Surgical therapy for Parkinson s disease

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1 J Neural Transm (2006) [Suppl] 70: # Springer-Verlag 2006 Surgical therapy for Parkinson s disease A. L. Benabid, S. Chabardès, E. Seigneuret, V. Fraix, P. Krack, P. Pollak, R. Xia, B. Wallace, and F. Sauter University Joseph Fourier and INSERM U318, Grenoble, France Summary. High frequency stimulation (HFS) has become the main alternative to medical treatment, due to its reversibility, adaptability, and low morbidity. Initiated in the thalamus (Vim) for the control of tremor, HFS has been applied to the Pallidum (GPi), and then to the subthalamic nucleus (STN), suggested by experiments in MPTP monkeys. STN- HFS is highly efficient on tremor, rigidity and bradykinesia and is now widely applied. Criteria for success are correct patient selection and precise electrode placement. The best outcome predictor is the response to Levodopa. The mechanisms of action might associate inhibition of cell firing, jamming of neuronal message and exhaustion of synaptic neurotransmitter release. The inhibition of glutamate STN release could be neuroprotective on nigral cells. Animal experiments support this hypothesis, not contradicted by the long term follow up of patients. Neuroprotection might have considerable impact on the management of PD patient and warrants clinical trials. Introduction Surgery was the first treatment for Parkinson s disease (PD), before the introduction of the levo-dopatherapy. In the years 1950, as a product of serendipity and random walk, thalamotomy and pallidotomy were used to suppress essential as well as parkinsonian tremors. The effects were usually very satisfactory but, depending on the size of the lesion, they could decrease along time or they could be associated to side effects and complications, particularly when surgery was performed bilaterally. In this context, during the sixties, the advent of levodopa, because also of its efficiency, sent surgery to archives. One has to wait until the early years 1980, to see the levodopa side effects raising the need for alternate solutions and the brain graft s saga starting (Bjorklund et al., 2003; Winkler et al., 2005). In 1987, the discovery of high frequency stimulation (HFS) reintroduced surgery in the field of the therapy of PD and movement disorders (Benabid et al., 1987; 2005). In 1992, Laitinen reintroduced pallidotomy (Laitinen et al., 1992) which was redesigned from the previous approach from Leksell (Svennilson et al., 1960). In 1993; HFS of the subthalamic nucleus (STN) becomes a treatment of advanced stages of PD (Pollak et al., 1993; Limousin et al., 1998). Since the year 2000, there is a real blossoming of surgical therapies for PD and movement disorders, based on HFS. Overall, HFS of STN is currently the prevalent surgical therapy for PD (Krack et al., 2003). HFS mimics lesion in all available targets and might act through functional inhibition 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

2 384 A. L. Benabid et al. 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 hemiballistic 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 dyskinesias, 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 choreoballic 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

3 Surgical therapy for Parkinson s disease 385 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 symptomatotopy 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

4 386 A. L. Benabid et al. 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. STN DBS does not cure PD but might be neuro-protective This has been shown in experimental animals using the Sauer and Oertel model (Sauer and Oertel, 1994) where intra-striatal injection of 6 OHDA in rats induces by retrograde transportation an ipsilateral degenerescence of the nigral cells in the substantia nigra compacta (Piallat et al., 1996). This is prevented if prior to 6 OHDA intra-striatal injection, a lesion is made into the STN using intra STN kainic acid lesion. Similar data have been observed by Paul et al. (2004). In primate experiments done in our laboratory, and so far not published, studies have been done on 30 monkeys either receiving a kainic acid lesion or DBS into the STN using the 3389 Medtronic electrode and a stimulator, before or after MPTP administration to make those animals parkinsonian. The primary outcome of those studies is the ratio of the right to the left side (the right side being the one where STN has been altered either by kainic acid lesion or STN stimulation) of the counts of the total number of cells stained by the Nissl stain or of the preoperative UPDRS III score. The remaining 38% of the patients improve, from UPDRS III 58 in pre-op to 38 at one year follow-up. Half of those patients, 19% of the total population of 89 patients so far tested, show a continuing and progressive decrease in the UPDRS III score showing a significant improvement along 5 years. However, this does not allow us to consider that neuroprotection is demonstrated as the period of off medication off stimulation has always been too short, for 2 to 4 hours in addition to the off during the night. This can be criticized as it might be possible that much longer off period (which is neither ethically possible nor accepted by most of the patients) might lead those patients to a level of their UPDRS III score which might be equivalent or even worse than their pre-operative basic score. Therefore, other studies are needed, including in particular non clinical outcome measures, such as metabolic outcomes provided by PET scan studies. The complications are mild, most of the time reversible, but not absent DBS surgery, although less risky than the ablative surgery, cannot be considered as risk less. Related to ventriculography, there is 1.5% of asymptomatic bleeding and 2.1% of superficial infection at the level of the skin. Related to the implantation of the electrode, 1.2% of bleeding has been symptomatic, 14.2% were asymptomatic (revealed by systematic post-operative MRI control). Confusion and bradyphrenia are observed in 21.8% of the cases and all resolved within 3 days to 3 weeks. Infection related to the hardware was observed in 1.4%, most of it being observed after a long time due to erosion of the skin in front of the bulky connectors and never propagated to the brain or cerebrospinal fluid spaces. Related to stimulation, complications are dyskinesias which always happen at voltages higher than the threshold for clinical improvement. Eyelid opening apraxia is observed at 15.6%, often appearing in patients who already had it before surgery and which

