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Background: Long term effects of subthalamic nucleus (STN) stimulation on cognition, mood, and behaviour are unknown., Objective: This study evaluated the cognitive, mood, and behavioural effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in patients with Parkinson's disease (PD) followed up for three years., Methods: A consecutive series of 77 PD patients was assessed before, one, and three years after surgery. Mean (SD) age at surgery was 55 (8). Seven patients died or were lost for follow up. Neuropsychological assessment included a global cognitive scale, memory, and frontal tests. Depression was evaluated using the Beck depression inventory. Assessment of thought disorders and apathy was based on the unified Parkinson's disease rating scale. Reports of the behavioural changes are mainly based on interviews done by the same neuropsychologist at each follow up., Results: Only two cognitive variables worsened (category fluency, total score of fluency). Age was a predictor of decline in executive functions. Depression improved whereas apathy and thought disorders worsened. Major behavioural changes were two transient aggressive impulsive episodes, one suicide, four suicide attempts, one permanent apathy, one transient severe depression, four psychoses (one permanent), and five hypomania (one permanent)., Conclusions: Comparing baseline, one year, and three year postoperative assessments, STN stimulation did not lead to global cognitive deterioration. Apathy scores mildly increased. Depression scores mildly improved. Behavioural changes were comparatively rare and mostly transient. Single case reports show the major synergistic effects of both medication and stimulation on mood and behaviour, illustrating the importance of a correct postoperative management.

The present renewal of the surgical treatment of Parkinson's disease, almost abandoned for twenty Years, arises from two main reasons. The first is the better understanding of the functional organization of the basal ganglia. It was demonstrated in animal models of Parkinson's disease that the loss of dopaminergic neurons within the substantia nigra, at the origin of the striatal dopaminergic defect, induces an overactivity of the excitatory glutamatergic subthalamo-internal pallidum pathway. The decrease in this hyperactivity might lead to an improvement in the pakinsonian symptoms. The second reason is the improvement in stereotactic neurosurgery in relation with the progress in neuroimaging techniques and with intraoperative electrophysiological microrecordings and stimulations, which help determine the location of the deep brain targets. In the 1970s chronic deep brain stimulation in humans was applied to the sensory nucleus of the thalamus for the treatment of intractable pain. In 1987, Benabid and colleagues suggested high frequency stimulation of the ventral intermediate nucleus of the thalamus in order to treat drug-resistant tremors and to avoid the adverse effects of thalamotomies. How deep brain stimulation works is not well known but it has been hypothetized that it could change the neuronal activities and thus avoid disease-related abnormal neuronal discharges. Potential candidates for deep brain stimulation are selected according to exclusion and inclusion criteria. Surgery can be applied to patients in good general and mental health, neither depressive nor demented and who are severely disabled despite all available drug therapies but still responsive to levodopa. The first session of surgery consists in the location of the target by ventriculography and/or brain MRI. The electrodes are implanted during the second session. The last session consists in the implantation of the neurostimulator. The ventral intermediate nucleus of the thalamus was the first target in which chronic deep brain stimulation electrodes were implanted in order to alleviate tremor. This technique can be applied bilaterally without the adverse effects of bilateral thalamotomies. Like pallidotomy, internal globus pallidum stimulation has a dramatic beneficial effect on levodopa-induced dyskinesia but its effects on the parkinsonian triad are less constant and opposite motor effects are sometimes observed in relation with the stimulated contact. The inconstant results, perhaps related to the complexity of the structure led to the development of subthalamic nucleus stimulation. The alleviation of motor fluctuations and the improvement in all motor symptoms allows a significant decrease in levodopa daily dose and in levodopa-induced dyskinesia. Presently, deep brain stimulation is a fashionable neurosurgical technique to treat Parkinson's disease. Subthalamic nucleus stimulation seems to be the most suitable target to control the parkinsonian triad and the motor fluctuations. Because of the possible adverse effects it must be reserved for disabled parkinsonian patients. No large randomized study comparing different targets and different neurosurgical techniques has been performed yet. Such studies, including cost benefit studies would be useful to assess the respective value of these different techniques.

Context: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported., Objective: To determine in Parkinson's disease (PD) patients using positron emission tomography (PET) and [11C]-Raclopride, whether STN stimulation induces a striatal DA release., Methods: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [11C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [11C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping., Results: For PD patients, the mean [(11C]-Raclopride BP (+/- SD) were, in Off stimulation condition: 1.7 +/- 0.3 for the right caudate nucleus, 1.8 +/- 0.4 for the left caudate nucleus, 2.6 +/- 0.5 for the right putamenand 2.6 +/- 0.5 for the left putamen. In On stimulation condition: 1.7 +/- 0.4 for the right caudate nucleus, 1.9 +/- 0.5 for the left caudate nucleus, 2.8 +/- 0.7 for the right putamen and 2.7 +/- 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted., Conclusion: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [11C]-Raclopride.

In order to assess the impact of bilateral subthalamic nucleus (STN) stimulation in PD on quality of life, the PD Quality of Life questionnaire was assessed in 60 consecutive patients with PD before surgery and 12 months after surgery. All aspects of quality of life, including motor (+48%), systemic (+34%), emotional (+29%), and social (+63%) dimensions, significantly improved with long-term STN stimulation.

