Multi-target strategy for Parkinsonian patients: The role of deep brain stimulation in the centromedian–parafascicularis complex

Abstract

The intra-laminar (IL) thalamic complex, composed of centromedian (CM) and parafascicular (Pf) nucleus, is a strategic crossroad for the activity of the basal ganglia and is recently regaining its position has a putative neurosurgical target for Parkinsonian syndromes. The multi-target approach we have encouraged since the late nineties has allowed the combined implantation of a standard target (the subthalamic nucleus—STN or the internal pallidus—GPi) plus an innovative one (CM/Pf) in well-identified Parkinson’s disease (PD) patients; hence, it is possible to study, in the same PD patients, the specific target-mediated effects on different clinical signs.

Here, we focus on the potential usefulness of implanting the CM/Pf complex when required in the management of contra-lateral tremor (resistant to standard deep brain stimulation—DBS – in STN – , n = 2) and disabling involuntary movements, partially responsive to GPi–DBS (n = 6). When considering global UPDRS scores, CM/Pf–DBS ameliorate extra-pyramidal symptoms but not as strongly as STN (or GPi) does. Yet, CM/Pf acts very powerfully on tremor and contributes to the long-term management of l-Dopa-induced involuntary movements.

The lack of cognitive deficits and psychic impairment associated with the improvement of their quality of life, in our small cohort of CM/Pf implanted patients, reinforces the notion of CM/Pf as a safe and attractive area for surgical treatment of advanced PD, possibly affecting not only motor but also associative functions.

Introduction

Many Parkinson’s disease (PD) patients manifest an unsatisfactory response to the best combination of drugs, as far as their clinical profile change with the disease progression. Disabling dyskinesias, whose treatment remain elusive, impairment of gait and postural imbalance, prominence of psychic or cognitive (mostly dis-executive) deficits, are some of the challenging issues the clinicians face with fluctuating degree of success [7], [9]. Deep brain stimulation (DBS) has provided an additional treatment strategy, enabling reduction of levodopa (l-Dopa) intake [16].

Since the pioneering experience of Benabid [5], the high-frequency stimulation (HFS) of the subthalamic nucleus (STN) was demonstrated as safe and consistently effective, at least in terms of management of motor cardinal signs [33]. Yet, the uncertain impact of STN–DBS on gait deficits and the risk of developing some non-motor side effects (perturbed verbal fluency and apathy), has rejuvenated the field of functional neurosurgery, making it imperative to investigate alternative targets.

At first, the on-going progression of the disease clinical spectrum – even in patients already submitted years ago to STN–DBS – is posing an unconventional question: could they receive an additional implantation in a different target area? Further, is it possible that the combined implantation ab origine of different structures turn out to provide a more complete and gratifying handling of both motor and non-motor PD signs?

In this context, we have long-term experience. Since the late nineties, our group has utilized the multi-target approach, by implanting, in well-selected PD patients, two basal ganglia (BG) structures in both hemispheres [20], [21], [22], [23], [24], [28], [30], [31], [36], [39]. Table 1 shows in detail the overall number of implanted patients and the major adverse events so far encountered. Notably, the comparison between standard mono-target STN surgery vs. “double target” surgery rules out increased risks with the latter.

Nevertheless, several limitations occur: first of all, the cost of this multi-target procedure, which imposes at least a double budget; second, the prolonged discomfort of patients, given that surgery outcome becomes slower; third, the requirement of a rather specialized peri- and post-operative team, including specific expertise in different fields (i.e. radiology, electrophysiology in regions not yet explored extensively in humans, psychiatry, rehabilitation units).

That said, the multi-target strategy drives key advantages: (1) the implicit progress of high technology devices (i.e. arch-less), which minimize time-consuming traditional stereo-tactic surgery; (2) the acquisition of original biochemical changes in basal ganglia stations other than STN, strictly correlated to STN–DBS-mediated clinical benefits [10], [11], [37], [38]; (3) more importantly, the putative control of those clinical signs relatively unaffected by STN–DBS. So far, the natural candidate have been PD patients afflicted by (i) involuntary movements, but reluctance to follow a decreased drug regimen; (ii) severe tremor less responsive to DBS–STN; (iii) ON-freezing or (iv) even patients whose eligibility to STN–DBS was doubtful in light of minor depression or fluctuating cognitive performance.

Our recent experience [21], [24], [30], albeit limited to small patient cohort, seems to indicate that CM/Pf (and, likewise, the pedunculopontine nucleus—PPN) represents a promising target area in the treatment of advanced and complex PD patients. What follows is a rapid excursus on the obtained results, their more parsimonious explanation, and final working hypotheses:

• CM/Pf–DBS on “STN–DBS resistant PD tremor”;

• CM/Pf–DBS against hyperkinetic movements;

• A new look towards the PPN–CM/Pf projection and extra-pyramidal disorders.