Article,
Deep brain stimulation.
Cell and Tissue research, 318 (1): 275--88 (October 2004)
DOI: 10.1007/s00441-004-0936-0
Abstract
During the last decade deep brain stimulation (DBS) has become a routine
method for the treatment of advanced Parkinson's disease (PD), leading
to striking improvements in motor function and quality of life of
PD patients. It is associated with minimal morbidity. The rationale
of targeting specific structures within basal ganglia such as the
subthalamic nucleus (STN) or the internal segment of the globus pallidus
(GPi) is strongly supported by the current knowledge of the basal
ganglia pathophysiology, which is derived from extensive experimental
work and which provides the theoretical basis for surgical therapy
in PD. In particular, the STN has advanced to the worldwide most
used target for DBS in the treatment of PD, due to the marked improvement
of all cardinal symptoms of the disease. Moreover on-period dyskinesias
are reduced in parallel with a marked reduction of the equivalent
daily levodopa dose following STN-DBS. The success of the therapy
largely depends on the selection of the appropriate candidate patients
and on the precise implantation of the stimulation electrode, which
necessitates careful imaging-based pre-targeting and extensive electrophysiological
exploration of the target area. Despite the clinical success of the
therapy, the fundamental mechanisms of high-frequency stimulation
are still not fully elucidated. There is a large amount of evidence
from experimental and clinical data that stimulation frequency represents
a key factor with respect to clinical effect of DBS. Interestingly,
high-frequency stimulation mimics the functional effects of ablation
in various brain structures. The main hypotheses for the mechanism
of high-frequency stimulation are: (1) depolarization blocking of
neuronal transmission through inactivation of voltage dependent ion-channels,
(2) jamming of information by imposing an efferent stimulation-driven
high-frequency pattern, (3) synaptic inhibition by stimulation of
inhibitory afferents to the target nucleus, (4) synaptic failure
by stimulation-induced neurotransmitter depletion. As the hyperactivity
of the STN is considered a functional hallmark of PD and as there
is experimental evidence for STN-mediated glutamatergic excitotoxicity
on neurons of the substantia nigra pars compacta (SNc), STN-DBS might
reduce glutamatergic drive, leading to neuroprotection. Further studies
will be needed to elucidate if STN-DBS indeed provides a slow-down
of disease progression.