To identify factors predictive of effective bilateral subthalamic nucleus (STN) stimulation for PD with severe motor complications, pre- and postoperative Unified PD Rating Scale (UPDRS) scores were analyzed in a series of 54 patients who received bilateral STN stimulation. Younger age and levodopa responsiveness predict a favorable response to bilateral STN stimulation. For individual PD symptoms, those that improve with a suprathreshold dose levodopa challenge are likely to improve with stimulation.

Background: The main advantage of deep brain stimulation (DBS) in the treatment of PD is that the electrical settings can be adjusted to optimize benefits and minimize adverse effects. The main objective of this study was to discover how varying these electrical parameters impacted on parkinsonian motor signs., Methods: Twelve patients with PD with chronic bilateral subthalamic nucleus (STN) stimulation were selected. The authors evaluated the effects of a variation in the voltages, frequencies, and pulse widths on tremor, bradykinesia, and rigidity using two different paradigms: one in which the total electrical energy delivered was held constant, and one in which this was varied. Up to 26 parameter conditions were tested under double blind randomized conditions., Results: Voltages >or=3 V and frequencies >or=130 Hz led to the greatest improvement in all three parkinsonian signs. A rate of 5 Hz significantly worsened akinesia. The combination of the highest voltage with the narrowest pulse width was most effective., Conclusions: This study confirms that the most beneficial effects induced by STN stimulation are obtained at high frequencies and that voltage is the most critical factor to obtain adequate alteration in STN activity. The mechanisms by which STN DBS improves parkinsonism remain speculative.

Clinical reports show that bilateral subthalamic nucleus (STN) stimulation is effective in improving parkinsonian gait. Quantitative analysis of the efficacy of STN stimulation on gait is of interest and can be carried out using a commercially available stride analyser. Ten parkinsonian patients (5 men, 5 women) with a mean age of 55.8, SD 9.6 years were included in our study. They had a mean duration of Parkinson's disease (PD) of 13.3, SD 4.5 years and a motor examination score (part III of the Unified Parkinson's Disease Rating Scale) (UPDRS) of 43, SD 13 in off-stimulation off-drug condition. All the patients had bilateral chronic STN stimulation which had started from 3 to 36 months before the study. Patients were evaluated in off-drug and on-drug conditions both with and without stimulation. We analysed the principal gait measures: velocity, cadence, stride length, gait cycle, duration of single and double limb support. The clinical parkinsonian signs were evaluated with the part III of the UPDRS. In the off-drug condition, STN stimulation significantly (p < 0.05) improved velocity and stride length. The effect was similar to that of levodopa. When STN stimulation was switched on at the best of the levodopa induced effect, no further improvement was observed. The UPDRS motor score was significantly (p < 0.001) decreased after both stimulation and levodopa. In conclusion, STN stimulation is effective on parkinsonian gait.

High-frequency stimulation of the subthalamic nucleus (STN) improves the motor signs of Parkinson's disease (PD). The three main components (motor, associative, and limbic) of the cortical-basal ganglia-cortical circuits pass through the STN. It is not known whether STN stimulation can influence the limbic loop. We present two PD patients in whom acute stimulation of an electrode located in the STN using high stimulation parameters (50% higher than therapeutic) induced funny associations, leading to infectious laughter and hilarity, whereas the therapeutic parameters induced a hypomanic behavior and marked improvement of akinesia. Our report suggests that the STN, with its sensorimotor, cognitive, and limbic parts is not only involved in motor, but also in psychomotor regulation., (Copyright 2001 Movement Disorder Society.)

Chronic high frequency (130 Hz) stimulation (HFS) of the thalamic target Vim, first used in our group in 1987 as a treatment of tremor of various origins, has been used over the last ten years in 137 patients. Since 1993, this method has been extended to two other targets (subthalamic nucleus (STN): 137 patients and the medial pallidum (GPi): 12 patients), based on recent experimental data in rats and monkeys. STN appears to be a target of major interest, able to control the three cardinal symptoms and to allow the decrease or suppression of levodopa treatment, which then also suppresses levodopa induced dyskinesias. The stereotactic technique is based on the determination of the target using ventriculography, MRI and electrophysiology, with both microrecording of single neuron activity and microstimulation inducing therapeutic symptom suppression and side effects. Chronic electrodes are then placed bilaterally at the best physiologically defined location and then connected to implantable stimulators (either 2 Itrel II or the new double channel Kinetra), operated at 130-185 Hz, 60 ms pulse width, 2.5 to 3.5 volts. There was no operative mortality and permanent morbidity was observed in 3 patients. The mechanisms of action of HFS are not fully understood, but are definitely related to high frequency and are probably different depending on the target. Inhibition of cellular activity or of neural network functions could be induced, by jamming of a retroactive loop for tremor, or by shutdown of neurotransmitter release in STN. Mechanisms within an individual target are also probably different for tremor or for other symptom alleviation. All cardinal symptoms are alleviated from tremor to akinesia and rigidity. This strong improvement allows the decrease of the drug dosage to approximately 30% of the preoperative level, which suppresses the levodopa-induced dyskinesias. The off period dystonias are also suppressed as well as freezings and falls. The effects remain stable over more than 5 years and in the same period, the off stimulation-off medication UPDRS remains stable and does not increase at the usual rate The low rate of permanent complications, the minor side effects and their immediate reversibility, the possibility of bilateral implantation in one session and the long-term persistence of symptom relief are strong arguments which support chronic HFS of STN as the method of choice when a surgical procedure is indicated for the treatment of Parkinson's disease and even more when a bilateral procedure is necessary. Recent data show that STN stimulation could be useful in the treatment of dystonia as well as some forms of epilepsy. It is therefore possible that DBS in STN as well as in other targets could become a potent therapeutic tool in the near future for neurological disorders.

