracted spectral EEG features representing (a) spectral power and (b) interhemispheric spectral coherence in frequencies between 1 and 25 Hz across several brain regions. We analyzed the differences between the seizure-free and non-seizure-free patients and employed a Naïve Bayes classifier using multiple spectral features to predict surgery outcomes. We trained the classifier using a leave-one-patient-out cross-validation scheme within the MC data set and then tested using the out-of-sample CC data set. Finally, we compared the predictive performance of normal scalp EEG-derived features against MRI abnormalities. RESULTS: We found that several spectral power and coherence features showed significant differences correlated with surgical outcomes and that they were most pronounced in the 10-25 Hz range. The Naïve Bayes classification based on those features predicted 1-year seizure freedom following ATL with area under the curve (AUC) values of 0.78 and 0.76 for the MC and CC data sets, respectively. Subsequent analyses revealed that (a) interhemispheric spectral coherence features in the 10-25 Hz range provided better predictability than other combinations and (b) normal scalp EEG-derived features provided superior and potentially distinct predictive value when compared with MRI abnormalities (>10% higher F1 score). SIGNIFICANCE: These results support that quantitative analysis of even a normal presurgical scalp EEG may help prognosticate seizure freedom following ATL in patients with drug-resistant TLE. Although the mechanism for this result is not known, the scalp EEG spectral and coherence properties predicting seizure freedom may represent activity arising from the neocortex or the networks responsible for temporal lobe seizure generation within vs outside the margins of an ATL.

Implicit, automatic semantic word categorisation in the left occipito-temporal cortex as revealed by fast periodic visual stimulation.

Conceptual knowledge allows the categorisation of items according to their meaning beyond their physical similarities. This ability to respond to different stimuli (e.g., a leek, a cabbage, etc.) based on similar semantic representations (e.g., belonging to the vegetable category) is particularly important for language processing, because word meaning and the stimulus form are unrelated. The neural basis of this core human ability is debated and is complicated by the strong reliance of most neural measures on explicit tasks, involving many non-semantic processes. Here we establish an implicit method, i.e., fast periodic visual stimulation (FPVS) coupled with electroencephalography (EEG), to study neural conceptual categorisation processes with written word stimuli. Fourteen neurotypical participants were presented with different written words belonging to the same semantic category (e.g., different animals) alternating at 4 Hz rate. Words from a different semantic category (e.g., different cities) appeared every 4 stimuli (i.e., at 1 Hz). Following a few minutes of recording, objective electrophysiological responses at 1 Hz, highlighting the human brain's ability to implicitly categorize stimuli belonging to distinct conceptual categories, were found over the left occipito-temporal region. Topographic differences were observed depending on whether the periodic change involved living items, associated with relatively more ventro-temporal activity as compared to non-living items associated with relatively more dorsal posterior activity. Overall, this study demonstrates the validity and high sensitivity of an implicit frequency-tagged marker of word-based semantic memory abilities.

Improving the prediction of epilepsy surgery outcomes using basic scalp EEG findings.

OBJECTIVE: This study aims to evaluate the role of scalp electroencephalography (EEG; ictal and interictal patterns) in predicting resective epilepsy surgery outcomes. We use the data to further develop a nomogram to predict seizure freedom. METHODS: We retrospectively reviewed the scalp EEG findings and clinical data of patients who underwent surgical resection at three epilepsy centers. Using both EEG and clinical variables categorized into 13 isolated candidate predictors and 6 interaction terms, we built a multivariable Cox proportional hazards model to predict seizure freedom 2 years after surgery. Harrell's step-down procedure was used to sequentially eliminate the least-informative variables from the model until the change in the concordance index (c-index) with variable removal was less than 0.01. We created a separate model using only clinical variables. Discrimination of the two models was compared to evaluate the role of scalp EEG in seizure-freedom prediction. RESULTS: Four hundred seventy patient records were analyzed. Following internal validation, the full Clinical + EEG model achieved an optimism-corrected c-index of 0.65, whereas the c-index of the model without EEG data was 0.59. The presence of focal to bilateral tonic-clonic seizures (FBTCS), high preoperative seizure frequency, absence of hippocampal sclerosis, and presence of nonlocalizable seizures predicted worse outcome. The presence of FBTCS had the largest impact for predicting outcome. The analysis of the models' interactions showed that in patients with unilateral interictal epileptiform discharges (IEDs), temporal lobe surgery cases had a better outcome. In cases with bilateral IEDs, abnormal magnetic resonance imaging (MRI) predicted worse outcomes, and in cases without IEDs, patients with extratemporal epilepsy and abnormal MRI had better outcomes. SIGNIFICANCE: This study highlights the value of scalp EEG, particularly the significance of IEDs, in predicting surgical outcome. The nomogram delivers an individualized prediction of postoperative outcome, and provides a unique assessment of the relationship between the outcome and preoperative findings.

