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INTRODUCTION/AIMS: F-wave testing frequently reveals after-discharges of varied morphologies in patients with primary peripheral nerve hyperexcitability syndrome (PNHS), although reports are scant. This study aimed to explore the morphological characteristics of the after-discharges during F-wave tests in PNHS, and to assess the association between after-discharges and the disease classification. METHODS: We conducted a retrospective analysis of patients diagnosed with PNHS between 2014 and 2022. The morphological characteristic and duration of after-discharges during F-wave tests were analyzed. After-discharges in the Morvan syndrome group were compared with those in non-Morvan group, and between groups with positive or negative voltage-gated potassium channel (VGKC) complex antibodies. RESULTS: Twenty-nine patients were included in the study, of which 25 exhibited after-discharges. All after-discharges in Morvan patients occurred following compound muscle action potential (CMAP). In non-Morvan patients, after-discharges occurred following F-wave (32%) and CMAP (47%). The durations of after-discharges following CMAP were significantly prolonged in Morvan (54.2 ± 18.8 ms) compared to non-Morvan patients (34.5 ± 15.0 ms). The majority of antibody-positive patients (18/20) exhibited after-discharges following CMAP, whereas 67% of antibody-negative patients (6/9) showed after-discharges following F-wave. DISCUSSION: The varying presentations of after-discharges, including their location (after CMAP or F-wave) and the duration of after-discharge can assist in clinically classifying PNHS.

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OBJECTIVE: Extraoperative electrical cortical stimulation (ECS) facilitates defining the seizure onset zone (SOZ) and eloquent cortex. The clinical relevance of stimulation-induced afterdischarges (ADs) is not well defined. METHODS: Fifty-five patients who underwent intracranial electroencephalogram evaluations with ECS were retrospectively identified. ADs were identified in these recordings and categorized by pattern, location, and association with stimulation-induced seizures. RESULTS: ADs were generated in 1774/9285 (19%) trials. Rhythmic spikes and irregular ADs within the stimulated bipolar contact pair were predictive of location within the SOZ compared to non-epileptogenic/non-irritative cortex (rhythmic spikes OR 2.24, p = 0.0098; irregular OR 1.39; p = 0.013). ADs immediately preceding stimulated seizures occurred at lower stimulation intensity thresholds compared to other stimulations (mean 2.94 ± 0.28 mA vs. 4.16 ± 0.05 mA respectively; p = 0.0068). CONCLUSIONS: Changes in AD properties can provide clinically relevant data in extraoperative stimulation mapping. SIGNIFICANCE: Although not exclusive to the SOZ, the generation of rhythmic spikes may suggest that a stimulation location is within the SOZ, while decreased stimulation intensity thresholds eliciting ADs may alert clinicians to a heightened probability of seizure generation with subsequent stimulation.

Asunto(s)

Electroencefalografía , Convulsiones , Humanos , Estudios Retrospectivos , Estimulación Eléctrica , Probabilidad , Convulsiones/diagnóstico

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We combined electrical perforant pathway stimulation with electrophysiological and fMRI recordings in the hippocampus to investigate the effects of neuronal afterdischarges (nAD) on subsequent fMRI BOLD signals in the presence of isoflurane and medetomidine. These two drugs already alter basal hemodynamics in the hippocampus, with isoflurane being mildly vasodilatory and medetomidine being mildly vasoconstrictive. The perforant pathway was stimulated once for 8 seconds with either continuous 20 Hz pulses (continuous stimulation) or 8 bursts of 20 high-frequency pulses (burst stimulation). Burst stimulation in the presence of medetomidine elicited long-lasting nAD that coincided with a brief positive BOLD response and a subsequent long-lasting decrease in BOLD signals. Under isoflurane, this stimulation elicited only short-lasting nAD and only a short-lasting decline in BOLD signals. In contrast, continuous stimulation under isoflurane and medetomidine caused a similar duration of nAD. Under isoflurane, this caused only a sharp and prolonged decline in BOLD signals, whereas under medetomidine, again, only a brief positive BOLD response was elicited, followed by a shorter and moderate decline in BOLD signals. Our results suggest that nAD simultaneously activate different neurovascular coupling mechanisms that then independently alter local hemodynamics in the hippocampus, resulting in an even more complex neurovascular coupling mechanism.