A retrospective study of a consecutive series of 19 patients with medically intractable dystonia treated with uni- or bilateral deep brain stimulation (DBS) is reported. A minimal follow-up of 6 months was available, up to eleven years in one patient. The first twelve consecutive patients (4 with primary and 8 with secondary dystonia) were treated with chronic stimulation of the posterior part of the ventrolateral thalamic nucleus (VLp). In this group global functional outcome was improved in 8 patients, although dystonia movement and disability scale scores did not show significant improvement. Of the 12 patients treated first by VLp DBS, three (1 primary and 2 secondary dystonia) underwent pallidal (GPi) DBS after the VLp DBS failed to improve their symptoms. The last seven consecutive patients (5 primary and 2 secondary dystonia) were treated directly with GPi DBS. Extracranial infection prevented chronic GPi DBS in one patient. In another GPi patient, preliminary negative tests with the electrodes discouraged implantation of the stimulators, and the patient was not treated with chronic DBS. In the remaining group of eight patients including those previously treated with VLp DBS, chronic GPi DBS resulted in a significant improvement in the dystonia movement scale and disability scores. Although this is a retrospective study dealing with dystonia of heterogeneous etiology, the results strongly suggest that GPi DBS has a better outcome than VLp DBS.

Background: In a previous study on a consecutive series of 62 patients with PD, the authors showed that bilateral subthalamic or pallidal continuous high-frequency deep brain stimulation (DBS) affects neither memory nor executive functions 3 to 6 months after surgery., Objective: To investigate the specific effects of DBS by comparing the performance of patients with the stimulator turned "on" and "off.", Methods: The performance of 56 patients on clinical tests of executive function was compared after 3 and 12 months of DBS of the subthalamic nucleus (STN; n = 48) or the internal globus pallidus (GPi; n = 8) with the stimulator "on" or "off." Global intellectual efficiency, verbal learning, and mood were also evaluated with the stimulator "on." The performance of another group of 20 patients was compared after 6 months of DBS of the STN (n = 15) or the GPi (n = 5) with the stimulator "on" or "off" on more experimental tests recently shown to be more sensitive to l-dopa therapy., Results: When the stimulator was "on," STN patients showed a mild but significant improvement in psychomotor speed and working memory. In comparison with the presurgical state, STN patients had no cognitive deficit at 12 months, except for lexical fluency. There was no differential effect of STN or GPi stimulation., Conclusions: 1) The specific effect of DBS seems to mimic the action of l-dopa treatment in the cognitive as in the motor domain; 2) the surgery associated with DBS does not appear to affect the cognitive performance of patients with PD 12 months later, except for a mild deficit in lexical fluency.

Deep brain stimulation by high frequency (HFS) has been developed starting in the thalamic target (Vim) from pragmatic observations and subsequently followed by other targets, such as the subthalamic nucleus (STN) and pallidum as an application of current knowledge from basic preclinical research in neuroscience. The mechanism involved by this neurosurgical approach is not completely solved. For Vim we have formed the hypothesis that HFS induces a jamming of sensory-motor loops but for the STN, from our experimental research in rats we have shown that HFS induces functional inhibition of cell activity in the target nuclei. In our patients the implantation of the stimulation electrodes was carried out stereotactically, under local anesthesia, using ventriculography, MRI, microrecordings and clinical evaluation of the effects of stimulation on rigidity. When the stimulation is turned ON in the STN area a significant decrease in rigidity was determined by the neurologists. Stimulation or even penetration of the electrode may be responsible for transient dyskinesias. The average location of the clinically efficient contact of the chronic stimulating electrodes is statistically located at 5.02 +/- 0.71 1/12 degrees of AC-PC in the AP direction, at -1.5 +/- 0.66 1/8 degrees of the height of the thalamus in the ventricle direction, with laterality at 11.98 +/- 1.12 mm in the lateral direction. The beneficial effects of STN stimulation are significant providing that the electrodes are correctly placed into the target. There is strong improvement of the symptoms of the triad in which akinesia, rigidity, and tremor are reduced on average to 41. 6, 48.6, and 27%, respectively, when compared with the previous preoperative level. From our experience, HFS of the STN could be considered the surgical therapy of choice at advanced stages of Parkinson's disease.