Resting-State Phase-Amplitude Coupling Between the Human Subthalamic Nucleus and Cortical Activity: A Simultaneous Intracranial and Scalp EEG Study.

It has been suggested that slow oscillations in the subthalamic nucleus (STN) reflect top-down inputs from the medial prefrontal cortex, thus implementing behavior control. It is unclear, however, whether the STN oscillations are related to cortical activity in a bottom-up manner. To assess resting-state subcortico-cortical interactions, we recorded simultaneous scalp electroencephalographic activity and local field potentials in the STN (LFP-STN) in 11 patients with Parkinson's disease implanted with deep brain stimulation electrodes in the on-medication state during rest. We assessed the cross-structural phase-amplitude coupling (PAC) between the STN and cortical activity within a wide frequency range of 1 to 100 Hz. The PAC was dominant between the δ/θ STN phase and ß/γ cortical amplitude in most investigated scalp regions and between the δ cortical phase and θ/α STN amplitude in the frontal and temporal regions. The cross-frequency linkage between the slow oscillations of the LFP-STN activity and the amplitude of the scalp-recorded cortical activity at rest was demonstrated, and similar involvement of the left and right STNs in the coupling was observed. Our results suggest that the STN plays a role in both bottom-up and top-down processes within the subcortico-cortical circuitries of the human brain during the resting state. A relative left-right symmetry in the STN-cortex functional linkage was suggested. Practical treatment studies would be necessary to assess whether unilateral stimulation of the STN might be sufficient for treatment of Parkinson's disease.

Absolute spike frequency and different comorbidities in temporal lobe epilepsy.

OBJECTIVE: The objective of this study was to examine if the absolute number of interictal epileptiform discharges (IED) is related to the presence of different comorbidities and refractivity in patients with temporal lobe epilepsy. METHODS: Analysis with scalp EEG of the IED of 30 patients with temporal epilepsy. The analysis was performed in three selected periods of the record during N2-N3 sleep. We analyzed the number of IED and the sum of the values obtained in the three selected segments to determine the absolute interictal spike frequency. RESULTS: The number of IED for patients varied from 11 to 450. The absolute interictal spike frequency showed a statistically significant relation with the presence of refractivity (p < 0.05), and neurological and/or psychiatric comorbidity (p < 0.05). Patients with an absolute interictal spike frequency ≤ 60 showed little refractoriness and no comorbidity. Patients with an absolute interictal spike frequency > 60 were mostly refractory and with neurological and/or psychiatric comorbidity. No significant relation was found of absolute interictal spike frequency with age at the onset of epilepsy, number of anticonvulsant drugs used, or base pathology (MRI). CONCLUSIONS: The absolute interictal spike frequency is capable of differentiating patients with temporal lobe epilepsy, identifying those with temporal lobe epilepsy according to the severity of the condition. Only those patients with non-frequent spikes (≤60 over the affected temporal lobe) have a low percentage of refractoriness with little or no presence of comorbidity.

Functional brain networks of patients with epilepsy exhibit pronounced multiscale periodicities, which correlate with seizure onset.

