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. 2019 Oct 14:6:2384-2395.
doi: 10.1016/j.mex.2019.10.012. eCollection 2019.

Rat subthalamic stimulation: Evaluating stimulation-induced dyskinesias, choosing stimulation currents and evaluating the anti-akinetic effect in the cylinder test

Antti Huotarinen  1 , Sakari Leino  2 , Raimo K Tuominen  2 , Aki Laakso  1
Affiliations

Rat subthalamic stimulation: Evaluating stimulation-induced dyskinesias, choosing stimulation currents and evaluating the anti-akinetic effect in the cylinder test

Antti Huotarinen et al. MethodsX. .

Abstract

In experimental deep brain stimulation of the subthalamic nucleus (STN HFS), stimulation currents just below the appearance threshold of stimulation-induced dyskinesias has often been used. The behavioral effect of STN HFS can be measured by the reversal of forelimb use asymmetry produced by hemiparkinsonism can be measured with the cylinder test among other tests. We used 18 Wistar rats with 6-hydroxydopamine induced hemiparkinsonism to test a customized scale to rate the severity of stimulation-induced dyskinesia; we then used these ratings to choose low and high stimulation currents. Subsequent cylinder tests showed that stimulation at the higher current, inducing mild and short-lived dyskinesias, was required for robust improvement in forelimb use, contradicting the use of currents below stimulation-induced dyskinesia threshold. It was also beneficial to separately count both all touches and first touches with the cylinder wall; this provided additional sensitivity and robustness to our results. •Scoring stimulation-induced dyskinesias can be used as a quantitative measure of dyskinesias and to choose stimulation currents.•Cylinder test scoring separately for both first and all touches can improve both sensitivity and reliability.•STN HFS at a current producing short-lived dyskinesias was required for robust improvement in forelimb use asymmetry.

Keywords: 6-OHDA; Cylinder test; Dyskinesia; Parkinson’s disease; STN DBS; STN HFS; Subthalamic high frequency stimulation, cylinder test.

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Conflict of interest statement

AH received funding for work from the Finnish Government (grants for academic healthcare research) and the Finnish Parkinson Foundation. Conference fees and travel expenses have been paid by Medtronic, St. Jude and AbbVie.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Experiment design. mfb = medial forebrain bundle, 6-OHDA = 6-hydroxydopamine.
Fig. 2
Fig. 2
A) Biochemical verification of successful 6-OHDA lesioning, using western blot for tyrosine hydroxylase above; confirms dopamine depletion on the lesioned side. Results of actin loading control below. (L) compared to un-lesioned (U) striata. B) An example of good electrode placement within the STN. C) An example of missed electrode placement, despite a good observed anti-akinetic stimulation effect and high level of dyskinesia. D) Electrode locations in relation to Paxinos and Watson rat brain atlas images, with corresponding coronal sections (4th edition, Figures 33–39, used with permission from Elsevier). Anatomical hits (n = 10) within 200 μm of STN border are represented by solid markers and misses (n = 8) by hollow markers. Triangles represent rats with high dyskinesia response (n = 12) and circles represent rats with low dyskinesia response. L = lesioned side, U = unlesioned side, MGP = medial globus pallidus, MCLH = magnocellular nucleus of the lateral hypothalamus. STN/STh = subthalamic nucleus, ZI = zona incerta, dashed line = STN, solid line = electrode.
Fig. 3
Fig. 3
A) Stimulation-induced dyskinesias by dyskinesia type across all stimulation currents (n = 18). B) Sum of all dyskinesia ratings without the orofacial dyskinesias across all currents (total dyskinesia score, TDS, theoretical maximum 204). Each bar represents an individual rat ordered from the lowest to highest value, as rated from video (researcher 1) and live during stimulation (researcher 2). C) Amplitudes used for low and high stimulation. Each square or circle represents a single animal. Data presented as mean; error bars represent 95% CI.
Fig. 4
Fig. 4
STN HFS, with both low and high stimulation, reduced forelimb use asymmetry in the cylinder test. A) The effect of STN HFS at two stimulation amplitudes on contralateral forelimb use was observed when counting all forepaw touches with the cylinder wall made during rearing movements. B) When counting only first forepaw touches with the wall during rearing movements, improvement in contralateral forelimb use was observed only with high stimulation. (A and B, stacked bar charts) C) Correlation was observed between measurements of contralateral forelimb use obtained by counting all touches (x-axis) and only first touches (y-axis) with the wall during rearing movements. Data presented as mean; error bars represent 95% CI. H = rats with high total dyskinesia score; L = rats with low total dyskinesia score. ** different from baseline: p < 0.01 Bonferroni-corrected post-hoc test. †† different from low stimulation: p < 0.01 Bonferroni-corrected post-hoc test.
Fig. 5
Fig. 5
Contralateral forelimb use in the cylinder test correlated with dyskinesia ratings without orofacial dyskinesia. A) Contralateral forelimb use as measured by counting all touches with the cylinder wall during rearing movements. B) Contralateral forelimb use as measured by counting only first touches with the wall during rearing movements, compared to dyskinesia ratings observed at similar amplitudes during previous test stimulations. When rats were divided into low and high dyskinesia groups, there was no difference in forelimb use asymmetry in the cylinder test using either C) all touches or D) first touches, showing that similar efficacy of STN HFS was achieved by tailoring stimulation amplitude according to sensitivity to dyskinesia. (C and D, stacked bar charts). Solid line represents linear regression; dashed line represents 95% CI H = rats with high total dyskinesia score; L = rats with low total dyskinesia score.
Fig. 6
Fig. 6
Comparison of forelimb use asymmetry between rats with good electrode placement and missed electrode placement in the cylinder test using A) all touches and B) first touches. (A and B, stacked bar charts) C) The sum of axial, forelimb, and locomotive dyskinesia ratings at low and high stimulation amplitudes, respectively. ** different from baseline: p < 0.01 Bonferroni-corrected post-hoc test. †† different from low stimulation: p < 0.01 Bonferroni-corrected post-hoc test.
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