Chronic high frequency (130 Hz) stimulation (HFS) of the thalamic target Vim has replaced thalamotomy as a treatment of tremor of various origins and was extended to two other targets (Subthalamic nucleus (STN) and the medial pallidus (GPi)), since 1993 based on recent experimental data in rats and monkeys. STN appears to be a target of major interest, able to control the three cardinal symptoms and to allow the decrease or suppression of levodopa treatment, which then suppresses also levodopa induced dyskinesias. The mechanisms of action of HFS are not fully understood, but are definitely related to high frequency and are probably different depending on the target. Inhibition of cellular activity or of network functions could be induced, by jamming of a retroactive loop for tremor, or by shutdown of neurotransmitter release in STN. All cardinal symptoms are alleviated from tremor to akinesia and rigidity. The effects remain stable over more than five years chronic HFS of STN, as the method of choice when a surgical procedure is indicated for the treatment of Parkinson's disease and even more when a bilateral procedure is necessary. Recent data show that STN stimulation could be useful in the treatment of dystonia as well as some forms of epilepsies. It is therefore possible that DAS in STN as well as in other targets could become a potent therapeutic tool in the future for neurological disorders. The future of brain stimulation will depend on new technologies (new circuits, electrodes, web based programmers), waveforms (alternatives to square waves, random distribution), targets (hypothalamic nuclei, locus coeruleus) and indications (dystonia, epilepsy, eating disorders.

Pallidotomy is now widely performed for the treatment of advanced Parkinson's disease (PD). Preliminary reports of the effect of globus pallidus pars interna deep brain stimulation (GPi DBS) have also been promising. We have analyzed a cohort of 22 consecutive patients enrolled in a multicenter study. Surgery was bilateral in 17 and unilateral in five patients. At 6-month follow-up, the bilaterally GPi-implanted patients demonstrated a marked improvement when examined after drug withdrawal ("off") and under optimal medication ("on") using the Unified Parkinson's Disease Rating Scale (UPDRS). The benefit induced by the stimulation in the "off" medication condition in the total motor score was 31% and in the activities of daily living (ADL) scores was 39%. During the "on" medication period, the reduction in the total "on" dyskinesias score was 66% and in the ADL score was 32%. A similar pattern of improvement was seen in the group of patients with unilateral GPi stimulation, although a second cohort of 12 patients not included in the multicenter study showed greater improvements in "on" motor functioning. Although the effect of DBS is predominantly reversible, electrode insertion alone resulted in measurable clinical effects in the absence of stimulation. Thus, at 6-month follow-up, the benefit observed without stimulation was up to 44% in the "on" dyskinesias score and 29% in timed tapping scores undertaken in the "off" medication state. Complications among 34 patients from all centers included perioperative infection (n=3), hardware fracture (n=2), and premature battery failure (n=3). These results show a positive antiparkinsonian effect of pallidal DBS. No specific complications were observed with bilateral procedures.

The technique of deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD) is evolving very rapidly. The subthalamic nucleus (STN) has become the preferred target in the past few years since our group demonstrated that high-frequency stimulation in this nucleus improves all cardinal features of PD, including resting tremor. This benefit in the parkinsonian symptoms allows a drastic reduction in daily levodopa requirements. Dyskinesias become drastically attenuated, possibly as a consequence of reduced dopaminergic medication but also because STN DBS may stabilize basal ganglia output activity, thus avoiding the problems associated with standard levodopa replacement therapy. DBS of the STN is associated with a marked improvement of motor function even in patients with advanced PD. Such a large degree of benefit in parkinsonian features relies on two crucial points that must be taken into consideration for achieving the best possible results with this technique: proper selection of patients and accuracy in targeting the STN. From a neurosurgical point of view, we believe that the most precise localization of the STN is obtained by using ventriculography to determine the stereotactic coordinates of the STN. This is complemented with intraoperative neuronal microrecording to define physiologically the sensorimotor region of the nucleus. Future advances in neuroimaging techniques may well lead to modifications of our current methodology.

We assessed the oral system of parkinsonian patients treated with bilateral chronic stimulation of the ventral intermediate nucleus of the thalamus (Vim), and of the subthalamic nucleus (STN) to compare the effects of these procedures on the articulatory organs. Force transducers were used to sample ramp-and-hold force contractions generated by the upper lip, lower lip and tongue at 1- and 2-newton target force levels, as well as maximal force. Fourteen healthy control subjects and 14 parkinsonian patients participated in this study. After an overnight fast the patients were evaluated under two conditions: during bilateral stimulation and 1 h after stopping stimulation. With Vim stimulation, dynamic and static control of the articulatory organs was worsened while with STN stimulation it was greatly improved. The target of stimulation differently influences the oral system and modulates neuronal structures involved in speech., (Copyright 2000 S. Karger AG, Basel.)