Epileptic seizure detection and prediction by using noninvasive measurements such as scalp EEG signals or invasive, intracranial recordings, has been at the heart of epilepsy studies for at least three decades. To this end, the most common approach has been to consider short-length recordings (several seconds to a few minutes) around a seizure, aiming to identify significant changes that occur before or during seizures. An inherent assumption in this approach is the presence of a relatively constant EEG activity in the interictal period, which is interrupted by seizure occurrence. Here, we examine this assumption by using long-duration scalp EEG data (21-94 hr) in nine patients with epilepsy, based on which we construct functional brain networks. Our results reveal that these networks vary over time in a periodic fashion, exhibiting multiple peaks at periods ranging between 1 and 24 hr. The effects of seizure onset on the functional brain network properties were found to be considerably smaller in magnitude compared to the changes due to these inherent periodic cycles. Importantly, the properties of the identified network periodic components (instantaneous phase) were found to be strongly correlated to seizure onset, especially for the periodicities around 3 and 5 hr. These correlations were found to be largely absent between EEG signal periodicities and seizure onset, suggesting that higher specificity may be achieved by using network-based metrics. In turn, this implies that more robust seizure detection and prediction can be achieved if longer term underlying functional brain network periodic variations are taken into account.

Behavioral, Physiological and EEG Activities Associated with Conditioned Fear as Sensors for Fear and Anxiety.

Anxiety disorders impose substantial costs upon public health and productivity in the USA and worldwide. At present, these conditions are quantified by self-report questionnaires that only apply to behaviors that are accessible to consciousness, or by the timing of responses to fear- and anxiety-related words that are indirect since they do not produce fear, e.g., Dot Probe Test and emotional Stroop. We now review the conditioned responses (CRs) to fear produced by a neutral stimulus (conditioned stimulus CS+) when it cues a painful laser unconditioned stimulus (US). These CRs include autonomic (Skin Conductance Response) and ratings of the CS+ unpleasantness, ability to command attention, and the recognition of the association of CS+ with US (expectancy). These CRs are directly related to fear, and some measure behaviors that are minimally accessible to consciousness e.g., economic scales. Fear-related CRs include non-phase-locked phase changes in oscillatory EEG power defined by frequency and time post-stimulus over baseline, and changes in phase-locked visual and laser evoked responses both of which include late potentials reflecting attention or expectancy, like the P300, or contingent negative variation. Increases (ERS) and decreases (ERD) in oscillatory power post-stimulus may be generalizable given their consistency across healthy subjects. ERS and ERD are related to the ratings above as well as to anxious personalities and clinical anxiety and can resolve activity over short time intervals like those for some moods and emotions. These results could be incorporated into an objective instrumented test that measures EEG and CRs of autonomic activity and psychological ratings related to conditioned fear, some of which are subliminal. As in the case of instrumented tests of vigilance, these results could be useful for the direct, objective measurement of multiple aspects of the risk, diagnosis, and monitoring of therapies for anxiety disorders and anxious personalities.

EEG before and after total corpus callosotomy for pharmacoresistant infantile spasms: Fast oscillations and slow-wave connectivity in hypsarrhythmia.

OBJECTIVE: We analyzed the features of fast oscillations (FOs) and connectivity in hypsarrhythmia to identify biomarkers for predicting seizure outcomes after total corpus callosotomy (TCC) in children with pharmacoresistant infantile spasms (IS). We hypothesize that the power of FOs and connectivity of slow waves in hypsarrhythmia would indicate the prognosis of IS. METHOD: We retrospectively identified 42 children with pharmacoresistant IS who underwent TCC from 2009 to 2014 at Nagasaki Medical Center. We collected preoperative hypsarrhythmia for 200 seconds from each child. Children were categorized into three groups with interictal epileptic discharges on EEG at 6 months after TCC: group A, no epileptic discharge; group B, lateralized epileptic discharges; and group C; bilateral epileptic discharges. We analyzed spectral power and phase synchronization in preoperative hypsarrhythmia among the three groups. RESULTS: We found 10 children in group A, 10 children in group B, and 22 children in group C. All group A and 1 in group B achieved seizure freedom after TCC. Six (67%) of 9 group B children who underwent further surgeries achieved seizure freedom. Ten (45%) of group C children had seizure reduction >50% after TCC, and 13 (87%) of 15 children who underwent further surgeries had residual seizures. The clinical profiles of the three groups did not differ significantly. The power of FOs (≥45 Hz) in hypsarrhythmia was significantly stronger in group C at the midline and temporal regions than in groups B and A (P = .014). The connectivity of theta (4-9 Hz) and FOs (29-70 Hz) tended to increase in group C, compared with the increased connectivity of 1-2 Hz in group A (P = .08). SIGNIFICANCE: The increased power and connectivity of FOs in hypsarrhythmia may correlate with pharmacoresistant and surgically resistant seizures in IS. The existence and connectivity of FOs are associated with unilateral/bilateral cortical epileptogenicity in hypsarrhythmia. Prominent slow waves and connectivity without FOs might correlate with seizure freedom after TCC. Modulation of the callosal system with subcortical/cortical epileptic discharges might play a role in generating hypsarrhythmia and IS.