5 Surgical therapy for Parkinson s disease 387 rarely needed additional treatment with injection of botilinum toxin. However, surgical complications are most of the time related to the surgical practice and therefore can and must be solved. Confusion is temporary, probably related to the caudate nucleus, which is bilaterally traumatized by the guide tubes for micro-recording. This happens less often if the tracks are parallel to the midline, going through the ventricle or far lateral, avoiding not only the ventricle itself but also its border, where is the caudate nucleus. Criteria for success are essentially the result of team cooperation The patient s selection is extremely important, concerning essentially idiopathic Parkinson s disease and the quality of the levodopa response is one of the major predictors of success (Charles et al., 2002). The surgical procedure depends on the quality of the targeting which is based on neuroradiology but also on electrophysiology using micro recording as stimulation and the quality of the surgical steps. The microrecording is quite often debated and, depending on the teams, might be considered as either dangerous or useless. Largest studies are needed to evaluate the benefit and the risk of this approach which in our opinion is valuable and participates to the optimal positioning of the final electrode. The use of intraoperative stimulation requires clinical examination under local anaesthesia and the presence of a neurologist in the neurosurgical operating room is always beneficial for the quality of the results. The follow up and tuning of the patient is creating a heavy burden on the shoulders of neurologist. There is a delicate stimulation-drug interplay which is sometimes critical to manage during the first three weeks. Then, further adjustments of parameters are usually needed along the evolution of the patients. This makes actually their follow up easier but because of the lack of a widespread education of general neurologists, this relies essentially on the shoulder of academic teams. This becomes sometimes a limiting factor. There is a clear need for education of neurologists, particularly those involved in movement disorders, to take care of this follow up, which however is much lighter than dealing unsuccessfully with the difficulties encountered by advanced Parkinson s patients. The patient s selection is critical: the best patients have idiopathic Parkinson s disease with levodopa responsiveness (the STN induced improvement and the Levodopa induced improvement shows a strong linear relationship). Patients with motor fluctuation and dyskinesias are the most improved patients because of the disappearance of their fluctuations and levodopa induced dyskinesias. The patients should not have already reached any level of neurocognitive alteration and there should not be any general contraindication. It seems reasonable to consider that STN stimulation could be proposed to patients when medication fails to maintain their quality of life, and particularly before their professional activity is jeopardized. One might define a quality index which would be the ratio of the medical improvement to the surgical improvement. This would allow the surgical teams to monitor the quality of their surgery, trying to keep this quality index as close as possible to 1. The quality of the surgery is a key factor The surgical procedure is a matter of debate and one should leave the surgical teams choosing what they feel the most comfortable according to their situation, expertise and equipment. There are different ways to skin a cat: however the stereotactic method ensures precision, the MRI, with or without ventriculography, provides the landmarks, the microrecording identifies the target, the stimulation simulates intraoperatively the final outcome, particularly as far as side effects are considered, the fixation to the skull