After 10 years of clinical practice (1987-1997), chronic thalamic deep brain stimulation (DBS) is considered to be effective in the treatment of drug-resistant parkinsonian tremor. DBS has produced few side-effects, which are usually reversible. More recently, DBS has been applied to other movement disorders (akinesia and rigidity, dyskinesias, dystonia), using new targets: internal pallidum, subthalamic nucleus. These targets have been selected on the basis of neurophysiological or anatomo-clinical data suggesting they could be effective. Control of L-Dopa peak-dose dyskinesias by thalamic ventralis intermedius nucleus (V.im.) stimulation has been reported by the Lille team, but not by the Grenoble team. We therefore re-examined all teleradioanatomical data of both teams, and compared them with the therapeutic effects. Location of 99 monopolar electrodes of thalamic stimulation, applied to treat parkinsonian tremor, has been retrospectively measured. The Lille team included 21 patients (22 electrodes); the Grenoble team included 52 patients (74 electrodes). L-Dopa dyskinesias were suppressed in all 9 patients in Lille, and improved clearly in only 8 out of 32 patients in Grenoble. The mean center of electrodes was significantly different between both teams, being deeper, more posterior and medial in Lille. This did not correspond to the coordinates of the V.im., but seems to be closer to those of the centromedian and parafascicular complex (CM-Pf), according to stereotactic atlases. Considering only the dyskinetic patients, the therapeutic effects on L-Dopa dyskinesias were related to the differences observed in the electrode position, but not to the team membership. Improvement of L-Dopa dyskinesias was significantly associated with deeper and more medial placement of electrodes. Retrospective analysis of ventriculographic data confirmed that the electrode position and therapeutic effects of DBS are strongly related. Our study suggested that CM-Pf stimulation could control both tremor and L-Dopa dyskinesias. This hypothesis is consistent with neuro-anatomical data showing that CM-Pf is connected to internal pallidum, the stimulation of which controls specifically L-Dopa dyskinesias.

The effect of high-frequency stimulation of the subthalamic nucleus on parkinsonian-like resting tremor was investigated in two monkeys (Macaca fascicularis). Unilateral tremor of the arm and leg was induced by electrical coagulation of the brainstem area including the substantia nigra and the red nucleus. The tremor was only seen at rest condition with a very stable frequency of 4.46+/-0.59 Hz (mean+/-S.D.). Apomorphine (0.10-0.4 mg/kg, s.c.) completely blocked the tremor, suggesting that it was a dopaminergic-dependent symptom just like the parkinsonian tremor. When the stimulating frequency varied from 20 to 1000 Hz, both mono- and bipolar stimulation (square pulses, 0-5 mA, 0.06 ms) of the subthalamic nucleus suppressed resting tremor in a frequency-dependent manner but monopolar stimulation was more effective. These effects remained stable for more than two years. The present results suggest that the subthalamic nucleus is involved in the control and mechanism of resting tremor and that the high-frequency stimulation of the subthalamic nucleus can be used as an alternative therapy in parkinsonian patients with akinesia, rigidity and resting tremor.

This study focuses on the speech organs of a parkinsonian patient who initially had been treated with levodopa for 13 years, and had become severely disabled by motor fluctuations. This patient has been treated with bilateral chronic stimulation of the subthalamic nucleus (STN) for the last 2 years. Upper lip, lower lip and tongue force production were examined before surgery under off and on medication conditions, and 2 years after surgery under off and on stimulation conditions. We compared the effect of stimulation and dopatherapy on the speech organs. L-Dopa had a poor effect whereas bilateral stimulation improved oral control and speech intelligibility. These results suggest that STN stimulation influences speech organs in a different way from the dopaminergic system and similarly affects oral and limb motor systems.

The recent resurgent interest in functional surgery for the treatment of Parkinson's disease (PD) has focused on the effects on akinesia and levodopa-induced dyskinesia. Stimulation of the subthalamic nucleus (STN) improves akinesia and rigidity but its effects on tremor have not been studied. The objective of this study was to assess the efficacy of STN stimulation on tremor in patients with the complete parkinsonian triad with motor fluctuations. Of 27 consecutive patients with STN stimulation (26 bilateral), 15 exhibited tremor rated at least 2/4 according to item 20 (rest tremor) of the Unified Parkinson's Disease Rating Scale (UPDRS) in at least one limb. The mean preoperative tremor score was 11.3+/-5.6 in off-drug and 1.2+/-2.4 in on-drug conditions. The postoperative tremor scores at the last follow up (from 1-12 months) were 2.2+/-2.2 off-drug/on-stimulation and 0.2+/-0.4 on-drug/on-stimulation. Both rest and action tremors were improved in all patients. The UPDRS tremor score was reduced by 80%, rigidity score by 65%, and akinesia score by 51% on average. For the three symptoms, the stimulation effect was close to that induced before surgery by a suprathreshold dose of levodopa given in the morning. STN stimulation can be considered an interesting alternative to thalamic or internal pallidal surgery even in PD patients with severe high-amplitude tremor. In keeping with electrophysiological data in monkeys rendered parkinsonian by MPTP injections, our results emphasize the importance of the oscillation of a neuronal loop involving the STN in the pathophysiology of parkinsonian tremor.