Interpreting the Tests of Focal Cortical Dysplasia for Epilepsy Surgery Referral.

OBJECTIVE: Focal cortical dysplasia (FCD) is a common cause of refractory, focal onset epilepsy in children. Interictal, scalp electroencephalograph (EEG) markers have been associated with these pathologies and epilepsy surgery may be an option for some patients. We aim to study how scalp EEG and magnetic resonance imaging (MRI) markers of FCD affect referral of these patients for surgical evaluation. METHODS: A single-center, retrospective review of children with focal onset epilepsy. Patients were included if they were between 1 month and 18 years of age, had focal onset seizures, prolonged scalp EEG monitoring, and an MRI conducted after 2 years of age. Statistics were carried out using the chi-squared and student's t-test, as well as a logistic regression model. RESULTS: Sixty-eight patients were included in the study. Thirty-seven of these patients were referred to a comprehensive pediatric epilepsy program (CPEP) for surgical evaluation, and of these 22% showed FCD EEG markers, 32% FCD MRI markers, and 10% had both. These markers were also present in patients not referred to a CPEP. The MRI markers were significantly associated with CPEP referral, whereas EEG markers were not. Neither marker type was associated with epilepsy surgery. CONCLUSION: This study found that children with focal onset epilepsy were more likely to be referred for surgical evaluation if they were medically refractory, or were diagnosed with FCD or tumor on MRI. Scalp EEG markers of FCD were not associated with CPEP referral. The online tool CASES may be a useful physician guide for identifying appropriate children for epilepsy surgery referral.

Interpréter les tests de détection de la dysplasie corticale focale en vue d'une évaluation préopératoire du traitement de l'épilepsie.Objectif: La dysplasie corticale focale (DCF) constitue une des causes communes des crises convulsives partielles réfractaires chez l'enfant. À la suite d'EEG effectués au niveau du cuir chevelu, des marqueurs de l'activité épileptique interictale ont été associés avec ce trouble pour lequel une intervention chirurgicale peut constituer, dans le cas de certains patients, une option. Nous voulons nous pencher sur la façon dont ces marqueurs et les marqueurs utilisés lors d'examens d'IRM pour la DCF peuvent affecter l'aiguillage de ces patients en vue d'une évaluation préopératoire. Méthodes: Dans un seul établissement hospitalier, nous avons effectué une analyse rétrospective de cas d'enfants chez qui sont apparues des crises convulsives partielles. Pour être inclus, les patients devaient être âgés de 1 mois à 18 ans, avoir été victimes de telles crises convulsives, avoir bénéficié de surveillance prolongée par EEG et avoir subi un examen d'IRM après l'âge de deux ans. Nous avons enfin effectué une analyse statistique à l'aide d'un modèle de régression logistique et des tests du X2 et de Student. Résultats: Au total, nous avons inclus soixante-huit patients dans cette étude. Trente-sept d'entre eux ont été redirigés vers un programme pédiatrique complet de traitement de l'épilepsie (comprehensive pediatric epilepsy program) en vue d'une évaluation préopératoire. Sur ces trente-sept patients, on a observé chez 22 % d'entre eux les marqueurs électroencéphalographiques associés à la DCF ; ce pourcentage atteignait 32 % dans le cas des marqueurs de la DCF utilisés en imagerie ; enfin, on a pu détecter ces deux types de marqueurs chez 10 % de ces trente-sept patients. Fait à souligner, ces marqueurs étaient aussi présents chez des patients n'ayant pas été orientés vers le type de programme cité ci-dessus. En outre, les marqueurs utilisés en imagerie se sont avérés étroitement associés au fait d'orienter des patients vers ce programme tandis que les marqueurs électroencéphalographiques ne l'étaient pas. Finalement, aucun de ces types de marqueurs n'a pu être associé à une intervention chirurgicale visant à traiter l'épilepsie. Conclusion: Cette étude a donc permis de constater que les enfants atteints de crises convulsives partielles étaient plus susceptibles d'être orientés en vue d'une évaluation préopératoire si leur trouble était de nature réfractaire ou s'ils avaient reçu un diagnostic de DCF ou de tumeur cancéreuse à la suite d'un examend'IRM. Les marqueurs électroencéphalographiques de la DCF n'ont pas été associés à un aiguillage vers un programme pédiatrique complet de traitement de l'épilepsie. Il se pourrait à cet égard que l'outil en ligne CASES soit un guide utile pour les médecins souhaitant identifier les enfants convenant à un aiguillage en vue d'un traitement chirurgical de l'épilepsie.

