RESUMEN
The grid-like activity pattern of cells in the mammalian entorhinal cortex provides an internal reference frame for allocentric self-localization. The same neurons maintain robust phase couplings with local field oscillations. We found that neurons of the human entorhinal cortex display consistent spatial and temporal phase locking between spikes and slow gamma band local field potentials (LFPs) during virtual navigation. The phase locking maintained an environment-specific map over time. The phase tuning of spikes to the slow gamma band LFP revealed spatially periodic phase grids with environment-dependent scaling and consistent alignment with the environment. Using a Bayesian decoding model, we could predict the avatar's position with near perfect accuracy and, to a lesser extent, that of heading direction as well. These results imply that the phase of spikes relative to spatially modulated gamma oscillations encode allocentric spatial positions. We posit that a joint spatiotemporal phase code can implement the combined neural representation of space and time in the human entorhinal cortex.
RESUMEN
The spatially periodic activity of grid cells in the entorhinal cortex (EC) of the rodent, primate, and human provides a coordinate system that, together with the hippocampus, informs an individual of its location relative to the environment and encodes the memory of that location. Among the most defining features of grid-cell activity are the 60° rotational symmetry of grids and preservation of grid scale across environments. Grid cells, however, do display a limited degree of adaptation to environments. It remains unclear if this level of environment invariance generalizes to human grid-cell analogs, where the relative contribution of visual input to the multimodal sensory input of the EC is significantly larger than in rodents. Patients diagnosed with nontractable epilepsy who were implanted with entorhinal cortical electrodes performing virtual navigation tasks to memorized locations enabled us to investigate associations between grid-like patterns and environment. Here, we report that the activity of human entorhinal cortical neurons exhibits adaptive scaling in grid period, grid orientation, and rotational symmetry in close association with changes in environment size, shape, and visual cues, suggesting scale invariance of the frequency, rather than the wavelength, of spatially periodic activity. Our results demonstrate that neurons in the human EC represent space with an enhanced flexibility relative to neurons in rodents because they are endowed with adaptive scalability and context dependency.
Asunto(s)
Corteza Entorrinal/fisiopatología , Epilepsia/fisiopatología , Neuronas , Adulto , Corteza Entorrinal/patología , Epilepsia/patología , Femenino , Humanos , MasculinoRESUMEN
PURPOSE: To determine whether pregabalin reduces SGTC seizures in clinically refractory epilepsy. DESIGN: Post hoc analysis performed on pooled data from three double-blind, placebo-controlled trials of similar design. PARTICIPANTS: Patients with partial seizures who failed > or =2 antiepileptic drugs at maximally tolerated doses. This analysis excluded those who did not have an SGTC seizure during baseline or treatment periods. OUTCOME MEASURE: Absolute and conditional reduction analyses examined change from baseline in SGTC seizure rates. The absolute reduction analysis used response ratio (RRatio) to compare reduction in seizure-frequency from baseline (B) during a 12-week treatment (T) period [RRatio=((T-B)/(T+B))x100]. The conditional analysis examined proportional risk of having SGTC seizure if a partial seizure had occurred. RESULTS: Of 1052 intent-to-treat patients, 409 were included. Sixteen were seizure-free during treatment and not included in the conditional analysis. A significant reduction in absolute SGTC seizures from baseline was observed in patients receiving pregabalin 600 mg/day (treatment RRatio, -33 versus placebo, -3.7; P=0.0005). A lower dose of pregabalin (300mg/day), administered in one study, demonstrated a trend (nonsignificant) toward reduced SGTC seizures (treatment, -24.7 versus placebo, -10.0; P=0.2493). CONCLUSION: As adjunctive therapy, pregabalin 600 mg/day is effective in reducing the absolute frequency of SGTC seizures in patients with refractory partial epilepsy, but not secondary generalization.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Convulsiones/prevención & control , Ácido gamma-Aminobutírico/análogos & derivados , Anticonvulsivantes/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Resistencia a Múltiples Medicamentos , Epilepsias Parciales/complicaciones , Humanos , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Pregabalina , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Terapia Recuperativa , Convulsiones/etiología , Ácido gamma-Aminobutírico/administración & dosificación , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
This review discusses the safety and tolerability of levetiracetam, as presented by the available literature, with attention paid to special populations. In Phase II/III trials, the adverse effects occurring more commonly in the treatment groups versus the placebo group were; somnolence (14.8 versus 8.4%), asthenia (14.7 versus 9.1%), infection (primarily common cold) (13.4 versus 7.5%), and dizziness (8.8 versus 4.1%). Adverse events usually appear within the first month after treatment initiation, are not dose-dependent, are mostly mild-to-moderate, generally resolve without medication withdrawal, and are transient when the medication is stopped. No significant changes in haematology and chemistry profiles or weight occurred. Hypersensitivity reactions were rare and no idiosyncratic event has been reported. Open-label studies have added patient data with other epileptic syndromes and from a wider patient pool, such as children and patients with prior psychiatric history. These studies have supported initial safety findings, but have reported increased behavioural adverse events in children and patients with a history of prior behavioural problems. Levetiracetam is proving to be safe and well-tolerated. So far, it appears to have a favourable safety profile in special populations, such as children, the elderly, and patients with hepatic dysfunction. Preliminary data in pregnancy are promising, but more data are needed on the impact of levetiracetam on the developing fetus and pharmacokinetic alterations caused in pregnancy. Adjustments in dosing are required for decreases in renal clearance.
Asunto(s)
Anticonvulsivantes/efectos adversos , Epilepsia/tratamiento farmacológico , Piracetam/análogos & derivados , Piracetam/efectos adversos , Anomalías Inducidas por Medicamentos/etiología , Adolescente , Adulto , Factores de Edad , Anciano , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Astenia/inducido químicamente , Densidad Ósea/efectos de los fármacos , Niño , Trastornos de la Conducta Infantil/inducido químicamente , Trastornos de la Conducta Infantil/complicaciones , Ensayos Clínicos como Asunto , Trastornos de Somnolencia Excesiva/inducido químicamente , Mareo/inducido químicamente , Evaluación Preclínica de Medicamentos , Femenino , Cefalea/inducido químicamente , Humanos , Infecciones/etiología , Enfermedades Renales/complicaciones , Levetiracetam , Hepatopatías/complicaciones , Masculino , Trastornos Mentales/inducido químicamente , Trastornos Mentales/complicaciones , Ratones , Persona de Mediana Edad , Aceptación de la Atención de Salud , Piracetam/farmacología , Piracetam/uso terapéutico , Embarazo , Complicaciones del Embarazo/tratamiento farmacológicoRESUMEN
About 20-40% of patients with epilepsy will be refractory to medical treatment with antiepileptic drugs. It is unclear whether patients are already drug-resistant at the time of their initial presentation, or whether they become so over the course of their illness. Identifying predictors for drug-refractory epilepsy may be important for directing epilepsy patients to an effective nonpharmacological treatment, such as surgery or the vagus nerve stimulator, in a timely manner. In addition, understanding the factors that lead to the drug-refractory state may facilitate the development of new therapies that are effective in the resistant subgroup. This paper identifies various predictors that have been associated with drug-refractory epilepsy, discusses the evidence behind each factor and recommends strategies for clarifying predictors of refractoriness.