Background: In many patients with idiopathic Parkinson's disease, treatment with levodopa is complicated by fluctuations between an "off" period, when the medication is not working and the motor symptoms of parkinsonism are present, and an "on" period, when the medication is causing improved mobility, often accompanied by debilitating dyskinesias. In animal models of Parkinson's disease, there is overactivity in the subthalamic nucleus, and electrical stimulation of the subthalamic nucleus improves parkinsonism. We therefore sought to determine the efficacy and safety of electrical stimulation of the subthalamic nucleus in patients with Parkinson's disease., Methods: We studied 24 patients with idiopathic Parkinson's disease in whom electrodes were implanted bilaterally in the subthalamic nucleus under stereotactic guidance with imaging and electrophysiologic testing of the location. Twenty were followed for at least 12 months. Clinical evaluations included the Unified Parkinson's Disease Rating Scale, a dyskinesia scale, and timed tests conducted before and after surgery, when patients were off and on medications., Results: After one year of electrical stimulation of the subthalamic nucleus, the patients' scores for activities of daily living and motor examination scores (Unified Parkinson's Disease Rating Scale parts II and III, respectively) off medication improved by 60 percent (P<0.001). The subscores improved for limb akinesia, rigidity, tremor, and gait. In the testing done on medication, the scores on part III improved by 10 percent (P<0.005). The mean dose of dopaminergic drugs was reduced by half. The cognitive-performance scores remained unchanged, but one patient had paralysis and aphasia after an intracerebral hematoma during the implantation procedure., Conclusions: Electrical stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson's disease. The severity of symptoms off medication decreases, and the dose of levodopa can be reduced with consequent reduction in dyskinesias.

We report three patients with bilateral GPi stimulation for stage 4 Parkinson's disease (PD) with severe levodopa-induced dyskinesias (LID). In all three it was possible to completely inhibit LID using high-stimulation parameters. Parallel to complete inhibition of LID, an inhibition of the anti-akinetic effect of levodopa was observed, whereas, at the same time, rigidity was markedly improved. GPi stimulation is adaptable over time, and stimulation parameters have to be programmed according to off- and on-period motor symptoms. The main interest of stimulation is the possibility of finding a compromise between LID alleviation in on-phase without loss of the beneficial motor effects and improvement in parkinsonism in off-phase. In some patients, residual dyskinesias have to be accepted so as not to aggravate on-period motor symptoms by a presumed overinhibition of basal ganglia outflow.

We studied the effects--on parkinsonian signs, on levodopa-induced dyskinesias, and on levodopa response--of acute experimental high-frequency stimulation of the internal pallidum (GPi) during off-drug and on-drug phases. Thirteen quadripolar electrodes were evaluated in 8 patients with Parkinson's disease (PD). Stimulation of the most ventral contacts, lying at the ventral margin of or just below the GPi, led to pronounced improvement in rigidity and a complete arrest of levodopa-induced dyskinesias. The antiakinetic effect of levodopa was also blocked and the patients became severely akinetic. Stimulation of the most dorsal contacts, lying at the dorsal border of the GPi or inside the external pallidum, usually led to moderate improvement of off-drug akinesia and could also induce dyskinesias in some patients. When using an intermediate contact for chronic stimulation, a good compromise between these opposite effects was usually obtained, mimicking the effect of pallidotomy. We conclude that there are at least two different functional zones within the globus pallidus, at the basis of a different pathophysiology of the cardinal symptoms of PD. The opposite effects may explain the variable results of pallidal surgery reported in the literature and may also largely explain the paradox of PD surgery. A possible anatomical basis for these differential functional effects could be a functional somatotopy within the GPi, with the segregation of the pallidofugal fibers from the outer portion of the GPi, on one hand, forming the ventral ansa lenticularis and from the inner portion of the GPi, on the other hand, forming the dorsal lenticular fasciculus.

Chronic electrical subthalamic nucleus (STN) stimulation is under investigation for alleviating parkinsonian symptoms. STN alterations may carry the risk of provoking abnormal involuntary movements (AIMs). We took advantage of the reversibility of the stimulation technique to assess the possibility of inducing AIMs, using different electrical variables with or without concomitant levodopa intake. Above a given threshold voltage, stimulation could induce contralateral distal mobile AIMs or hemiballism in the off-drug condition in two patients. AIMs occurred after a latency that varied from a few minutes up to several hours after switching on the stimulator. Hemiballism immediately disappeared upon switching off the stimulator. In these patients, levodopa had never provoked that type of AIMs before surgery. Levodopa-induced AIMs were not modified by electrical stimulation, but off-phase dystonia disappeared in one patient. Stimulation of the STN induced AIMs that resembled both those observed following spontaneous lesions of the STN and levodopa-induced diphasic AIMs in parkinsonian patients. As electrical stimulation provoked AIMs and antiparkinsonian benefit occurred with different electrical variables and different timing, the mechanisms responsible for these two effects could be distinct.

Tremor was suppressed by test stimulation of the thalamic ventralis intermedius (VIM) nucleus at high frequency (130 Hz) during stereotaxy in nonanesthetized patients suffering from Parkinson's disease or essential tremor. Ventralis intermedius stimulation has since been used by the authors over the last 8 years as a treatment in 117 patients with movement disorders (80 cases of Parkinson's disease, 20 cases of essential tremor, and 17 cases of various dyskinesias and dystonias including four multiple sclerosis). Chronic electrodes were stereotactically implanted in the VIM and connected to a programmable stimulator. Results depend on the indication. In Parkinson's disease patients, tremor, but not bradykinesia and rigidity, was selectively suppressed for as long as 8 years. Administration of L-Dopa was decreased by more than 30% in 40 Parkinson's disease patients. In essential tremor patients, results were satisfactory but deteriorated with time in 18.5% of cases, mainly for patients who presented an action component of their but deteriorated with time in 18.5% of cases, mainly for patients who presented an action component of their tremor. In other types of dyskinesias (except multiple sclerosis), results were much less favorable. Fifty-nine patients underwent bilateral implantation and 14 other patients received implantation contralateral to a previous thalamotomy. Thirty-seven patients (31.6%) experienced minor side effects, which were always well tolerated and immediately reversible. Three secondary scalp infections led to temporary removal of the implanted material. There was no permanent morbidity. This tremor suppression effect could be due to the inhibition or jamming of a retroactive loop. Chronic VIM stimulation, which is reversible, adaptable, and well tolerated even by patients undergoing bilateral surgery (74 of 117 patients) and by elderly patients, should replace thalamotomy in the regular surgical treatment of parkinsonian and essential tremors.

