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Multiple stimulation parameters influence efficacy of deep brain stimulation in parkinsonian mice
Jonathan S. Schor, Alexandra B. Nelson
Jonathan S. Schor, Alexandra B. Nelson
Published June 13, 2019
Citation Information: J Clin Invest. 2019;129(9):3833-3838. https://doi.org/10.1172/JCI122390.
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Concise Communication Neuroscience

Multiple stimulation parameters influence efficacy of deep brain stimulation in parkinsonian mice

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Abstract

Deep brain stimulation (DBS) is used to treat multiple neuropsychiatric disorders, including Parkinson’s disease (PD). Despite widespread clinical use, its therapeutic mechanisms are unknown. Here, we developed a mouse model of subthalamic nucleus (STN) DBS for PD, to permit investigation using cell type–specific tools available in mice. We found that electrical STN DBS relieved bradykinesia, as measured by movement velocity. In addition, our model recapitulated several hallmarks of human STN DBS, including rapid onset and offset, frequency dependence, dyskinesia at higher stimulation intensity, and associations among electrode location, therapeutic benefit, and side effects. We used this model to assess whether high-frequency stimulation is necessary for effective STN DBS and whether low-frequency stimulation can be effective when paired with compensatory adjustments in other parameters. We found that low-frequency stimulation, paired with greater pulse width and amplitude, relieved bradykinesia. Moreover, a composite metric incorporating pulse width, amplitude, and frequency predicted therapeutic efficacy better than frequency alone. We found a similar relationship between this composite metric and movement speed in a retrospective analysis of human data, suggesting that correlations observed in the mouse model may extend to human patients. Together, these data establish a mouse model for elucidating mechanisms of DBS.

Authors

Jonathan S. Schor, Alexandra B. Nelson

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Figure 2

STN DBS in parkinsonian mice recapitulates key features of human DBS.

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STN DBS in parkinsonian mice recapitulates key features of human DBS.
(A...
(A) Average abnormal involuntary movement (AIM) score of parkinsonian mice during 1-minute stimulation epochs as a function of current (upper panel), pulse width (middle panel), or frequency (lower panel), holding the other 2 parameters constant (n = 9 mice, 5 trials per mouse per condition). (B) Stimulation sites across all mice, as determined postmortem (n = 9 mice; red dots). (C) Correlation between dorsoventral (DV) stimulation site and velocity increases for individual mice at standard parameters (n = 9 mice). (D) Correlation between the stimulation site/pyramidal tract distance and average AIM score for individual mice at the parameter setting shown (n = 9 mice). Significance determined by 1-way repeated measures ANOVA (performed on all stimulation parameters shown in A) followed by Tukey’s honest significant difference test. *P < 0.05 compared with lowest stimulation setting.
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