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Background: Postictal refractoriness, i.e., the inability to elicit a new epileptic seizure immediately after the first one, is present in mature animals. Immature rats did not exhibit this refractoriness, and it is replaced by postictal potentiation. In addition to the immediate postictal potentiation, there is a delayed potentiation present at both ages. These phenomena were studied using cortical epileptic afterdischarges as a model. Objective: We aimed to analyze participation of adenosine A1 receptors in postictal potentiation and depression. Methods: Adenosine A1 receptors were studied by means of Western blotting in the cerebral cortex with a focus on the age groups studied electrophysiologically. Stimulation and recording electrodes were implanted epidurally in 12- and 25-day-old rats. The first stimulation always induced conditioning epileptic afterdischarge (AD), and 1 min after its end, the stimulation was repeated to elicit the second, testing AD. Then, the drugs were administered and paired stimulations were repeated 10 min later. A selective agonist CCPA (0.5 and 1 mg/kg i.p.) and a selective antagonist DPCPX (0.1, 0.5 and 1 mg/kg i.p.) were used to examine the possible participation of adenosine A1 receptors. Results: Control younger animals exhibited potentiation of the testing AD and a moderate increase in both conditioning and testing ADs after an injection of saline. The A1 receptor agonist CCPA shortened both post-drug ADs, and neither potentiation was present. The administration of an antagonist DPCPX resulted in marked prolongation of the conditioning AD (delayed potentiation), and the second testing AD was shorter than the post-drug conditioning AD, i.e., there was no longer immediate potentiation of ADs. To eliminate effects of the solvent dimethylsulfoxide, we added experiments with DPCPX suspended with the help of Tween 80. The results were similar, only the prolongation of ADs was not as large, and the testing ADs were significantly depressed. The older control group exhibited a nearly complete suppression of the first testing AD. There was no significant change in the conditioning and testing ADs after CCPA (delayed potentiation was blocked). Both groups of DPCPX-treated rats (with DMSO or Tween) exhibited significant augmentation of delayed potentiation but no significant difference in the immediate depression. Adenosine A1 receptors were present in the cerebral cortex of both age groups, and their quantity was higher in 12- than in 25-day-old animals. Conclusions: An agonist of the A1 receptor CCPA suppressed both types of postictal potentiation in 12-day-old rats, whereas the A1 antagonist DPCPX suppressed immediate potentiation but markedly augmented the delayed one. Immediate postictal refractoriness in 25-day-old rats was only moderately (non-significantly) affected; meanwhile, the delayed potentiation was strongly augmented.

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Peripheral nerve hyperexcitability is an uncommon but treatable condition in neurology. Voltage-gated potassium channelopathies, especially contactin-associated protein-like 2 (CASPR2) antibody, are commonly implicated. We present the case of a 16-year-old boy with tremulousness of both feet and twitching of muscles all over the body for three months. Examination revealed irregular, arrhythmic, small-amplitude twitching movements of the toes along with fasciculations in both thighs. Nerve conduction studies were within normal limits. F-wave studies showed a prolonged polyphasic large-amplitude discharge following the compound muscle action potential and obscuring the F waves. Electromyography showed extensive myokymic discharges. The serum autoimmune antibody profile showed strong positivity for CASPR2. He started lacosamide as a symptomatic treatment. In view of the good symptomatic response, further immunomodulation was deferred and he remains on follow-up. We present this case to highlight the role of motor afterdischarges as a diagnostic clue to peripheral nerve hyperexcitability and to review the literature on this interesting finding.

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OBJECTIVE: We previously studied efficacy of cognitive tasks on afterdischarge termination in patients undergoing cortical stimulation and found that diffuse wavelet cross-coherence changes on electrocorticography were associated with termination efficacy. We now report wavelet cross-coherence findings during different time segments of trials during which afterdischarges ended. METHODS: For 12 patients with implanted subdural electrodes, we compared wavelet cross-coherence findings among several 1-second portions of cognitive tasks, reflecting task presentation, patient replies, and afterdischarge termination. RESULTS: Coherence decreased significantly and progressively over time for 16.89, 22.53, and 30.03 Hz frequency ranges, but increased with afterdischarge termination. Coherence first increased, and then decreased for the 7.13 Hz frequency range. CONCLUSIONS: The findings suggest that cumulative but non-specific factors, likely related primarily to attention, influence the coherence results throughout the task, with a separate effect due to resolution of the afterdischarges at the end. SIGNIFICANCE: Task performance is well known to localize to specific brain regions and to be restricted in timing. In contrast, attention and overall mental activation might be due to emergent properties of brain as a whole and that are less circumscribed in space or time. Cognitive tasks might modify seizures and other neurological disorders.