In monkeys rendered parkinsonian, lesions and electrical stimulation of the subthalamic nucleus reduce all major motor disturbances. The effect of electrical stimulation of the subthalamic nucleus was assessed in three patients with disabling akinetic-rigid Parkinson's disease and severe motor fluctuations. Quadripolar electrodes connected to a pulse generator were implanted in the subthalamic nuclei on both sides. Patients were evaluated with the unified Parkinson's disease rating scale and timed motor tests. 3 months after surgery, activities of daily living scores had improved by 58-88% and motor scores by 42-84%. This improvement was maintained for up to 8 months in the first patient operated upon. One patient was confused for 2 weeks after surgery, and another developed neuropsychological impairment related to a thalamic infarction which improved over 3 months. In one patient, stimulation could induce ballism that was stopped by reduction of stimulation. This is the first demonstration in human beings of the part played by the subthalamic nuclei in the pathophysiology of Parkinson's disease.

Based on Benabid's experimental and clinical findings that low-frequency (50 Hz) electrical stimulation of the ventral intermediate thalamic nucleus may increase tremor, while higher frequencies (> 100 Hz) lead to suppression of the tremor, we implanted a stimulation electrode in 33 thalami among 27 patients. Six patients were implanted bilaterally. 23 suffered from Parkinson's disease, 4 from essential tremor. All patients had a drug-resistant tremor. The Vim target was calculated based on stereotactic ventriculography. An intra-operative neurophysiological target control was performed on all patients. After a monopolar (12 thalami) or quadripolar (21 thalami) lead was implanted we then connected it to a percutaneous extension lead. In the days following the surgery a test stimulation was performed. In all but one patient stimulation resulted in a suppression of the tremor. In a second procedure, a pulse generator (ITREL II; MEDTRONIC) was implanted and connected subcutaneously to the thalamic lead. After implantation of the pulse generator all patients stimulate chronically while some turn off the stimulator at night. In 21 thalami total suppression of tremor was observed, 6 showed major improvement, 4 only minor improvement. There was no significant effect on any other existing symptom of Parkinson's disease. Due to the proximity of Vim to the sensory thalamus the majority of the patients (27 thalami) report slight temporary paraesthesias when the pulse generator is turned on. Two report permanent paraesthesias when stimulation is on. In 4 cases a slight dysarthria occurs under stimulation. In 2 the dysarthria is marked. In one case dysequilibrium occurs under stimulation. All these side effects are reversible when stimulation is turned off. In 3 patients, the lead was displaced due to an insufficient lead fixation, thus making a second procedure necessary to correct the electrode position. We had one complication due to bleeding at the burr hole side. Follow-up ranges from 3 to 48 months. So far in no cases has the effect of stimulation worn off. In conclusion we regard Vim neurostimulation as an effective and safe alternative to conventional thalamotomy and recommend that it should be considered in cases in which drug therapy has failed to affect Parkinsonian or essential tremor. Moreover, we believe that this procedure is a less invasive and equally efficient alternative to classic thalamotomy and thus should be given preference.

In animal models of Parkinson's disease (PD), it is postulated that the excessive output from the subthalamic nucleus (STN) plays a critical role. Selective lesions or high frequency electrical stimulation of the STN can alleviate parkinsonian symptoms in MPTP-treated monkeys. We decided to carry out STN stimulation in patients suffering from severe akinetic forms of PD. After approval of the institutional ethical committee, we operated on a parkinsonian patient aged 51, suffering for 8 years from a strongly disabling akinetorigid form of PD, complicated by an on-off effect (Hoehn and Yahr stage 5 in the worst-off motor phase). Stereotactic surgery was done on one side under local anesthesia. The theoretical target was chosen according to stereotactic atlases, based on ventriculographic landmarks such as anterior and posterior commissures (AC and PC). The final position of the chronic electrodes was optimized using electrophysiological recording and stimulation along with clinical assessment and surface EMG of agonist and antagonist muscles of the examined limbs. A spontaneous increase in neuronal activity was recorded in an area located 2-4 mm under the level of the intercommissural plane, 10 mm from the midline, at mid-distance between AC and PC. Within the same place, a 130-Hz stimulation induced acute and reversible akinesia alleviation mainly on the contralateral limbs, comparable to that obtained with dopaminergic drugs. No dyskinesia, such as hemiballism, was induced by introduction of electrodes or by stimulation. Then a long-term quadripolar DBS Medtronic electrode was inserted in this area. Studies of the effects of chronic stimulation were extensively performed to determine the best spatiotemporal and electrical stimulation variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Progress in biomedical engineering has provided implantable and programmable stimulators which allowed application of neurophysiological knowledge to therapeutic attempts on human neurological diseases. Chronic electrodes can be implanted accurately and safely into the brain, against the spinal cord and around the nerves. Therapeutic applications, mainly on pain, dyskinesias and epilepsy are therefore available, which call for careful clinical evaluation, basic and technological research to improve indications and diminish the cost of these methods.

