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Sustained Reduction of Parkinsonian Symptoms After “Coordinated Reset” Neuromodulation

Zwagerman, Nathan T.; Turner, Robert S.; Richardson, R. Mark

Free Access

The modern evolution of Parkinson disease (PD) treatment has been marked by 2 critical breakthroughs that now have become gold standards. The first leap was the development of L-Dopa therapy. Side effects associated with L-Dopa, namely dyskinesias, encouraged the development of non-pharmacological treatments. The discovery of deep brain stimulation, targeting brain structures previously targeted for therapeutic ablation, addressed that need and is now clearly the next leap forward. Although stimulation parameters and outcomes have remained relatively stable since the advent of deep brain stimulation (DBS), electrophysiological recordings obtained during DBS surgery have progressively improved our understanding of the abnormalities in network activity that contribute to the genesis of Parkinsonian signs. The recent discovery of abnormal synchronization of neuronal activity in the basal ganglia and associated cortical networks has prompted the development of new neuromodulation paradigms to specifically counteract this pathological pattern of neuronal activity. In this regard, the next major therapeutic leap may be “coordinated reset” neuromodulation.

The motor signs of PD have been consistently associated with abnormally synchronized oscillatory activity at multiple levels of the basal ganglia–cortical loop. This activity is suppressed by dopaminergic therapies and deep-brain stimulation, but the effect quickly wears off with cessation of therapy. New closed-loop techniques were recently shown to be more effective than classical DBS in reducing motor signs and pathological oscillatory activity in primates,1 indicating the potential for developing more effective stimulation algorithms. In parallel, theoretical work over the past decade suggested a novel form of open-loop stimulation that is designed specifically to counteract pathological synchronization.2 Termed “coordinated reset” (CR) stimulation, the proposal was to deliver brief, high-frequency low-amplitude pulse trains through successively different contacts of a DBS electrode, selected at random, with the goal of not blocking neuronal firing, but rather resetting the firing phase of the targeted neurons. Network desynchronization was predicted to result from a division of the stimulated neuronal field into functional subpopulations by administering the pulse trains through different electrode contacts at different times.

Now, Tass et al (Coordinated Reset Has Sustained Aftereffects in Parkinsonian Monkeys. Ann Neurol. 2012;72(5):816-820)3 have applied this method in a monkey model of Parkinson's disease and demonstrated for the first time that CR neuromodulation in the vicinity of the subthalamic nucleus had significant acute and long-lasting anti-Parkinsonian effects. Three MPTP-treated monkeys that exhibited stable Parkinsonism underwent testing in a crossover designed trial that included (1) CR with DBS-like intensity (0.6 ± 0.1 mA; pulse width, 120 μs; CR frequency, 7 Hz; intraburst frequency, 150 Hz; 3 cycles on were followed by 2 cycles off; pulse trains were randomly applied monopolar through the 3 lower electrode contacts); (2) CR with low intensity (0.2 ± 0.1 mA; other parameters were similar to CR with DBS-like intensity); and (3) classical DBS (0.6 ± 0.1 mA; pulse width, 120 μs; frequency, 130 Hz). Stimulation was delivered through macroelectrodes, similar to those used clinically but scaled down for use in monkeys that were implanted chronically in the left and right STN. Each subsequent testing session was performed only once akinesia had returned to the pre-trial baseline. Subjects were evaluated using a Parkinsonian monkey rating scale with blinded videotape recordings.

The results were clear. Coordinated reset stimulation at low intensity had sustained therapeutic aftereffects that remained significant for an astonishing 35 days as compared to the classical DBS aftereffect that lasted less than 30 minutes. Coordinated reset at low intensity additionally had more pronounced aftereffects than when the same form of stimulation was delivered at DBS-like stimulation intensity. This observation indicates a mechanism of action that is distinct from classical DBS and one that is relevant for understanding how to achieve improved therapeutic results in PD patients. These results constitute first peer-reviewed report to support the authors' hypothesis, generated from modeling studies, that abnormal networks may be desynchronized by the unlearning of pathological connectivity between neurons. The authors postulate that CR stimulation works by decreasing the synaptic connectivity that sustains synchronized pathological oscillatory activity within the motor circuitry. The very long duration of CR aftereffects implies that long-term changes in synaptic plasticity that contribute to the pathophysiology of PD may also be harnessed to yield more effective and efficient forms of anti-Parkinsonian stimulation therapy.

This study by Tass et al adds to a growing literature regarding the evolution of neuromodulation algorithms in the treatment of PD and highlights several concepts critical to continued neurosurgical development in this field. While an implantable pulse generator for applying CR is currently not available, the initial application of this stimulation strategy in patients is eagerly awaited.

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REFERENCES

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Figure. Long-lasting...
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1. Rosin B, Slovik M, Mitelman R, et al.. Closed-loop deep brain stimulation is superior in ameliorating parkinsonism. Neuron. 2011;72(2):370–384.

2. Tass PA. Desynchronizing double-pulse phase resetting and application to deep brain stimulation. Biol Cybern. 2001;85(5):343–354.

3. Tass PA, Qin L, Hauptmann C, et al.. Coordinated reset has sustained aftereffects in Parkinsonian monkeys. Ann Neurol. 2012;72(5):816–820.

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