RESUMEN
Over the last decades, extensive basic and clinical knowledge has been acquired on the use of subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson's disease (PD). It is now clear that mechanisms involved in the effects of this therapy are far more complex than previously anticipated. At frequencies commonly used in clinical practice, neural elements may be excited or inhibited and novel dynamic states of equilibrium are reached. Electrode contacts used for chronic DBS in PD are placed near the dorsal border of the nucleus, a highly cellular region. DBS may thus exert its effects by modulating these cells, hyperdirect projections from motor cortical areas, afferent and efferent fibers to the motor STN. Advancements in neuroimaging techniques may allow us to identify these structures optimizing surgical targeting. In this review, we provide an update on mechanisms and the neural elements modulated by STN DBS.
Asunto(s)
Estimulación Encefálica Profunda/métodos , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Animales , HumanosRESUMEN
High-frequency deep brain stimulation (DBS) is an effective treatment for some movement disorders. Though mechanisms underlying DBS are still unclear, commonly accepted theories include a "functional inhibition" of neuronal cell bodies and the excitation of axonal projections near the electrodes. It is becoming clear, however, that the paradoxical dissociation "local inhibition" and "distant excitation" is far more complex than initially thought. Despite an initial increase in neuronal activity following stimulation, cells are often unable to maintain normal ionic concentrations, particularly those of sodium and potassium. Based on currently available evidence, we proposed an alternative hypothesis. Increased extracellular concentrations of potassium during DBS may change the dynamics of both cells and axons, contributing not only to the intermittent excitation and inhibition of these elements but also to interrupt abnormal pathological activity. In this article, we review mechanisms through which high extracellular potassium may mediate some of the effects of DBS.
Asunto(s)
Potenciales de Acción , Encéfalo/fisiología , Excitabilidad Cortical , Estimulación Encefálica Profunda , Inhibición Neural , Neuronas/fisiología , Animales , Axones/fisiología , Humanos , Conducción Nerviosa , Potasio/fisiologíaRESUMEN
Experimental evidences point out the participation of nonsynaptic mechanisms (e.g., fluctuations in extracellular ions) in epileptiform bursting and spreading depression (SD). During these abnormal oscillatory patterns, it is observed an increase of extracellular potassium concentration [K(+)](o) and a decrease of extracellular calcium concentration [Ca(2+)](o) which raises the neuronal excitability. However, whether the high [K(+)](o) triggers and propagates these abnormal neuronal activities or plays a secondary role into this process is unclear. To better understand the influence of extracellular potassium dynamics in these oscillatory patterns, the experimental conditions of high [K(+)](o) and zero [Ca(2+)](o) were replicated in an extended Golomb model where we added important regulatory mechanisms of ion concentration as Na(+)-K(+) pump, ion diffusion and glial buffering. Within these conditions, simulations of the cell model exhibit seizure-like discharges (ictal bursting). The SD was elicited by the interruption of the Na(+)-K(+) pump activity, mimicking the effect of cellular hypoxia (an experimental protocol to elicit SD, the hypoxia-induced SD). We used the bifurcation theory and the fast-slow method to analyze the interference of K(+) dynamics in the cellular excitability. This analysis indicates that the system loses its stability at a high [K(+)](o), transiting to an elevated state of neuronal excitability. Effects of high [K(+)](o) are observed in different stages of ictal bursting and SD. In the initial stage, the increase of [K(+)](o) creates favorable conditions to trigger both oscillatory patterns. During the neuronal activity, a continuous growth of [K(+)](o) by outward K(+) flow depresses K(+) currents in a positive feedback way. At the last stage, due to the depression of K(+) currents, the Na(+)-K(+) pump is the main mechanism in the end of neuronal activity. Thus, this work suggests that [K(+)](o) dynamics may play a fundamental role in these abnormal oscillatory patterns.