Asunto(s)

Electroencefalografía , Convulsiones , Humanos , Electroencefalografía/métodos , Encéfalo/fisiología , Atención , Cognición , Estimulación Eléctrica/métodos

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AIMS: The blue light-sensitive chloride-conducting opsin, stGtACR2, provides potent optogenetic silencing of neurons. The present study investigated whether activation of stGtACR2 in granule cells of the dentate gyrus (DG) inhibits epileptic afterdischarges in a rat model. METHODS: Rats were bilaterally injected with 0.9 µl of AAV2/7-CaMKIIα-stGtACR2-fusionred in the DG. Three weeks later, afterdischarges were recorded from the DG by placing an optrode at the injection site and a stimulation electrode in the perforant path (PP). Afterdischarges were evoked every 10 min by unilateral electrical stimulation of the PP (20 Hz, 10 s). During every other afterdischarge, the DG was illuminated for 5 or 30 s, first ipsilaterally and then bilaterally to the PP stimulation. The line length metric of the afterdischarges was compared between illumination conditions. RESULTS: Ipsilateral stGtACR2 activation during afterdischarges decreased the local field potential line length only during illumination and specifically at the illuminated site but did not reduce afterdischarge duration. Bilateral illumination did not terminate the afterdischarges. CONCLUSION: Optogenetic inhibition of excitatory neurons using the blue-light sensitive chloride channel stGtACR2 reduced the amplitude of electrically induced afterdischarges in the DG at the site of illumination, but this local inhibitory effect was insufficient to reduce the duration of the afterdischarge.

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Canales de Cloruro , Epilepsia , Ratas , Animales , Ratas Sprague-Dawley , Canales de Cloruro/farmacología , Hipocampo , Neuronas , Estimulación Eléctrica

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LiCl/pilocarpine status epilepticus (SE) induced in immature rats leads, after a latent period, to hippocampal hyperexcitability. The excitability may be influenced by adenosine, which exhibits anticonvulsant activity. The concentration of adenosine is regulated by adenosine kinase (ADK) present in two isoforms-ADK-L and ADK-S. The main goal of the study is to elucidate the changes in ADK isoform expression after LiCl/pilocarpine SE and whether potential changes, as well as inhibition of ADK by 5-iodotubercidin (5-ITU), may contribute to changes in hippocampal excitability during brain development. LiCl/pilocarpine SE was elicited in 12-day-old rats. Hippocampal excitability in immature rats was studied by the model of hippocampal afterdischarges (ADs), in which we demonstrated the potential inhibitory effect of 5-ITU. ADs demonstrated significantly decreased hippocampal excitability 3 days after SE induction, whereas significant hyperexcitability after 20 days compared to controls was shown. 5-ITU administration showed its inhibitory effect on the ADs in 32-day-old SE rats compared to SE rats without 5-ITU. Moreover, both ADK isoforms were examined in the immature rat hippocampus. The ADK-L isoform demonstrated significantly decreased expression in 12-day-old SE rats compared to the appropriate naïve rats, whereas increased ADK-S isoform expression was revealed. A decreasing ADK-L/-S ratio showed the declining dominance of ADK-L isoform during early brain development. LiCl/pilocarpine SE increased the excitability of the hippocampus 20 days after SE induction. The ADK inhibitor 5-ITU exhibited anticonvulsant activity at the same age. Age-related differences in hippocampal excitability after SE might correspond to the development of ADK isoform levels in the hippocampus.

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Pilocarpina , Estado Epiléptico , Adenosina/metabolismo , Adenosina Quinasa/metabolismo , Animales , Anticonvulsivantes/farmacología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Pilocarpina/toxicidad , Isoformas de Proteínas/metabolismo , Ratas , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/metabolismo

