. Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol. 2009 May;65(5):586-95. PubMed.

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  1. Comment by Bechir Jarraya and Stephane Palfi on Gradinaru et al.

    What Are We Stimulating in the Brain?
    Deep brain stimulation (DBS) has proved to be a very powerful technique to modulate behavior in an On/Off manner. This led to an intensive development of DBS as a therapeutic option for neurological and psychiatric disorders. The case for Parkinson disease (PD) is a unique demonstration of how tremendous can be the behavioral shift following electrical stimulation of subthalamic nucleus (STN) region. Because a very localized electrical stimulation of the brain can shift symptoms, accurate localization of DBS target becomes of primary importance. DBS holds potential to successfully treat debilitating neurological conditions and drug-resistant psychiatric disorders. The fine understanding of the neurobiological mechanisms of DBS would be of a great interest to improve the field and help developing future applications. It is commonly thought that DBS ameliorates PD by inhibiting STN neuron activity.

    Up to now, the “inhibition” hypothesis was difficult to investigate because of challenging technological issues. Indeed, when you electrically stimulate the STN and record neuronal activity anywhere in the brain in the same time, a huge stimulation-generated artifact makes interpretation very difficult to achieve. Optogenetics is a recent field that permits fine and precise temporospatial control of neuronal excitation. Moreover, using selective gene transfer, optogenetics has the other major advantage of precisely discriminating STN afferent fiber excitation from STN neuron excitation and allowing neuronal recording in the same time.

    Using optogenetics tools, Gradinaru et al. have made a major contribution to the DBS field. They rigorously dissected the cortico-subcortical neuronal networks using elegant optogenetic technology. Specifically, a dedicated device called an “optrode” allows recording of neuronal activity during light stimulation, without any concomitant artifact. They clearly demonstrated that DBS improves parkinsonism, not by inhibiting STN neurons, as commonly thought, but through the neuromodulation of afferent fibers to the STN. Hence, neuromodulation of axon tracts afferent to the STN are the highly probable mechanism through which electric DBS electrodes implanted to the STN region work in PD patients.

    How can these rodent findings be translated into clinical reality?

    As the authors pointed out, cortical areas projecting into the STN are definitely the brain target that holds the potential to alleviate PD symptoms. From a practical point of view, cortical stimulation offers a more accessible region for surgery, and such a simplification of the surgical procedure is critical for the widespread use of DBS. From a clinical point of view, a cortical approach can provide a more selective stimulation to modify specific behavioral dysfunctions. A recent preclinical study in parkinsonian monkeys has already demonstrated that high-frequency motor cortex modulation is technically feasible and could induce a behavioral correction by inhibiting efferent fibers within the STN and the globus pallidus, another important nucleus in the cortico-basal ganglia system (Drouot et al., 2004) However, Phase 1 clinical studies remain controversial because of concerns surrounding the behavioral efficacy of cortical stimulation in PD patients. One explanation is related to remaining technical issues that need to be solved. In fact, as pointed out in the current paper, cortical stimulation should selectively target a deep layer V, which requires refinement of electrical cortical stimulation devices in order to achieve that goal. Thus, a similar translational research program is certainly necessary in the gold standard animal model of neurological diseases to make optogenetics ready for clinical use.

    References:

    . Functional recovery in a primate model of Parkinson's disease following motor cortex stimulation. Neuron. 2004 Dec 2;44(5):769-78. PubMed.

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