Optogenetics-based neuromodulation for the treatment of Parkinson's disease

Abstract

Parkinson's disease is a neurodegenerative disorder with severe motor deficits such as bradykinesia, muscle rigidity, tremor at rest and abnormal posture. From neurophysiological perspective, the most prominent feature of Parkinsonian pathophysiology is enhanced beta-band power (1340 Hz beta oscillations) in the local field potentials (LFPs) in motor cortex and in several basal ganglia nuclei. Currently, the most effective treatment for advanced Parkinson's disease is the electrical deep brain stimulation (eDBS) targeting at the subthalamic nucleus or internal globus pallidus, in which electrical current at about 125 Hz is continuously injected in to the target area. Even though eDBS significantly alleviates motor symptoms of the disease, it does not provide a complete cure. Therefore, there have been ongoing efforts to develop more effective brain stimulation paradigms, e.g. exploration of alternative areas for stimulation, or employment of advanced stimulation paradigms. A major obstacle against these efforts has been the ambiguities associated with electrical stimulation. Due to nonspecific nature of electrical stimulation and its incompatibility with simultaneous electrophysiology, it has been challenging to fine tune stimulation parameters and target specific neuronal groups or circuits with eDBS. In this work, we demonstrate optogenetics-based brain stimulation as a potential alternative to electrical brain stimulation in the treatment of Parkinson's disease. Optogenetics, with its cellular specificity and compatibility with electrophysiology, offers unique opportunities to monitor the neural activity while modulating the activity of targeted neuronal populations. In our study, we address two important premises for assessment of an optogenetics-based therapeutic brain stimulation paradigm: (1) validation of therapeutic value of precisely targeted deep brain optogenetic modulation; (2) demonstration of potential benefits of spatiotemporally patterned optogenetic stimulation of the motor cortex by characterizing the spatiotemporal dynamics of pathological cortical beta-band activity. In 6-OHDA-induced hemi-Parkinsonian rat model, we used excitatory opsins (ChR2 and C1V1) or inhibitory opsins (iC1C2 and NpHR) to excite or inhibit the subthalamic nucleus. Neural activity across motor cortex was recorded with microelectrode arrays (MEAs, 400μm electrode pitch) implanted unilaterally (6×6 MEA) or bilaterally (two 5×5 MEAs) into the anterior forelimb area of motor cortices. Recording/stimulation sessions were performed during free behavior or during behavioral assays (e.g. amphetamine-induced rotation and mobility test) to quantify and compare therapeutic efficacies of optogenetic stimulation and eDBS. The spatiotemporal dynamics of LFPs were examined with spectral, correlation, and coherence analyses. Our data confirmed the motor deficits such as akinesia and rotational bias in h-P rats. eDBS of subthalamic nucleus improved these motor deficits to some extent, but not completely. In agreement with earlier findings (Gradinaru et al., Science, 2009), optogenetic excitation of subthalamic nucleus did not lead to behavioral improvements; by contrast we found that optogenetic inhibition of subthalamic did alleviate akinesia and rotational bias. Accompanying the motor deficits, elevated betaband power in LFPs was observed on the lesioned side of motor cortex. Interestingly, these beta oscillations appeared intermittently only at certain locations as distinct spatial activity patterns. A linear discriminant analysis showed that the beta band power at some recording sites was indistinguishable from control levels. However, further analysis indicated that these sites could be distinguished from control sites by their phase coherence. We found, within the lesioned motor cortex, excess phase coherence at the beta band between pairs of recording sites. The beta synchrony was not distributed uniformly; it was more pronounced between sites with higher beta power. Single-site optogenetic modulation of subthalamic nucleus led to behavioral improvements, but effects were limited as in eDBS. Our results show that optogenetics-based brain stimulation could be used as a therapeutic interference in Parkinson's disease. On the other hand, the variation of beta power and phase across motor cortex implied inhomogeneity in the extent of Parkinsonism, and hence, the potential therapeutic benefit of differential neuromodulation at different cortical sites. Therefore, given the anatomical and functional location of the motor cortex within motor circuitry and its large size, our results imply that spatiotemporally-specific optogenetic modulation of motor cortex might be a potential approach for therapeutic brain stimulation. Such modulation paradigm could allow more specific control of motor cortical activity, and thereby alleviate motor symptoms. Our next step is to investigate the therapeutic potential of spatiotemporally-specific optogenetic modulation of the motor cortex, for which we will use custom optoelectrode arrays with capabilities of multi-site light delivery and electrophysiology.