6 388 A. L. Benabid et al. of the electrode is a very crucial step, which prevents migration of the electrodes, and hardware implantation should be performed extremely carefully in order to prevent infection. But the cat must be properly skinned out, and variations, deviations, innovations are welcome but they should be validated if they provide equal or even better outcome, using again the quality index which should be used as a criterion to validate those differences from the main classical techniques. The precision of the surgical procedure is the key and there is a direct relationship between the distance of a given contact to the coordinate of the theoretical best target (which is the point defined by the average coordinates of the clinically defined best contacts in a large series of patients). In our series, the average distance of 394 clinical contacts to the target is equal to millimetres. Measuring and calculating those distances for each patient allow us to predict correctly in 54% of the cases the contact which will be chosen and in 91% including the up or lower contact, next to it. This might help the neurologists in their screening for the best contact. All efforts must be spent to reach the optimum and surgeons hours which are saved might cost years of patient s discomfort. The tuning and follow-up are most of the time done by the neurologists There are not 64 parameter combinations as often stated. Most of the time, stimulation can be monopolar (the case positive and only one contact activated) at 130 Hz frequency, 60 microsecond pulse width, and around 2.5 volts amplitude. Any need for change because of insufficient effect and=or side effects means more or less electrode misplacement. The tuning needs training. There is a non simple optimal compromise between symptoms, side effects, drug dosages and parameters. STN high frequency stimulation plus levodopa induces dyskinesias, increasing the voltage induces a current spread and then the recruitment of side effects. The battery end of life must be prevented by regular checking to avoid dramatic situations when the battery finally fails abruptly. This must be performed or carefully controlled by the neurologist. The concept of spatial overdose can be described in a case of a patient with simulation at 130 Hz, 60 microseconds and 3 volts on contact no. 2, which highly improved the patient but then induced apathy. Then, in order to improve this apathy, which was considered as a remaining part of the Parkinson s symptoms, the contact no. 3 has been added, keeping the other parameters equal. This led to hypomania and laughter. Then adding a third contact (contact no. 1) again without changing parameters induced aggressivity and loss of temper. This should teach us that complications, and particular neuropsychological complications, might be in part due to inadequate tuning of the parameters and to inadequate choice of contacts. One must absolutely locate the sites of side effect Where do they come from? Is STN responsible for all those changes? The case by the group of Paris (Bejjani et al., 1999) of a patient who was acutely and strongly depressed by deep brain stimulation in the STN area was initially related to the position of the electrode in STN and then to the Substantia nigra reticulata. This explanation are not necessarily easy to state: this is probably not occurring in STN as patients exhibiting these side effects are exceptional, as well as we have now the knowledge, through STN stimulation for epilepsy, that this type of behaviour is not induced in those cases. Similarly the laughter which has been reported in several situations by simulation at the STN site, but at higher voltages, makes difficult to relate exactly this abnormal behaviour considered as a side effect and a real location where this neurophysiological effect is induced. On the contrary, the dyskinesias or

7 Surgical therapy for Parkinson s disease 389 hemiballistic type which are induced very easily during surgery or during the tuning of the patient by STN stimulation are clearly equivalents of hemiballism or of dyskinesias: there are due to too strong parameters of stimulation of this structure. However it is not possible to rule out the role of the limbic part of the STN nucleus. What did we learn from this experience along 12 years of STN stimulation in Parkinson s disease and of 17 years of stimulation of the thalamus? We know for sure that high frequency stimulation induces functional inhibition which is frequency dependent, within a plateau area from 100 to about 2,500 Hz, that ganglia and not bundles are involved by this functional frequency dependent inhibition. This does not create a de novo process but it seems that HFS disrupts a wrong information processing. There are conflicting data which need clarification and a generalized theory. The mechanism is unknown but the causes are probably multiple. This mechanism could be due, as we initially suggested it in the thalamus, to a jamming which is supported by experiments in the monkey, (Hashimoto et al., 2003) where STN stimulation induced at the level of GPI dual effects mixing silencing and bursting. Silencing of STN neurons has been observed in human during stimulation (Welter et al., 2004) at frequencies starting about 80 Hz, as well as after the stimulation period (Filali et al., 2004). These data are difficult to obtain and to analyze, because of the stimulation artefact. Similar effects have been observed in GPI (Dostrovsky et al., 2000) and they have been interpreted as the results of activation of afferent GABAergic terminals. It could be neurotransmitter depletion by exhaustion of the biochemical process ensuring the replenishment of the synaptic vesicles. Non published data from our group have shown that stimulation of cells in culture was able to diminish the prolactine release of GH3 cells as well as the release of dopamine, epinephrine and norepinephrine in PC12 cells, suggesting that exhaustion of the neurotransmitter production could be part of the mechanism involved. This leads to a putative model of the mechanism of HFS encompassing the globality of these mechanisms, which might all of them play altogether a specific role leading to this very clinically efficient effect, acute and reversible as well as titrable, of deep brain stimulation. What did we learn also in terms of global functioning? It seems clear that there are therapeutical networks and nodes, but not simple targets: for instance the tremor can be altered by stimulation in Vim, CM-Pf, STN and GPI, while bradykinesia and rigidity are improved by stimulation of STN and GPI, and that the recent observation of OCD improvement might encompass the STN, the GPI, the accumbens as well as CM-Pf. These circuits overlap in part with those used by dopamine and subcomponents may account for subtle differences in effects. What are the alternatives? There is no better future for a method than being replaced by an even better one. This could be gene transfer as it has been already tried (Luo et al., 2002) using AAV mediated gene transfer of GAD in STN: this nucleus has been transformed from a glutamatergic to gabaergic nucleus. Similarly the infusion of growth factors such as GDNF directly in the caudate nucleus and putamen has been reported (Gill et al., 2003). Although this has not been confirmed by a multicenter clinical trial (Nutt et al., 2003), there is probably something to use in this approach and new methods should be designed and refined. Motor cortex stimulation has been reported in MPTP monkeys to improve rigidity at high