Unusual ictal propagation patterns suggesting poor prognosis after temporal lobe epilepsy surgery: Switch of lateralization and bilateral asynchrony.

OBJECTIVE: The objective of this study was to investigate unusual ictal propagation patterns in patients with drug-resistant temporal lobe epilepsy (TLE) and reveal their electrophysiological, neuroimaging, and prognostic properties after surgery. METHODS: Among 248 patients with TLE who underwent scalp video-electroencephalographic (EEG) monitoring, 24 patients with 'switch of lateralization' or 'bilateral asynchrony' in at least one of their seizures (9.3%) were analyzed retrospectively. The postoperative outcome was determined in 16 patients who had undergone epilepsy surgery. RESULTS: All but 5 of the included patients had hippocampal sclerosis (HS) as their magnetic resonance imaging (MRI) findings. Twelve out of 16 patients (75%) who had surgery were seizure-free for at least 1 year. Nine out of 12 patients (75%) with good outcome had unilateral interictal EEG discharges in temporal regions whereas 3 out of 4 patients with poor outcome had bilateral temporal interictal spiking (p = 0.018). CONCLUSION: Unusual ictal propagation patterns are not always related to poor prognosis after surgery in patients with TLE. Patients with unilateral interictal spiking in the temporal region tend to have good outcome despite these unusual patterns. These patterns can also be seen in patients with TLE with other etiologies besides the well-known HS in MRI.

High-frequency oscillations: The state of clinical research.

Modern electroencephalographic (EEG) technology contributed to the appreciation that the EEG signal outside the classical Berger frequency band contains important information. In epilepsy, research of the past decade focused particularly on interictal high-frequency oscillations (HFOs) > 80 Hz. The first large application of HFOs was in the context of epilepsy surgery. This is now followed by other applications such as assessment of epilepsy severity and monitoring of antiepileptic therapy. This article reviews the evidence on the clinical use of HFOs in epilepsy with an emphasis on the latest developments. It highlights the growing literature on the association between HFOs and postsurgical seizure outcome. A recent meta-analysis confirmed a higher resection ratio for HFOs in seizure-free versus non-seizure-free patients. Residual HFOs in the postoperative electrocorticogram were shown to predict epilepsy surgery outcome better than preoperative HFO rates. The review further discusses the different attempts to separate physiological from epileptic HFOs, as this might increase the specificity of HFOs. As an example, analysis of sleep microstructure demonstrated a different coupling between HFOs inside and outside the epileptogenic zone. Moreover, there is increasing evidence that HFOs are useful to measure disease activity and assess treatment response using noninvasive EEG and magnetoencephalography. This approach is particularly promising in children, because they show high scalp HFO rates. HFO rates in West syndrome decrease after adrenocorticotropic hormone treatment. Presence of HFOs at the time of rolandic spikes correlates with seizure frequency. The time-consuming visual assessment of HFOs, which prevented their clinical application in the past, is now overcome by validated computer-assisted algorithms. HFO research has considerably advanced over the past decade, and use of noninvasive methods will make HFOs accessible to large numbers of patients. Prospective multicenter trials are awaited to gather information over long recording periods in large patient samples.

Sparse asynchronous cortical generators can produce measurable scalp EEG signals.