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OBJECTIVE: It is well known that activity in, or coordination among, brain regions, can underlie movement, sensation, language, and cognition but there are observations that tasks unrelated to specific brain regions can nonetheless alter activity in those regions. These tasks might invoke activity in multiregional networks, but it also is possible that they are associated with changes beyond these networks. We therefore evaluated the possibility that more widespread, or even whole-cortical, mechanisms might complement or alter focal or multifocal cortical activity. METHODS: We assessed the extent of electroencephalographic changes occurring outside areas with epileptiform activity, but that were associated with termination of the epileptiform activity. To do this, we measured the distribution of wavelet cross-coherence changes based on electrocorticography from 15 patients who showed regional afterdischarges in response to electrical brain stimulation prior to epilepsy surgery and in whom cognitive tasks were used in attempts to end the afterdischarges. There were 1276 electrodes implanted in these patients, and we analyzed a total of 55,494 electrode combinations. We compared recordings when cognitive effort was versus when it was not successful in ending afterdischarges. RESULTS: We found that when afterdischarges were suppressed there were changes in electrocorticographic coherence that were similar throughout cortex, regardless of the distance between sites. CONCLUSIONS: The similarity implies coordination of the changes, and the similarity regardless of distance or location implies a pan-cortical effect. SIGNIFICANCE: Our results provide physical support for hypotheses that pan-cortical processes complement the well-known regional and multiregional networks. These processes may participate in, be recruited by, modify, or underlie the conative experiences of waking life.

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Electrocorticografía , Epilepsia , Encéfalo/fisiología , Mapeo Encefálico/métodos , Corteza Cerebral/fisiología , Electrocorticografía/métodos , Electroencefalografía/métodos , Humanos

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PURPOSE: The purpose of this study was to demonstrate the prognostic value of afterdischarges(ADs) on surgical outcome by comparing the disparate properties in epilepsy patients with different surgical outcomes METHODS: 27 lesional epilepsy patients were retrospectively analyzed. The brain region covered by subdural electrodes in each patient was dichotomized into the area of the brain lobe(s) where the MRI lesion is located (region ML) and other brain areas (region nML). The occurrence of ADs and ADs evolving into clinical seizure, ADs threshold and ADs duration in region ML and nML were compared between seizure-free (SF) and non-seizure-free (nSF) patients. RESULTS: A total of 2535 contacts were analyzed, and the total occurrence of ADs was 18.6% (471/2535). The overall occurrence of ADs in region ML (24.8%) was significantly higher than that in region nML (10.3%) (P < 0.001). In region ML, compared with SF patients, nSF patients had a lower occurrence of ADs (19.2% vs. 31.2%, P < 0.001), a higher occurrence of ADs evolves into clinical seizure (8.7% vs. 2.4%, P = 0.006), a higher ADs threshold (12.8 ± 4.1 mA vs. 11.0 ± 3.7 mA, P < 0.001) and a shorter ADs duration (15.3 ± 14.2 s vs. 20.6 ± 17.0 s, P < 0.001). However, in region nML, there was no significant difference in properties of ADs between SF and nSF patients. CONCLUSION: Higher occurrence of ADs in region ML might predict a good outcome, whereas higher occurrence of ADs evolving into clinical seizure, higher ADs threshold and shorter ADs duration might predict an unfavorable surgical outcome. ADs might help predict surgical outcomes in epilepsy patients.

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Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Corteza Cerebral/cirugía , Electrocorticografía , Epilepsia/patología , Epilepsia/fisiopatología , Epilepsia/cirugía , Procedimientos Neuroquirúrgicos , Evaluación de Resultado en la Atención de Salud , Adulto , Estimulación Eléctrica , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , Adulto Joven

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The GluN2A subunit of N-methyl-D-aspartate (NMDA) receptors becomes dominant during postnatal development, overgrowing the originally dominant GluN2B subunit. The aim of our study was to show changes of anticonvulsant action of the GluN2A subunit-preferring antagonist during postnatal development of rats. Possible anticonvulsant action of GluN2A-preferring antagonist of NMDA receptors P = [[[(1S)-1-(4-bromophenyl)ethyl]amino](1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl]phosphonic acid tetrasodium salt (PEAQX) (5, 10, 20 mg/kg s.c.) was tested in 12-, 18-, and 25-day-old rats in three models of convulsive seizures. Pentylenetetrazol-induced generalized seizures with a loss of righting reflexes generated in the brainstem were suppressed in all three age groups in a dose-dependent manner. Minimal clonic seizures with preserved righting ability exhibited only moderately prolonged latency after the highest dose of PEAQX. Anticonvulsant action of all three doses of PEAQX against cortical epileptic afterdischarges (generated in the forebrain) was found in the 25-day-old animals. The highest dose (20 mg/kg) was efficient also in the two younger groups, which might be due to lower specificity of PEAQX and its partial affinity to the GluN2B subunit. Our results are in agreement with the postero-anterior maturation gradient of subunit composition of NMDA receptors (i.e., an increase of GluN2A representation). In spite of the lower selectivity of PEAQX, our data demonstrate, for the first time, developmental differences in comparison with an antagonist of NMDA receptors with a dominant GluN2B subunit.

