Deep brain stimulation in the caudal zona incerta versus best medical treatment in patients with Parkinson’s disease: a randomised blinded evaluation

Abstract

BackgroundSeveral open-label studies have shown good effect of deep brain stimulation (DBS) in the caudal zona incerta (cZi) on tremor, including parkinsonian tremor, and in some cases also a benefit on akinesia and axial symptoms. The aim of this study was to evaluate objectively the effect of cZi DBS in patients with Parkinson’s disease (PD).Method25 patients with PD were randomised to either cZi DBS or best medical treatment. The primary outcomes were differences between the groups in the motor scores of the Unified Parkinson’s Disease Rating Scale (UPDRS-III) rated single-blindly at 6 months and differences in the Parkinson’s Disease Questionnaire 39 items (PDQ-39). 19 patients, 10 in the medical arm and 9 in the DBS arm, fulfilled the study.ResultsThe DBS group had 41% better UPDRS-III scores off-medication on-stimulation compared with baseline, whereas the scores of the non-surgical patients off-medication were unchanged. In the on-medication condition, there were no differences between the groups, neither at baseline nor at 6 months. Subitems of the UPDRS-III showed a robust effect of cZi DBS on tremor. The PDQ-39 domains ‘stigma’ and ‘ADL’ improved only in the DBS group. The PDQ-39 summary index improved in both groups.ConclusionThis is the first randomised blinded evaluation of cZi DBS showing its efficacy on PD symptoms. The most striking effect was on tremor; however, the doses of dopaminergic medications could not be decreased. cZi DBS in PD may be an addition to existing established targets, enabling tailoring the surgery to the needs of the individual patient.

Zona incerta as a therapeutic target in Parkinson’s disease

“…The stimulated region was located between the red nucleus and STN, slightly posteromedially to the posterior tail of the latter structure. In an agreement with previous studies [47,49], DBS of this region induced a profound effect on tremor, had less influence on akinesia and was free of negative influence on speech [50]. Special involvement of the caudal ZI and prelemniscal radiation (located posteromedially to the posterodorsal STN) in tremor, in general, was proven also by findings that DBS of this region had strong effect on PD voice tremor, proximal, distal and axial essential tremor, postural and intention component of multiple sclerosis tremor, Holmes tremor (resting, postural and intention) and dystonic tremor [49,[51][52][53][54].…”

“…Two years later Plaha and coworkers reported a dramatic mitigation of resting (94.8%) and postural (88.2%) tremor in PD patients as a result of bilateral stimulation of the caudal zone of the ZI [49]. Finally, Blomstedt and coworkers [50] chose this part of the ZI for DBS in 19 PD patients. The stimulated region was located between the red nucleus and STN, slightly posteromedially to the posterior tail of the latter structure.…”

“…However, according to general opinion of neurosurgeons, DBS of the caudal sector of the ZI was the most therapeutically effective, especially with respect to reduction of different forms of tremor, including parkinsonian tremor [46,47,[49][50][51][52][53]. The most probable explanation of this effect is that DBS affects the cerebellothalamic glutamatergic fibres arising from subcortical deep cerebellar nuclei [150] which traverse this region and form there collaterals and terminals [88,90,100].…”

Direct visualization and characterization of the human zona incerta and surrounding structures

“…We discovered that commonly used T2w indirect anatomical 459 target and optimal stimulation locations appeared at the boundary of the cZI with the PSA (Figure 4 and 460 Supplementary Figure S4). These findings are in line with other work suggesting that a proportion of benefit 461 is derived from stimulation of wayward white matter tracts in the fct (raprl) (Blomstedt et al, 2018;Mohadjer 462 et al, 1990;Mundinger, 1965;Spiegel et al, 1964;Velasco et al, 1972) based measures, ultra high-field T1 mapping has higher SNR, is less prone to image distortions, require 466 generally less scan time, less post-processing, and is acquired at inherently higher resolution (0.7 mm 467 isotropic compared to 2-3 mm). We have determined that the dimensions of the fct within the PSA is ~4-5 468 mm along its longest axis, representing 1-3 voxels if relying on DTI alone compared to 5-7 voxels using our 469 protocol.…”

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

“…As in humans, greater improvements in velocity were seen with more dorsal STN stimulation ( Figure 2C). This may relate to targeting sensorimotor STN territories (19,20) or the zona incerta, stimulation of which is also therapeutic (21,22). We next correlated electrode distance from the pyramidal tract with the dyskinesia score in response to stimulation at 120 Hz, 300 μA, and 120 μs (parameters that reliably evoked dyskinesias in over half of mice).…”