New Targets for Deep Brain Stimulation Treatment of Parkinson's Disease

Anna Castrioto; Elena Moro


Expert Rev Neurother. 2013;13(12):1319-1328. 

In This Article

Combined Targets

STN stimulation alone greatly improves cardinal PD signs and motor and non-motor fluctuations,[2–4,71] but it is not able to manage levodopa unresponsive symptoms, such as axial signs and cognitive impairment. On the other hand, the stimulation of the other 'alternative targets' has showed to be neither equal nor superior to the STN in improving levodopa responsive signs. For instance, PPN stimulation can improve, although not consistently, axial signs but not the other PD cardinal signs.[24,25] Hence, stimulation of combined targets has been postulated in order to better address different PD symptoms. The stimulation of combined targets might allow a modulation of the basal ganglia loop due to the reciprocal strong interconnection among these structures, as the case for PPN and STN.

So far, different target combinations have been tried.

Studies investigating combined bilateral PPN and STN stimulation have showed no antagonism, but rather an additive effect.[23,35] Other studies have focused on the combination of bilateral PPN and cZi stimulation.[27–29] In a PET study, combined low-frequency PPN/cZi stimulation induced additive brain activation changes.[29] In a group of seven PD patients, PPN or cZi stimulation alone and combined stimulation significantly improved motor axial scores in the off-medication condition.[27] However, combined stimulation did not provide any significant further improvement compared with cZi stimulation alone.[27] Conversely, in the on-medication condition only combined cZi and PPN stimulation achieved a significant improvement of axial signs.[27] Interestingly, the authors found different effects at different stimulation frequencies.[27,29] When stimulating PPN alone, 10–20 Hz allowed the greatest postural instability improvement, but worsened gait. Stimulation with frequencies above 60 Hz improved gait, but worsened postural instability. The best compromise was achieved with 60 Hz stimulation. Stimulation of cZi alone achieved the best results at frequencies around 130 Hz. However, when combined stimulation of PPN and cZi was performed, stimulation of cZi at 130 Hz was associated with postural instability impairment. The best compromise was stimulation of both targets with frequencies around 60 Hz. These different frequency effects of combined stimulation have not been for STN and PPN stimulation.[24] In this study, the assessment in the off-STN stimulation condition was not performed because not tolerated by the patients (marked worsening of parkinsonian symptoms following the arrest of STN stimulation – unpublished data). These different results might depend on the different target choices in these two studies.[24,27] It has been described that stimulation of pallidothalamic fibers might block the effects of levodopa, and thus induce a worsening of axial signs. Since pallidothalamic fibers pass through the Zi and medially to the STN before reaching the thalamus, it cannot be excluded that stimulation of the cZi at high frequency might diffuse to the pallidofugal fibers.

The SNr is the main output nucleus of the basal ganglia along with the GPi. Combined STN-SNr stimulation has also been proposed in order to better manage axial signs. The effects of bilateral SNr DBS on different parameters of gait have been investigated in seven PD patients with bilateral STN stimulation.[72] In this study, patients were assessed with stimulation either of the contacts within the SNr or within the STN (all contacts were in the same lead). SNr DBS allowed only control of axial signs, whereas STN stimulation allowed also control of distal parkinsonian signs. Lately, a case report of combined bilateral stimulation of both STN and SNr has been published.[73] Interestingly, in this report the authors used interleaving stimulation, a new approach allowing delivering the current simultaneously on two different contacts on the same lead in alternating order. There was a slight improvement of gait with STN stimulation alone, and a sustained improvement with combined STN and SNr stimulation. Following this observation, a double-blind crossover trial comparing STN stimulation and interleaving stimulation of STN and SNr is underway and the results are awaited.[74]