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INTRODUCTION: Peripheral nerve hyperexcitability syndrome (PNHS) is characterized by muscle fasciculations and spasms. Nerve hyperexcitability and after-discharges can be observed in electrophysiological studies. Autoimmune mechanisms play a major role in the pathophysiology of primary PNHS. METHODS: We retrospectively conducted a case-control study recruiting patients with clinical and electrophysiological features of PNHS. Control patients were diagnosed with other neuronal or muscular diseases. Contactin-associated protein2 (CASPR2) and leucine-rich glioma-inactivated1 (LGI1) antibodies were examined. RESULTS: A total of 19 primary PNHS patients and 39 control patients were analyzed. The most common symptoms for the case group were fasciculations (11/19) and muscle spasms (13/19). Case group patients were likely to demonstrate electrodiagnostic findings of nerve hyperexcitability (17/19) and after-discharges in the tibial nerve (19/19). We found high prevalence of CASPR2 (9/19) and LGI1 (6/19) antibodies in the case group. DISCUSSION: Primary PNHS patients were likely to show after-discharges in the tibial nerve. The pathogenesis of PNHS is autoimmune CASPR2 and LGI1 antibodies are possible pathogenic antibodies for primary PNHS.

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Autoanticuerpos/inmunología , Fasciculación/diagnóstico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Espasmo/diagnóstico , Adulto , Anciano , Estudios de Casos y Controles , Moléculas de Adhesión Celular Neuronal/inmunología , Electrodiagnóstico , Fasciculación/inmunología , Fasciculación/fisiopatología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/inmunología , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Estudios Retrospectivos , Espasmo/inmunología , Espasmo/fisiopatología , Adulto Joven

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BACKGROUND: Postictal potentiation presented immediately after cortical seizures in immature rats might be due to imbalance between excitation and inhibition. The aim of the present study was to determine whether augmentation of inhibition mediated by GABAA receptors could also suppress the postictal potentiation. METHODS: Twelve-day old rats with implanted electrodes were used in our study. Five drugs were tested: the agonist muscimol, the positive modulator midazolam and three neurosteroids affecting GABAA receptors-allopregnanolone, pregnanolone sulphate and pregnanolone glutamate. RESULTS: None of the five drugs was able to suppress potentiation appearing immediately after cortical epileptic afterdischarges, but all of them exhibited delayed anticonvulsant action 10 (in the case of midazolam and muscimol) or 20 min (all three steroids) after cortical seizures. CONCLUSION: Our results support a role of GABA in augmentation of cortical after discharges after longer intervals, whereas immediate postictal potentiation is not affected by GABAergic drugs. Due to similar effect with GABAergic drugs, the main mechanism of action of the three steroids tested is potentiation of GABAergic inhibition.

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Anticonvulsivantes/farmacología , Neuroesteroides/farmacología , Receptores de GABA-A/efectos de los fármacos , Convulsiones/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Electrodos Implantados , Masculino , Midazolam/farmacología , Muscimol/farmacología , Ratas , Ratas Wistar , Receptores de GABA-A/metabolismo , Factores de Tiempo