We investigate to what degree the synchronous activation of a smooth patch of cortex is necessary for observing EEG scalp activity. We perform extensive simulations to compare the activity generated on the scalp by different models of cortical activation, based on intracranial EEG findings reported in the literature. The spatial activation is modeled as a cortical patch of constant activation or as random sets of small generators (0.1 to 3cm(2) each) concentrated in a cortical region. Temporal activation models for the generation of oscillatory activity are either equal phase or random phase across the cortical patches. The results show that smooth or random spatial activation profiles produce scalp electric potential distributions with the same shape. Also, in the generation of oscillatory activity, multiple cortical generators with random phase produce scalp activity attenuated on average only 2 to 4 times compared to generators with equal phase. Sparse asynchronous cortical generators can produce measurable scalp EEG. This is a possible explanation for seemingly paradoxical observations of simultaneous disorganized intracranial activity and scalp EEG signals. Thus, the standard interpretation of scalp EEG might constitute an oversimplification of the underlying brain activity.

Detectability of Fast Ripples (>250 Hz) on the Scalp EEG: A Proof-of-Principle Study with Subdermal Electrodes.

To evaluate the possibility of detecting fast ripples (FRs) on the surface EEG of patients with focal pharmacoresistant epilepsy, and to investigate the relationship between scalp FRs and localization of the seizure onset zone (SOZ). We included 10 patients undergoing combined surface-intracranial EEG with ≥10 spikes in the surface EEG during the first 30 consecutive minutes of N3 sleep. FRs (≥4 consecutive oscillations above 250 Hz with an amplitude clearly exceeding that of the background) on the surface EEG (F3-C3, C3-P3, Fz-Cz, Cz-Pz, F4-C4, C4-P4) were visually marked, and verified by two EEG experts. FRs were categorized as related to the SOZ, if localized in the brain lobe of the SOZ. Low-amplitude FRs with a rate of 0.09/min were found in 6/10 patients: two exhibited events related to the SOZ, three showed no relationship with the SOZ, and in one patient the SOZ was not identified. It may be possible to detect FRs with surface EEG using subdermal electrodes in patients with focal epilepsy. The relationship between surface FRs and the SOZ remains unclear. Future studies aiming at a higher spatial EEG coverage are needed to elucidate their significance.

Size of cortical generators of epileptic interictal events and visibility on scalp EEG.

Growing evidence indicates that fast oscillations (>80 Hz) can be recorded interictally in the scalp EEG of patients with epilepsy, and that they may point to the seizure-onset zone. However, mechanisms underpinning the emergence of scalp fast oscillations, and whether they differ from those of interictal epileptic discharges (IEDs), are yet to be understood. The visibility of cortical electric activity on scalp EEG recordings is dependent on two factors: the characteristics of the cortical generator and the background level. We studied this issue using scalp EEG recordings and detailed simulations, with a finite element model including 8 million elements and 8 different tissues. We observed an almost linear relationship between the amplitude of scalp electric potential and the extent of the generator on the cortex. However, this relationship is subject to substantial variability, with variations in factors greater than 3 occurring simply by changing the location on the cortex of generators of fixed extent. In addition, we showed that the background power in scalp EEG recordings decreases at higher frequency bands, being inversely proportional to a power of 2.5 of the frequency. In the specific case of fast oscillations, they can be detected within the lower noise level of the ripple band (80-200 Hz) even though their median amplitude on scalp EEG recordings is more than 10 times smaller than IEDs and consistent with cortical generators of approximately 1 cm(2). In conclusion, the physics governing the propagation of electrical activity from the brain to the scalp are consistent with the hypothesis that scalp fast oscillations and intracranial high-frequency oscillations (HFOs, 80-500 Hz) are expressions of common generators. Given the potential role of HFOs as biomarkers in epilepsy, the possibility to obtain some of the associated information from scalp EEG is of high clinical significance.

Extent of cortical generators visible on the scalp: effect of a subdural grid.

The effect of the non-conducting substrate of a subdural grid on the scalp electric potential distribution is studied through simulations. Using a detailed head model and the finite element method we show that the governing physics equations predict an important attenuation in the scalp potential for generators located under the grid, and an amplification for generators located under holes in the skull filled with conductive media. These effects are spatially localized and do not cancel each other. A 4 × 8 cm grid can produce attenuations of 2 to 3 times, and an 8 × 8 cm grid attenuation of up to 8 times. As a consequence, when there is no subdural grid, generators of 4 to 8 cm(2) produce scalp potentials of the same maximum amplitude as generators of 10 to 20 cm(2) under the center of a subdural grid. This means that the minimum cortical extents necessary to produce visible scalp activity determined from simultaneous scalp and subdural recordings can be overestimations.

