Functional neurosurgery for movement disorders: a historical perspective

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Abstract

Since the 1960s, deep brain stimulation and spinal cord stimulation at low frequency (30 Hz) have been used to treat intractable pain of various origins. For this purpose, specific hardware have been designed, including deep brain electrodes, extensions, and implantable programmable generators (IPGs). In the meantime, movement disorders, and particularly parkinsonian and essential tremors, were treated by electrolytic or mechanic lesions in various targets of the basal ganglia, particularly in the thalamus and in the internal pallidum. The advent in the 1960s of levodopa, as well as the side effects and complications of ablative surgery (e.g., thalamotomy and pallidotomy), has sent functional neurosurgery of movement disorders to oblivion. In 1987, the serendipitous discovery of the effect of high-frequency stimulation (HFS), mimicking lesions, allowed the revival of the surgery of movement disorders by stimulation of the thalamus, which treated tremors with limited morbidity, and adaptable and reversible results. The stability along time of these effects allowed extending it to new targets suggested by basic research in monkeys. The HFS of the subthalamic nucleus (STN) has profoundly challenged the practice of functional surgery as the effect on the triad of dopaminergic symptoms was very significant, allowing to decrease the drug dosage and therefore a decrease of their complications, the levodopa-induced dyskinesias.

In the meantime, based on the results of previous basic research in various fields, HFS has been progressively extended to potentially treat epilepsy and, more recently, psychiatric disorders, such as obsessive–compulsive disorders, Gilles de la Tourette tics, and severe depression. Similarly, suggested by the observation of changes in PET scan, applications have been extended to cluster headaches by stimulation of the posterior hypothalamus and even more recently, to obesity and drug addiction.

In the field of movement disorders, it has become clear that STN stimulation is not efficient on the nondopaminergic symptoms such as freezing of gait. Based on experimental data obtained in MPTP-treated parkinsonian monkeys, the pedunculopontine nucleus has been used as a new target, and as suggested by the animal research results, its use indeed improves walking and stability when stimulation is performed at low frequency (25 Hz). The concept of simultaneous stimulation of multiple targets eventually at low or high frequency, and that of several electrodes in one target, is being accepted to increase the efficiency. This leads to and is being facilitated by the development of new hardware (multiple-channel IPGs, specific electrodes, rechargeable batteries). Still additional efforts are needed at the level of the stimulation paradigm and in the waveform. The recent development of nanotechnologies allows the design of totally new systems expanding the field of deep brain stimulation. These new techniques will make it possible to not only inhibit or excite deep brain structures to alleviate abnormal symptoms but also open the field for the use of recording cortical activities to drive neuroprostheses through brain–computer interfaces. The new field of compensation of deficits will then become part of the field of functional neurosurgery.

Introduction

Parkinson's disease (PD) is due to the nigral degenerescence of dopaminergic neurons, leading to a disorganization of functional circuits in the basal ganglia (BG). This involves primarily the substantia nigra pars compacta (SNc) sending both inhibitory and excitatory dopaminergic projections to the caudate putamen or striatum. From the striatum, two descending parallel pathways project either directly (GABAergic output) to the globus pallidus internus (GPi)/substantia nigra pars reticulata (SNr) complex, or indirectly through (gamma-aminobutyric acid) GABAergic projections to the external pallidum (GPe) and then to the subthalamic nucleus (STN). The STN projects through a glutamatergic pathway to the GPi–SNr complex. This complex is considered to be the final output structure of the BG and projects through a GABAergic projection to the motor thalamus, which itself projects to the cortex. In turn, the cortex sends a strong glutamatergic projection to the STN, which receives also a glutamatergic projection from the centrum medianum–parafascicularis (CM–Pf) complex, and from the pedunculopontine nucleus (PPN).

The decrease of the dopaminergic output of the SNc induces an imbalance between the two output pathways from the striatum to the pallidum. GPi is disinhibited and hyperexcited and, as a consequence, increases its inhibitory output to the thalamus and then to the cortex, which is therefore inhibited. This is the putative pathogenicity of akinesia and rigidity, which are two main symptoms of the parkinsonian triad. The third component, tremor, can be explained as the symptomatic expression of the disorganization of the BG, leading to a periodic or oscillatory behavior.

Section snippets

Therapy for movement disorders: a random walk around a logical thread

The underlying logic or rationale is that a lesion of the motor system would weaken the motor function, and thereby the motor disturbance and disorders. These lesions can be produced by pyramidotomies or corticectomies, but essentially by lesions in the motor control system (Hassler et al., 1960; Meyers, 1942).

Serendipity has played a role in the discovery of surgical solutions to treat movement disorders. Cooper (1953), during a surgical procedure to perform pyramidotomy, had an accidental

The thalamic ventral intermedius nucleus (VIM)

Stimulation of the thalamic VIM works essentially on tremor with a long-lasting effect that does not change along time (Benabid et al. (1991), Benabid et al. (1996)), even not over a period of 20 years (Fig. 2).

As tremor in PD is equally improved by STN HFS (Benabid et al., 2009), the indications of VIM stimulation have strongly decreased. They are currently restricted to essential tremor where VIM is still the consensual target, although data are being reported on the efficiency of STN

Deep brain stimulation: a preferred tool in functional neurosurgery?

DBS has advantages, particularly flexibility, in addition to reversibility and adjustability of the intensity of stimulation (Table 1). The best demonstration is given in PD patients suffering from freezing of gait, where bilateral STN stimulation at 130 Hz is able to control akinesia and rigidity and simultaneous bilateral simulation of the PPN at 25 Hz improves the freezing of gait (Mazzone et al., 2005; Plaha and Gill, 2005; Stefani et al., 2007). This combination of targets at different

The pharmacology of STN high frequency stimulation

From depression to normal mood and then hypomania, there is a continuum that can be traveled along the intensity of any treatment, whether pharmacological or electrical. There is a narrow band called “normality,” corresponding to an optimal value of DBS treatment or drug dosage. Below these levels, one may see bradykinesia, doubt, obsessions, depression, sadness (Bejjani et al., 1999), and apathy (Krack et al., 2003; Funkiewiez et al., 2004). For higher values than needed, one may see

Conclusions

The saga of functional neurosurgery for movement disorders runs over almost a century. It has been driven by the combined and intertwined forces of therapeutic needs from the pathology, available tools from technology and pharmacology, scientific knowledge from clinical and basic research, anatomy, and neurophysiology. Its course has been shaped by creativity of investigators, positive thinking, luck, and serendipity. The increasing amount of technologies, the improved efficiency of

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