Multiple stimulation parameters influence efficacy of deep brain stimulation in parkinsonian mice
Jonathan S. Schor, Alexandra B. Nelson
Jonathan S. Schor, Alexandra B. Nelson
View: Text | PDF
Concise Communication Neuroscience

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

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

×

Figure 1

STN DBS alleviates bradykinesia in parkinsonian mice across a wide range of frequencies.

Options: View larger image (or click on image) Download as PowerPoint
STN DBS alleviates bradykinesia in parkinsonian mice across a wide range...
(A) Experimental time line. (B) Sagittal schematic showing unilateral 6-OHDA medial forebrain bundle (MFB) injection. (C) Representative coronal section immunostained for tyrosine hydroxylase (TH) showing ipsilateral depletion of striatal TH. Scale bar: 750 μm. (D and E) Coronal schematic (D) and histological section (E) showing ipsilesional STN targeting of DBS electrode (dotted white line and terminal electrolytic lesion). Scale bars: 250 μm (left panel); 750 μm (right panel). (F) Representative open field movement before, during, and after 120 Hz STN DBS in a parkinsonian mouse (5 minutes each). (G) Representative raw velocity traces over standard 11-minute trials, consisting of 5 one-minute bouts of 5 Hz, 20 Hz, 120 Hz, and 160 Hz STN DBS interleaved with 6 one-minute rest bouts. (H) Average velocity of parkinsonian mice during stimulation epochs across frequencies with constant pulse width (60 μs) and constant current (200 μA). Healthy refers to nonparkinsonian mice. Pre and post refer to 30 seconds before and after stimulation. Box extends from 25th to 75th percentile; median is indicated by horizontal line. Whiskers represent maximum and minimum values. n = 9 healthy mice; n = 9 parkinsonian mice. Significance determined by 1-way repeated measures ANOVA followed by Tukey’s honest significant difference test. *P < 0.05 compared with prestim period. Ctx, cortex; Str, striatum; SNc, substantia nigra pars compacta; IC, internal capsule.