Epileptic scalp ripples are associated with corticothalamic BOLD changes.

OBJECTIVE: Interictal high frequency oscillations (HFOs) in the 40-200 Hz range have been identified in scalp electroencephalography (EEG) recordings of patients with focal epilepsy. HFOs usually co-occur with interictal epileptiform discharges (IEDs), and are specific and accurate markers for the epileptic focus, but the brain regions involved when HFOs are generated are unknown. We investigated this question with combined EEG-functional magnetic resonance imaging (fMRI), measuring the blood oxygenation level-dependent (BOLD) signal, and examined HFOs in the gamma (40-80 Hz) and ripple (80-200 Hz) bands. METHODS: Twenty-eight consecutive patients with focal epilepsy who underwent HFO and EEG-fMRI studies were selected; six were excluded because of negative EEG-fMRI. The remaining 22 patients were divided into two equal groups (11 patients each) based on the frequency of co-occurrence of gamma or ripples with IEDs: low versus high gamma (LG/HG) and low versus high ripples (LR/HR). RESULTS: No significant changes were found in the BOLD characteristics between the LG and HG groups. As a group, HR had a larger IED concordant BOLD cluster than the LR group, despite similar IED rates. In addition, the HR group had significantly more thalamic BOLD changes than the LR group (11/11 vs. 2/11). In HR, 5 of 11 patients had thalamic activation only, 4 of 11 had thalamic deactivation only, and 2 of 11 had activation and deactivation in different thalamic regions. In the LR group, 2 of 11 had thalamic activation. The lateralization of thalamic BOLD responses was concordant with the lateralization of cortical ripples in 12 of 13 patients. SIGNIFICANCE: Scalp IEDs, when frequently accompanied by HFOs in the ripple but not in the gamma band, are associated with larger cortical metabolic responses and with thalamic involvement lateralized to the side of cortical ripples. We propose that a high rate of epileptic ripples is associated with a more active pathologic cortical-thalamocortical network.

EEG-based spatiotemporal dynamics of fast ripple networks and hubs in infantile epileptic spasms.

OBJECTIVE: Infantile epileptic spasms (IS) are epileptic seizures that are associated with increased risk for developmental impairments, adult epilepsies, and mortality. Here, we investigated coherence-based network dynamics in scalp EEG of infants with IS to identify frequency-dependent networks associated with spasms. We hypothesized that there is a network of increased fast ripple connectivity during the electrographic onset of clinical spasms, which is distinct from controls. METHODS: We retrospectively analyzed peri-ictal and interictal EEG recordings of 14 IS patients. The data was compared with 9 age-matched controls. Wavelet phase coherence (WPC) was computed between 0.2 and 400 Hz. Frequency- and time-dependent brain networks were constructed using this coherence as the strength of connection between two EEG channels, based on graph theory principles. Connectivity was evaluated through global efficiency (GE) and channel-based closeness centrality (CC), over frequency and time. RESULTS: GE in the fast ripple band (251-400 Hz) was significantly greater following the onset of spasms in all patients (P < 0.05). Fast ripple networks during the first 10s from spasm onset show enhanced anteroposterior gradient in connectivity (posterior > central > anterior, Kruskal-Wallis P < 0.001), with maximum CC over the centroparietal channels in 10/14 patients. Additionally, this anteroposterior gradient in CC connectivity is observed during spasms but not during the interictal awake or asleep states of infants with IS. In controls, anteroposterior gradient in fast ripple CC was noted during arousals and wakefulness but not during sleep. There was also a simultaneous decrease in GE in the 5-8 Hz range after the onset of spasms (P < 0.05), of unclear biological significance. SIGNIFICANCE: We identified an anteroposterior gradient in the CC connectivity of fast ripple hubs during spasms. This anteroposterior gradient observed during spasms is similar to the anteroposterior gradient in the CC connectivity observed in wakefulness or arousals in controls, suggesting that this state change is related to arousal networks.