A new form of deep-brain stimulation (DBS) in which the stimulus responds to brain activity has shown promise in a primate model of Parkinson’s disease, Israeli researchers report.
They say that real-time adaptive DBS could potentially be used to treat not only Parkinson’s disease but also other neurologic disorders that are characterized by pathologic patterns of brain activity.
DBS is widely used to treat patients with advanced Parkinson’s disease and other motor disorders. Although the underlying mechanisms of benefit remain unclear, the approach – which involves continuous delivery of high-frequency electrical stimulation – is effective in alleviating symptoms.
At present, DBS is considered an “open loop” system because the stimulation parameters – frequency, pulse width, and intensity – are determined by an external stimulator and adjusted manually at 3-12 month intervals.
“The goal of the stimulator programming is to adjust the DBS parameters in order to achieve an updated optimal trade-off between maximization of clinical improvement and minimization of stimulation-induced side effects,” explain Boris Rosin (The Hebrew University of Jerusalem, Israel) and co-workers in the journal Neuron.
However, this results in stimulation that does not keep up with the dynamic nature of Parkinson’s disease, the researchers note in a press statement.
In this study, Rosin’s team developed an alternative “closed-loop” paradigm in which neuronal activity in a reference brain area (the basal ganglia) was monitored in real time and used as the trigger for stimulating the target area (the globus pallidum).
They tested this approach in a series of experiments involving two monkeys with experimental parkinsonism, induced with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Rosin et al showed that, compared with standard open-loop DBS and matched control stimulation paradigms, corticopallidal closed-loop stimulation had a significantly greater effect on akinesia and on cortical and pallidal discharge patterns.
The new paradigm also led to dissociation between changes in basal ganglia discharge rates and patterns, thereby “providing insights into Parkinson’s disease pathophysiology,” according to the authors.
They conclude: “Closed-loop DBS paradigms, by modulating pathological oscillatory activity rather than the discharge rate of the basal ganglia-cortical networks, may afford more effective management of advanced Parkinson’s Disease.
“Such strategies have the potential to be effective in additional brain disorders in which a pathological neuronal discharge pattern can be recognized.”
In an accompanying editorial, Fernando Santos (Instituto Gulbenklan de Ciência, Oeiras, Portugal) and co-authors say the study offers important insights into how DBS works.
They write: “It is becoming increasingly apparent that several diseases like schizophrenia, epilepsy, obsessive-compulsive disorders, Tourette syndrome, and depression could be treated using brain stimulation, and the real-time adaptive stimulation paradigm presented here could also offer significant advantages in the treatment of the associated symptoms.
“Hopefully, future studies in animal models will help disentangle not only how these pathologies emerge, but also define the best strategies to improve clinical outcomes.”
Closed-Loop Deep Brain Stimulation Is Superior in Ameliorating Parkinsonism
Neuron, Volume 72, Issue 2, 370-384, 20 October 2011
Continuous high-frequency deep brain stimulation (DBS) is a widely used therapy for advanced Parkinson’s disease (PD) management. However, the mechanisms underlying DBS effects remain enigmatic and are the subject of an ongoing debate. Here, we present and test a closed-loop stimulation strategy for PD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD. Application of pallidal closed-loop stimulation leads to dissociation between changes in basal ganglia (BG) discharge rates and patterns, providing insights into PD pathophysiology. Furthermore, cortico-pallidal closed-loop stimulation has a significantly greater effect on akinesia and on cortical and pallidal discharge patterns than standard open-loop DBS and matched control stimulation paradigms. Thus, closed-loop DBS paradigms, by modulating pathological oscillatory activity rather than the discharge rate of the BG-cortical networks, may afford more effective management of advanced PD. Such strategies have the potential to be effective in additional brain disorders in which a pathological neuronal discharge pattern can be recognized.
Authors – Boris Rosin, Maya Slovik, Rea Mitelman, Michal Rivlin-Etzion, Suzanne N. Haber, Zvi Israel, Eilon Vaadia, Hagai Bergman