Parkinsonian tremor can be abolished by chronic high frequency thalamic stimulation of the ventral intermediate nucleus. We have studied six patients with unilateral Parkinson's disease. The patients had an electrode chronically implanted in the ventral intermediate nucleus of the thalamus. We measured changes in cerebral activity by positron emission tomography using an index of regional cerebral blood flow (rCBF). Each patient was scanned in three states: (i) tremor without stimulation (condition A); (ii) tremor with ineffective stimulation (condition B); (iii) tremor abolished by effective stimulation (condition C). The suppression of tremor (C compared with B) was specifically associated with a decrease of rCBF in the cerebellum, whereas the ineffective stimulation (B compared with A) induced a decrease of rCBF in homolateral cerebral cortex. The results give evidence for different contributions from cortex and cerebellum to the generation of parkinsonian tremor and suggest that tremor suppression is mainly associated with a decrease of synaptic activity in the cerebellum.

In Parkinson's disease, experimental studies favour a neuronal hyperactivity of the subthalamic nucleus. We carried out a subthalamic nucleus electrical stimulation in a patient aged 51, suffering for 8 years from a severe akineto-rigid form of Parkinson's disease, complicated with an on-off effect. Stereotaxic surgery was done under local anaesthesia on one side. Within the theoretical target, a 130 Hz stimulation induced akinesia alleviation mainly on the contralateral limbs. No abnormal movement was noticed. Then a long-term quadripolar DBS Medtronic electrode was inserted in that area. The study of the effects of chronic stimulation is in progress to determine the best temporal and electrical stimulation variables.

Stereotactic thalamotomy of the VIM (ventral intermediate) nucleus is considered as the best neurosurgical treatment for Parkinsonian and essential tremors. However, this surgery, especially when bilateral, still presents a risk of recurrence and neurological complications. We observed that acute VIM stimulation at frequencies higher than 60 Hz during the mapping phase of the target suppressed the tremor of Parkinson's disease (PD) and essential tremor (ET). This effect was immediately reversible at the end of the stimulation. This was initially proposed as an additional treatment for patients already thalamotomized on the contralateral side, and then extended as a regular procedure for extra-pyramidal dyskinesias. Since January 1987, we implanted 126 thalami in 87 patients (61 PD, 13 ET, 13 dyskinesias of various origins). Deep brain stimulation electrodes were stereotactically implanted under local anaesthesia, using stimulation and micro-recording to delineate the best site of stimulation. Electrodes were subsequently connected to implantable programmable stimulators. The optimal frequency was around 130 to 185 Hz. The results (evaluated by a neurologist from 0 = no effect to 4 = perfect relief) are related to the type of tremor. Altogether, 71% of the 80 patients benefited from the procedure with grade 3 and 4 results. In 88% of the PD cases, the results were good (grade 3) or excellent (grade 4) and stable with time. Rigidity was moderately for a long improved but akinesia was not. The same level of improvement was observed in 68% of the ET patients and only in 18% of the other types of dyskinesias.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereotactic ventral intermediate nucleus (Vim) thalamotomy may improve drug resistant severe parkinsonian tremor. However, tremor may recur and bilateral thalamotomy is known to induce unacceptable side effects in a proportion of patients. A high frequency (130 Hz) chronic Vim stimulation was performed in 4 parkinsonian patients, 2 of them having previously undergone a thalamotomy on the other side. Tremor was suppressed in all patients at the price of slight paresthesias. This improvement has been lasting from 2 to 14 months. Beneficial and adverse effects were suppressed at once each time the stimulation was stopped. These preliminary results are encouraging but a longer delay and more patients are obviously needed.

Stereotactic thalamotomy of the thalamic nucleus ventralis intermedius (VIM) is routinely used for movement disorders. During this procedure, it has been observed that high-frequency (100 Hz) stimulation of VIM was able to stop the extrapyramidal tremor. In patients with bilateral tremor of extrapyramidal origin, who were resistant to drug therapy, the therapeutic protocol associated (1) a radiofrequency VIM thalamotomy for the most disabled side, and (2) a continuous VIM stimulation for the other side using stereotactically implanted electrodes, connected to subcutaneous stimulators. VIM thalamotomy relieved the tremor in all operated cases. Side effects were mild and regressive. VIM stimulation strongly decreased the tremor but failed to suppress it as completely as thalamotomy did. This was due in part to the fact that programmable stimulator frequency rate is limited to 130 Hz, while it appeared that the optimal stimulation frequency was 200 Hz. This therapeutic protocol appears to be of interest for patients with bilateral extrapyramidal movement disorders.