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OBJECTIVE: Intraoperative stimulation has emerged as a crucial adjunct in neurosurgical oncology, aiding maximal tumor resection while preserving sensorimotor and language function. Despite increasing use in clinical practice of this stimulation, there are limited data on both intraoperative seizure (IS) frequency and the presence of afterdischarges (ADs) in patients undergoing such procedures. The objective of this study was to determine risk factors for IS or ADs, and to determine the clinical consequences of these intraoperative events. METHODS: A retrospective chart review was performed for patients undergoing awake craniotomy (both first time and repeat) at a single institution from 2013 to 2018. Hypothesized risk factors for ADs/ISs in patients were evaluated for their effect on ADs and ISs, including tumor location, tumor grade (I-IV), genetic markers (isocitrate dehydrogenase 1/2, O 6-methylguanine-DNA methyltransferase [MGMT] promoter methylation, chromosome 1p/19q codeletion), tumor volume, preoperative seizure status (yes/no), and dosage of preoperative antiepileptic drugs for each patient. Clinical outcomes assessed in patients with IS or ADs were duration of surgery, length of stay, presence of perioperative deficits, and postoperative seizures. Chi-square analysis was performed for binary categorical variables, and a Student t-test was used to assess continuous variables. RESULTS: A total of 229 consecutive patients were included in the analysis. Thirty-five patients (15%) experienced ISs. Thirteen (37%) of these 35 patients had experienced seizures that were appreciated clinically and noted on electrocorticography simultaneously, while 8 patients (23%) experienced ISs that were electrographic alone (no obvious clinical change). MGMT promoter methylation was associated with an increased prevalence of ISs (OR 3.3, 95% CI 1.2-7.8, p = 0.02). Forty patients (18%) experienced ADs. Twenty-three percent of patients (9/40) with ISs had ADs prior to their seizure, although ISs and ADs were not statistically associated (p = 0.16). The presence of ADs appeared to be correlated with a shorter length of stay (5.1 ± 2.6 vs 6.1 ± 3.7 days, p = 0.037). Of the clinical features assessed, none were found to be predictive of ADs. Neither IS nor AD, or the presence of either IS or AD (65/229 patients), was a predictor for increased length of stay, presence of perioperative deficits, or postoperative seizures. CONCLUSIONS: ISs and ADs, while commonly observed during intraoperative stimulation for brain mapping, do not negatively affect patient outcomes.

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Mapeo Encefálico/efectos adversos , Craneotomía , Electrocorticografía/efectos adversos , Complicaciones Intraoperatorias/etiología , Monitoreo Intraoperatorio/efectos adversos , Convulsiones/etiología , Adulto , Biomarcadores de Tumor , Mapeo Encefálico/métodos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/fisiopatología , Neoplasias Encefálicas/cirugía , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Femenino , Humanos , Complicaciones Intraoperatorias/fisiopatología , Isocitrato Deshidrogenasa/genética , Tiempo de Internación , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio/métodos , Regiones Promotoras Genéticas , Estudios Retrospectivos , Factores de Riesgo , Convulsiones/fisiopatología , Carga Tumoral , Proteínas Supresoras de Tumor/genética , Vigilia

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Cortical stimulation has been used for brain mapping for over a century, and a standard assumption is that stimulation interferes with task execution due to local effects at the stimulation site. Stimulation can however produce afterdischarges which interfere with functional localization and can lead to unwanted seizures. We previously showed that (a) cognitive effort can terminate these afterdischarges, (b) when termination thus occurs, there are electrocorticography changes throughout the cortex, not just at sites with afterdischarges or sites thought functionally important for the cognitive task used, and (c) thresholds for afterdischarges and functional responses can change among stimulation trials. We here show that afterdischarge termination can occur prior to overt performance of the cognitive tasks used to terminate them. These findings, taken together, demonstrate that task-related brain changes are not limited to one or a group of functional regions or a specific network, and not limited to the time directly surrounding overt task execution. Discrete locations, networks and times importantly underpin clinical behaviors. However, brain activity that is diffuse in location and extended in time also affect task execution and can affect brain mapping. This may in part reflect fluctuating levels of attention, engagement, or motivation during testing.

