Effects of <scp>GPi DBS</scp> on Sensorimotor Integration in Dystonia: A Pilot <scp>ON</scp>/<scp>OFF</scp> Study

Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) is an effective therapy for severe dystonia; however, the mechanism by which DBS improves dystonia is still poorly understood.1-3 To determine the role of cholinergic modulation in dystonia and DBS, we measured short-latency afferent inhibition (SAI), a transcranial magnetic stimulation (TMS) protocol sensitive to cortical cholinergic function.4 We studied patients with dystonia in both DBS-ON and DBS-OFF conditions, expecting that DBS state would modify SAI. Although cholinergic modulation is known to influence long-term plasticity,5 SAI has never been studied in GPi-DBS. The SAI protocol consisted of 120 TMS pulses (at the lowest stimulator intensity producing a motor evoked potential (MEP) of approximately 1 mV in 5/10 trials) delivered to the dominant motor cortex, preceded by suprathreshold (meaning 2X perceptual threshold) electrical nerve stimulation (NS) applied to the contralateral median nerve using three interstimulus intervals (ISI, 21, 25, and 27 ms) (Fig. 1A). SAI is defined as the inhibition induced by the NS conditioned compared to unconditioned TMS trials (Fig. 1B) and is represented as a ratio. Testing was performed with DBS-ON or -OFF first and repeated after a 20-minute washout/rest between conditions. In 10 patients (3M/7F, 57.6 ± 12.9 years) with GPi-DBS, there were no significant differences in SAI comparing DBS-ON (mean SAI = 0.9052) and DBS-OFF (mean SAI = 0.7441) (paired t-test, t[9] = 2.63, P = 0.0803). At least one of the ISIs produced inhibition in all but one patient. Similarly, the sex- and age-matched control group (3M/7F; 57.6 ± 11.9 years) displayed no difference between SAI in the first versus second testing condition (t[9] = −0.048, P = 0.582). A two-way ANOVA comparing SAIs between conditions (ON/OFF) and groups (Patient/Control) showed no statistically significant interaction between effects and group (F[1] = 0.879, P = 0.355) (Fig. 1D). Neither group nor condition was statistically related to the mean amplitude of SAI (F(1) = 1.655, P = 0.207; F(1) = 3.016, P = 0.091). SAI was normal in dystonia subjects relative to age- and sex-matched controls, and GPi-DBS did not alter SAI. As in previous reports,4 SAI was quite variable (Fig. 1B); age, experimental environment, cognitive attention, sleep, and other factors can influence SAI. SAI has been reported to be both normal and abnormal in dystonia,6 and DBS in subthalamic nucleus is believed to normalize it.2 Because our protocol was limited by the short time available for testing, it is possible that the brief interruption in DBS in chronic DBS patients may have been insufficient, preventing a statistically significant change in SAI to be measured. Similarly, mixed medication use within a heterogeneous cohort may have been a factor. It is also possible that increased inhibition may have been observed using a higher peripheral nerve stimulation intensity. We previously showed that DBS in the rodent equivalent of GPi results in cholinergic modulation of neuronal activity with extracellular recordings in patients during surgery confirming similar findings.7 SAI, however, is thought to depend on cortical cholinergic activity that may be unrelated to local DBS effects in the basal ganglia. Compared to subthalamic (STN)-DBS, which works faster to treat dystonia,2 clinical benefits occur gradually with GPi-DBS for dystonia.3 This is consistent with our results because only one of our patients had worsening dystonia OFF GPi-DBS. The different time course of response to STN-DBS and GPi-DBS does suggest different mechanisms of action for the two treatments, and cholinergic activity may still play a role in the long-term brain plasticity associated with DBS improvement. Also, variability in plasticity measures has not only been acknowledged but has also been suggested to be informative in dystonia.8 SAI changes between DBS-ON and -OFF states approach significance in our small and heterogeneous patient cohort following brief DBS interruption; this warrants further mechanistic inquiry into GPi-DBS in dystonia aimed to delineate sources of variability in plasticity measures such as those that may modify cholinergic function. This study was funded by the Dystonia Medical Research Foundation and the Natural Sciences and Engineering Research Council (NSERC) of Canada. A.P.A. holds a BRAIN-CREATE Postdoctoral Fellowship, and R.E.S. held an NSERC studentship. We thank all study participants for agreeing to be part of our study. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. (4) Patient recruitment. A.P.A.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B N.A.Z.: 1A, 1B, 1C, 2A, 2B, 2C, 3B R.E.S.: 1A, 2C, 3B Z.H.T.K.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 4 L.R.B.: 1B, 1C, 2C D.M.: 1A, 3B, 4 The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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