Frequency-Specific Optogenetic Deep Brain Stimulation of Subthalamic Nucleus Improves Parkinsonian Motor Behaviors

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapy for the motor symptoms of Parkinson's disease (PD). However, the neural elements mediating symptom relief are unclear. A previous study concluded that direct optogenetic activation of STN neurons was neither necessary nor sufficient for relief of parkinsonian symptoms. However, the kinetics of the channelrhodopsin-2 (ChR2) used for cell-specific activation are too slow to follow the high rates required for effective DBS, and thus the contribution of activation of STN neurons to the therapeutic effects of DBS remains unclear. We quantified the behavioral and neuronal effects of optogenetic STN DBS in female rats following unilateral 6-hydroxydopamine (6-OHDA) lesion using an ultrafast opsin (Chronos). Optogenetic STN DBS at 130 pulses per second (pps) reduced pathologic circling and ameliorated deficits in forelimb stepping similarly to electrical DBS, while optogenetic STN DBS with ChR2 did not produce behavioral effects. As with electrical DBS, optogenetic STN DBS exhibited a strong dependence on stimulation rate; high rates produced symptom relief while low rates were ineffective. High-rate optogenetic DBS generated both increases and decreases in firing rates of single neurons in STN, globus pallidus externa (GPe), and substantia nigra pars reticular (SNr), and disrupted b band oscillatory activity in STN and SNr. High-rate optogenetic STN DBS can indeed ameliorate parkinsonian motor symptoms through reduction of abnormal oscillatory activity in the STN-associated neural circuit, and these results highlight that the kinetic properties of opsins have a strong influence on the effects of optogenetic stimulation.

Deep Brain Stimulation of the Subthalamic Nucleus Modulates Reward-Related Behavior: A Systematic Review

“…However, these experiments stimulated at 130 Hz, while kinetics of the variants of ChR2 available at the time were not able to follow such high stimulation frequencies (Gunaydin et al, 2010). More recent studies with mutated opsins [i.e., Chronos, which is capable of following frequencies over 100 Hz (Saran et al, 2018)] have suggested that activation of cell bodies at frequencies relevant to DBS may indeed rescue motor deficits in a PD model (Yu et al, 2020). As with DBS, these investigations demonstrate a frequencydependence of optogenetic effects, and have elucidated multiple neural mechanisms driving the therapeutic motor effects of STN-DBS in animal models.…”

Optogenetic investigation into the role of the subthalamic nucleus in motor control

“…Application of optogenetics in rodent parkinsonian models have shown that optogenetic excitation of cortico-subthalamic fibers in the hyperdirect pathway improves motor symptoms while its inhibition worsened them 10,11,20 . Recently, optogenetic STN-DBS verified the contribution of the STN structure in mediating beneficial effects on motor dysfunction 21 . While the use of optogenetics in parkinsonian models have thus begun to answer fundamental questions around STN-DBS mechanisms, the natural role of the STN as a gate in motor control has been poorly explored.…”

Frequency matters: Up- and Down-Regulation of Dopamine Tone Induces Similar Frequency Shifts in Cortico-Basal Ganglia Beta Oscillations

“…However, amphetamine significantly increased the number of oscillatory cortical narrow (χ 2 (4)=11.70, p=0.0197, Cramér's V=0. 19) and pallidal (χ 2 (4)=38.75, p=7.8e-8, Cramér's V=0.15) units (Fig.S3, post-hoc at Table S5).…”

“…However, there are some differences between human and NHP characteristic beta oscillations. Human beta range spans higher frequencies, and it is common to find beta oscillations in two separate beta ranges, low (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) and high (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), in some but not all patients. Therefore, we defined active beta range (low-beta, high-beta or both) manually for each patient according to their mean nPSD.…”

“…Both were alleviated by dopamine replacement therapy (DRT) or deep brain stimulation (DBS) 10,12,[17][18][19] . Based on these studies of beta activity in PD patients and animal models, dopamine has been suggested to play an important role in modulating the power of beta signaling in the CBG network.…”