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OBJECTIVE: We introduce a novel animal model of somatosensory stimulation-induced reflex seizures which generates focal seizures without causing damage to the brain. METHODS: Specifically, we electrically stimulated digits or forepaws of adult rats sedated with dexmedetomidine while imaging cerebral blood volume and recording neurophysiological activity in cortical area S1FL. For the recordings, we either inserted a linear probe into the D3 digit representation or we performed surface electrocorticography (ECoG) recordings. RESULTS: Peripheral stimulation of a digit or the forepaw elicited seizures that were followed by a refractory period with decreased neuronal activity, or another seizure or normal response. LFP amplitudes in response to electrical pulses during the seizures (0.28 ±â€¯0.03 mV) were higher than during normal evoked responses (0.25 ±â€¯0.05 mV) and refractory periods (0.2 ±â€¯0.08 mV). Seizures generated during the stimulation period showed prolonged after-discharges that were sustained for 20.9 ±â€¯1.9 s following the cessation of the stimulus. High-frequency oscillations were observed prior to and during the seizures, with amplitudes higher than those associated with normal evoked responses. The seizures were initially focal. Optical imaging of the cerebral blood volume response showed that they propagated from the onset zone to adjacent cortical areas, beyond the S1FL representation of the stimulated digit or forepaw. The spatial extent during seizures was on average 1.74 times larger during the stimulation and 4.1 times following its cessation relative to normal evoked responses. Seizures were recorded not only by probes inserted into cortex but also with ECoG arrays (24.1 ±â€¯5.8 seizures per rat) placed over the dura matter, indicating that the seizures were not induced by damage caused by inserting the probes to the cortex. Stimulation of the forepaw elicited more seizures (18.8 ±â€¯8.5 seizures per rat) than stimulation of a digit (1.7 ±â€¯0.7). Unlike rats sedated with dexmedetomidine, rats anesthetized with urethane showed no seizures, indicating that the seizures may depend on the use of the mild sedative dexmedetomidine. SIGNIFICANCE: Our proposed animal model generates seizures induced by electrical sensory stimulation free of artifacts and brain damage. It can be used for studying the mechanisms underlying the generation and propagation of reflex seizures and for evaluating antiepileptic drugs.

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Potenciales Evocados Somatosensoriales/fisiología , Reflejo/fisiología , Convulsiones/fisiopatología , Corteza Somatosensorial/fisiopatología , Animales , Modelos Animales de Enfermedad , Estimulación Eléctrica , Electrocorticografía , Ratas

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OBJECTIVE: Mental activation has been reported to modify the occurrence of epileptiform activity. We studied its effect on afterdischarges. METHOD: In 15 patients with implanted electrodes we presented cognitive tasks when afterdischarges occurred. We developed a wavelet cross-coherence function to analyze the electrocorticography before and after the tasks and compared findings when cognitive tasks did or did not result in afterdischarge termination. Six patients returned for functional MRI (fMRI) testing, using similar tasks. RESULTS: Cognitive tasks often could terminate afterdischarges when direct abortive stimulation could not. Wavelet cross-coherence analysis showed that, when afterdischarges stopped, there was decreased coherence throughout the brain in the 7.13-22.53 Hz frequency ranges (p values 0.008-0.034). This occurred a) regardless of whether an area activated on fMRI and b) regardless of whether there were afterdischarges in the area. CONCLUSIONS: It is known that cognitive tasks can alter localized or network synchronization. Our results show that they can change activity throughout the brain. These changes in turn can terminate localized epileptiform activity. SIGNIFICANCE: Cognitive tasks result in diffuse brain changes that can modify focal brain activity. Combined with a seizure detection device, cognitive activation might provide a non-invasive method of terminating or modifying seizures.

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Atención/fisiología , Ondas Encefálicas/fisiología , Encéfalo/fisiología , Cognición/fisiología , Convulsiones/fisiopatología , Adulto , Encéfalo/diagnóstico por imagen , Electrodos Implantados , Electroencefalografía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Convulsiones/diagnóstico por imagen , Adulto Joven

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Objective: The adenosinergic system may influence excitability in the brain. Endogenous and exogenous adenosine has anticonvulsant activity presumably by activating A1 receptors. Adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) may thus bolster anticonvulsant effects, but its action and the number of A1 receptors at different developmental stages are not known. Methods: Hippocampal epileptic afterdischarges (ADs) were elicited in 12-, 15-, 18-, 25-, 45-, and 60-day-old rats. Stimulation and recording electrodes were implanted into the dorsal hippocampus. The A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 0.5 or 1 mg/kg) was administered intraperitoneally 10 min before the first stimulation. Control animals were injected with saline. All rats were stimulated with a 2-s series of 1-ms biphasic pulses delivered at 60 Hz with increasing stepwise intensity (0.05-0.6 mA). Each age and dose group contained 9-14 animals. The AD thresholds and durations were evaluated, and the A1 receptors were detected in the hippocampus in 7-, 10-, 12-, 15-, 18-, 21-, 25-, 32-, and 52-day-old rats. Results: Both CCPA doses significantly increased hippocampal AD thresholds in 12-, 15-, 18-, and 60-day-old rats compared to controls. In contrast, the higher dose significantly decreased AD threshold in the 25-day-old rats. The AD durations were significantly shortened in all age groups except for 25-day-old rats where they were significantly prolonged. A1 receptor expression in the hippocampus was highest in 10-day-old rats and subsequently decreased. Significance: The adenosine A1 receptor agonist CCPA exhibited anticonvulsant activity at all developmental stages studied here except for 25-day-old rats. Age-related differences might be due to the development of presynaptic A1 receptors in the hippocampus.

