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Closed‐loop stimulation: The future of surgical therapy of brain disorders?

Surgical therapy for neurological and psychiatric conditions was originally developed in the first half of the previous century but became less popular after the discovery of major therapeutic drugs such as antipsychotics, antidepressants, and levodopa. However, because of the prominent side effects of L-dopa therapy, deep brain stimulation (DBS) was reintroduced in the early 1990s after it was shown to improve Parkinsonian symptoms with limited side effects. Since then, DBS targeting basal ganglia nuclei such as the subthalamic nucleus (STN), the internal part of the globus pallidus (GPi), the striatum, and more recently the pedunculopontine nucleus has been proposed as an alternative treatment not only in Parkinson’s disease (PD), but also in dystonia or even severe obsessive compulsive disorders. Surprisingly enough, despite the obvious efficiency in improving motor symptoms in PD, the mechanisms underlying its effects are still puzzling and controversial. This treatment also has several drawbacks, such as the necessity of frequent adjustment of stimulation parameters in order to balance between clinical improvement, side effects, and battery lifespan. Moreover, nonvarying stimulation does not cope very well with the fluctuating nature of PD symptoms. It is also heuristically disappointing because whatever mechanism is put forward to explain how it works, it is clear that the high-frequency stimulation of DBS only disrupts a pathological dynamic state of the network without restoring proper information processing in the cortex-basal ganglia loop. In a recent paper published in Neuron entitled ‘‘Closed-Loop Deep Brain Stimulation Is Superior in Ameliorating Parkinsonism,’’ Professor Bergman’s team from the Hebrew University of Jerusalem, a pioneer of the rebirth of deep brain surgery in PD, proposed the first alternative approach to classical DBS based on brain-computer technology. Their elegant idea is to replace the continuous stimulation of DBS by short bursts of 130-Hz stimuli applied in the GPi and triggered by cortical spikes. The rationale behind this is to restore connectivity between the cortex and the output nuclei of the basal ganglia, reclosing the loop that was disconnected at striatal level after dopamine depletion. They tested this hypothesis in a primate model of PD and demonstrated that the effect of such a closed-loop method is far better than classical DBS protocols when they are applied at GPi level. There is, however, still work to be done in order to develop a usable human system. For theoretical reasons, the authors chose to perform stimulation at the GPi level, which is not now universally considered to be the best DBS target. Therefore, the effects should at least be compared to those of classical STN DBS in order to assess absolute improvement in PD symptoms. Another limitation is that the method relies on spike detection, but the signal-to-noise ratio notoriously degrades in chronically implanted electrodes after a few months. In the next decade, the development of further closed-loop approaches in animal models and in humans is to be expected.