8 390 A. L. Benabid et al. frequency by mechanisms which are not fully understood but might involve a decrease in activity in STN and in the pallidum (Drouot et al., 2004). Finally the neural grafts are still the ultimate elegance. An extremely large and skillful amount of work has been done during the last decades, unfortunately not leading to a currently routine therapeutic approach, but there is no doubt that in the future the improvement of the method and may be the use of new paradigms, particularly using solutions such as stem cells or genetically modified host cells, could be providing solutions which would be truly therapeutic and curative instead of substitutive methods (Bjorklund et al., 2003). There is a need for a consensus: we must compare our targets and our results, although we know that neurosurgical methodological consensus is an utopy. We need a consensus on data communication: for instance coordinates on MRI or on ventriculography should be provided with x, y, z coordinates versus common standardized landmarks such as anterior commissure, posterior commissure, AC-PC line, the height of the thalamus and the midline and means and standard deviations as well as the number of cases should be provided to allow fair comparison between results of different teams Similarly, the outcomes should be provided as percentages of improvement on global scales used and agreed on by all teams such as UPDRS, and quality of life scales. The quality index (ratio of the improvement of stimulation versus the improvement of medication) and the outcome should provide the percentage of improvement on commonly agreed scales, the quality index should be also used to rationalize the results of the patients according to their initial status. At this level again means of the deviation and number of cases should be provided. There should be comparison between series and coordinates and we should not see anymore sentences such as our results are similar to what is reported in the literature. Conclusion We do have a tool as HFS of STN is a current surgical option for treatment of Parkinson s disease. It is safe, reversible, and adaptable and leaves open the future. There is no cognitive decline, and psychological side effect are multi factorial and should benefit from psychological support or prevention. Its mechanism is unknown and it provides access to the pathophysiology of movement disorders. It should and will be replaced by new methods if these new methods provide better outcome. References Ardouin C, Pillon B, Peiffer E, Bejjani P, Limousin P, Damier P, Arnulf I, Benabid AL, Agid Y, Pollak P (1999) Bilateral subthalamic or pallidal stimulation for Parkinson s disease affects neither memory nor executive functions: a consecutive series of 62 patients. Ann Neurol 46: Aziz TZ, Peggs D, Sambrook MA, Crossman AR (1991) Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 6: Bejjani BP, Damier P, Arnulf I, Thivard L, Bonnet AM, Dormont D, Cornu P, Pidoux B, Samson Y, Agid Y (1999) Transient acute depression induced by highfrequency deep-brain stimulation. N Engl J Med 340: Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J (1987) Combined (thalamotomy and stimulation) stereotactic surgery of the Vim thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 50: Benabid AL, Wallace B, Mitrofanis J, Xia R, Piallat B, Chabardes S, Berger F (2005) A putative generalized model of the effects and mechanism of action of high frequency electrical stimulation of the central nervous system. Acta Neurol Belg 105: Benazzouz A, Gross C, Feger J, Boraud T, Bioulac B (1993) Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci 5: Benazzouz A, Piallat B, Pollak P, Benabid AL (1995) Responses of substantial nigra reticulata and globus pallidus complex to high frequency stimulation of the subthalamic nucleus in rats: electrophysiological data. Neuroscience Lett 189: 77 80

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10 392 A. L. Benabid et al.: Surgical therapy for Parkinson s disease injection: behavioural and immunohistochemical studies. Eur J Neurosci 8: Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, Hoffmann D, Gentil M, Perret JE (1993) Effets de la stimulation du noyau sousthalamique dans la maladie de Parkinson. Rev Neurol (Paris) 149: Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59: Siegfried J, Lippitz B (1994) Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. J Neurosurg 35: Sturm V, Lenartz D, Koulousakis A, Treuer H, Herholz K, Klein JC, Klosterkotter J (2003) The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders. J Chem Neuroanat 26: Svennilson E, Torvik A, Lowe R, Leksell L (1960) Treatment of parkinsonism by stereotactic thermolesions in the pallidal region. A clinical evaluation of 81 cases. Acta Psychiatr Neurol Scand 353: Welter ML, Houeto JL, Bonnet AM, Bejjani PB, Mesnage V, Dormont D, Navarro S, Cornu P, Agid Y, Pidoux B (2004) Effects of high-frequency stimulation on subthalamic neuronal activity in parkinsonian patients. Arch Neurol 61: Winkler C, Kirik D, Bjorklund A (2005) Cell transplantation in Parkinson s disease: How can we make it work? Trends Neurosci 28: Author s address: A. L. Benabid, Unite Inserm 318 Neurosciences Precliniques, Pavillon B, Centre hospitalier universitaire, BP 217, Grenoble Cedex 09, France, Alim-Louis.Benabid@ujf-grenoble.fr