RESUMEN

Spinal motoneurons exhibit sustained afterdischarges and plateau potentials following a brief high-frequency stimulation of Ia afferents. Also, there is evidence that spinal cord interneurons exhibit plateau potentials. However, to our knowledge, there are no reports about the possible afterdischarge behavior of lumbar spinal interneurons activated by Ia afferents. Given that there are spinal interneurons receiving monosynaptic inputs from Ia afferents, these cells could then be activated in parallel to motoneurons after repetitive muscle stretch. We explored this possibility in cats with a precollicular-postmammillary decerebration. We found that a brief high-frequency stimulation of Ia afferents produces afterdischarges that are highly correlated to a DC slow potential recorded at the cord dorsum. We conclude that in the cat spinal cord, not only the motoneurons but also the interneurons from the superficial and deep dorsal horn produce sustained afterdischarges, thus highlighting the importance of interneurons in the spinal neuronal circuitry. The significance of our finding is that it opens the possibility that the spinal cord interneurons activated by Ia afferents could also exhibit bistability, a relevant phenomenon well-characterized in the motoneurons.

RESUMEN

INTRODUCTION: Afterdischarges (ADs) are a common and unwanted byproduct of direct cortical stimulation during invasive electroencephalography (EEG) recordings. Brief pulse stimulation (BPS) can sometimes terminate ADs. This study investigated AD characteristics and their relevance for emergence of stimulation seizures. In addition, AD response to BPS was analyzed. MATERIAL AND METHODS: Invasive EEG recordings including mapping with direct cortical stimulation in patients with refractory epilepsy at the Erlangen Epilepsy Center were retrospectively reviewed. Afterdischarge defined as stimulation-induced rhythmic epileptiform discharges of more than a two-second duration were analyzed regarding incidence, localization, duration, propagation pattern, morphology, and seizure emergence. In addition, the influence of AD characteristics and stimulation settings on BPS success rate was studied. RESULTS: A number of 4261 stimulation trials in 20 patients were investigated. Afterdischarge occurred in 518 trials (14.2%) and lasted 12.4 s (standard deviation [SD]: 8.6 s) on average. We elicited ADs in the seizure onset zone (SOZ) (n = 64; 19.4%), the irritative zone (n = 105, 20.0%), and outside the irritative area (n = 222, 12.5%). Rhythmic spikes (30.5%) and spike-wave complexes (30.3%) represented predominant morphologies. Afterdischarge morphology in the SOZ and hippocampus differed from other areas with polyspikes and sequential spikes being the most common types there (p = 0.0005; p < 0.0001 respectively). Hippocampal ADs were particularly frequent (n = 50, 38.2%) and long-lasting (mean: 16.6, SD: 8.3 s). Brief pulse stimulation was applied in 18.1% of the AD trials (n = 94) and was successful in 37.4% (n = 40). Success rates were highest when BPS was delivered within 9.5 s (p = 0.0048) and in ADs of spike-wave morphology (p = 0.0004). Fifteen clinical seizures emerged from ADs (3.55%), mostly evolving from sequential spikes. Afterdischarges in patients with stimulation seizures appeared more widespread (p < 0.0001) and lasted longer (mean duration 7.0 s) than in those without (mean duration 21.0 s, p = 0.0054). CONCLUSION: Afterdischarges appear in the epileptogenic and nonepileptogenic cortex. Duration and propagation patterns can help to quantify the risk of stimulation seizures, with sequential spikes being most susceptible to seizure elucidation. The hippocampus is highly sensitive to AD release. Brief pulse stimulation is a safe and efficacious way to terminate ADs, especially when delivered quickly after AD onset.

Asunto(s)

Corteza Cerebral/fisiopatología , Epilepsia Refractaria/fisiopatología , Electroencefalografía/métodos , Epilepsia Refractaria/diagnóstico , Estimulación Eléctrica/métodos , Electrodos Implantados , Femenino , Humanos , Masculino , Estudios Retrospectivos , Convulsiones/diagnóstico , Convulsiones/fisiopatología , Adulto Joven