HFS mimics lesion in all available targets and might act through functional inhibition

All About Parkinson's Disease

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This is based on the fact that the effects of HFS mimic those of ablative surgery. This was observed, or at least related to HFS, for the first time in 1987 (Benabid et al., 1987) during a thalamotomy for essential tremor where it became clear that, in a frequency dependant manner, there was a paradoxical lesion like effect of stimulation at frequencies around or above 100 hertz. This led to the surgical concept that ''HFS is equivalent to lesion''. As a consequence, HFS has replaced ablative surgery in all available targets, including the thalamus, the pallidum, and the STN nucleus, where it is considered, although we do not know exactly how this happens, that HFS induces a functional inhibition.

The effects are immediate and reversible

This is easily observed in the thalamus where the tremor can stop within seconds after the onset of stimulation and recur as quickly when the stimulation is stopped. This is also the case during pallidal stimulation which suppresses levodopa induced dyskinesias immediately as well as reversibly (Siegfried et al., 1994). Finally, a similar observation can de done in STN, following the demonstration in MPTP monkeys in 1990 (Bergmann et al., 1990) and in 1991 (Aziz et al., 1991), that it could be a new as well as an efficient surgical target (Pollak et al., 1993; Limousin et al., 1998), after it has been shown also that HFS in monkeys would produce the same effect than lesions without inducing the hemi-ballistic expected side effects (Benazzouz et al., 1993). Since, we learnt that STN HFS is efficient on akinesia, rigidity and tremor as well as, indirectly, on levodopa induced dyskinesias in a very acute and reversible manner.

Clinical benefits of HFS of STN in advanced stages of PD

The long term effect of STN HFS are stable and a three year follow up in 1998 (Limousin et al., 1998), as well as a five year follow up in (Krack et al., 2003), were published, showing that most of the symptoms, such as tremor, rigidity and akinesia, and to a lesser but still very significant degree, instability, gait and activities of daily living, as well the indexes of Schwab and England and total UPDRS III are stably improved, at least at 50% for most of them and around 65 to 70% for tremor and rigidity. However, speech and writing are not so spectacularly improved. Besides of these cohort studies after 3 and 5 years, one might take into account that in 2005, we gathered 12 years of experience in more than 250 bilateral STN cases, confirming the stability and the quality of those long term results. In addition, drug doses, and therefore the iatrogenic dyskine-sias, can be decreased because of the quality of the stimulation effects, which allow reducing the levodopa equivalent doses by an average of 60%, which in turn as a consequence decreases disability due to dyskinesias by more than 70% and duration of dyskinesias by an average of 65% along these five years. There is also a progressive decrease of chor-eoballic dyskinesias induced by a levodopa challenge as well as by STN HFS which, as compared to preoperative control values, are decreased at 6 months and even more at 12 months, and barely inducible around 2 years after surgery. The speech is less improved than motricity: according to the rating scales, the average improvement of speech is around 35%, as compared to the 60% (UPDRS III) observed in the same series of patients for the motor symptoms (Gentil et al., 2001). This insufficient benefit on speech and language might be due to a possible existence of a ''symptomatotopy'': the target is explored mainly by the clinical evaluation of the improvement of the rigidity of the wrist during the intraoperative tests, which determines the final placement of the chronic stimulating electrode. One might imagine that, if symptoms were depending on various subparts of the STN, one might systematically miss the language area, if any, explaining why this function is often, but not always, less improved than the rest of the motor functions. Dysarthria, which appears usually at higher

Fig. 1. Upper Lane: Anteroposterior and Lateral X-Ray views of a bilateral implantation in STN with 2 electrodes on the right side and one electrode in the left side. Lower Lane: Lower right corner: Connection of the 2 electrodes on the right side to a Kinetra and of the left electrode to a Soletra. Lower left corner: Sketch of the prototype of a programmable multiplexer

Fig. 1. Upper Lane: Anteroposterior and Lateral X-Ray views of a bilateral implantation in STN with 2 electrodes on the right side and one electrode in the left side. Lower Lane: Lower right corner: Connection of the 2 electrodes on the right side to a Kinetra and of the left electrode to a Soletra. Lower left corner: Sketch of the prototype of a programmable multiplexer voltages, is probably due to the spreading of current to the corticobulbar fibres of the internal capsule and the solution could be provided by multiple electrode implantations, allowing a finer coverage of the volume of the STN. An implantable and programmable multiplexer is being designed and tested to achieve this goal (Fig. 1). Actually, multiple electrodes can be implanted, as it has been done in several instances, either with multiple electrodes in one target (in some cases the choice for the best of 5 electrodes on one STN was difficult and in 25 patients 2 electrodes were implanted, sometimes with connexion of the 2 electrodes on one side to a Kinetra® and the other one to Soletra®) (Fig. 1) or in some cases in two different targets for the same patient (as it has been done in 2 cases of dystonia with 2 electrodes implanted bilaterally in STN and implanted also bilaterally in the internal pallidum). The hypothesis that there might be a ''symptoma-

totopy'' into the STN nucleus, may explain why some symptoms such as speech are not so well improved. The main symptom on which the electrodes are targeted is the rigidity of the wrist. Rigidity might be taken care of by other parts of the STN nucleus than the one controlling the speech. The idea has come to implant several electrodes into the STN and particularly to put the five electrodes into the five channels explored by micro-electrodes. A prototype of a programmable implantable multiplexer has been developed and will be submitted to clinical trial. There is no cognitive decline as shown with follow ups of 3 years and 5 years (Ardouin et al., 1999; Jahanshahi et al., 2000) using the Mattis, Beck and frontal score scales at 3 years and then confirmed at 5 years follow up. Depression is observed post-operatively in 20% of the cases and one suicide has been observed in the entire series of 250 cases. Their causes might be multifactorial. Part of the mechanism could be due to the decrease (in average about 50 to 65%) in levodopa doses which might induce strong withdrawal effects of this potent psychotonic drug. The role of the pre-existing neuropsychological background should not be neglected.

Also, the strong improvement provided by DBS stimulation in STN is responsible for profound changes in patients' live (the patients quite often say ''Surgery was my second birthday''). However a possible role of the limbic part of the STN, which could be involved by the spreading of the current, cannot be ruled out and will be further explored.

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